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OP RESEARCH PRO00030489 HMCC-BR22-001 NIRAVATH	

Types:      Research Oncology Treatment
Synonyms:  L NMMA, L-NMMA, NAB-PACLITAXEL, NAB PACLITAXEL, APLELISIB

Cycle 1	Repeat 1 time	Cycle length: 21 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	Treatment conditions and management for Nab-paclitaxel: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11.  
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22. 
			Nursing Orders
  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	HOLD and notify provider if 
o ANC LESS than 1000; 
o Platelets LESS than 100,000; 
o Total bilirubin GREATER than 1.5X ULN; 
o AST GREATER than 10X ULN.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Nursing Orders
  	ONC NURSING COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	Physical exam will include vital sign (blood pressure, oral or temporal temperature, pulse, and respiratory rate) and weight measurements.
		  	MEASURE WEIGHT	Interval: --	Occurrences: --		  	ONC NURSING COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect ECOG performance status.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect  AEs and SAEs.
		  	ONC NURSING COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect concomitant medications.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	CRC & Treating Team to Order as clinically indicated:  
o MUGA Scan or ECHO. 
o 12-Lead EKG. 
o Urinalysis. 
			Labs
  	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		  	FASTING GLUCOSE LEVEL	Interval: --	Occurrences: --			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Pre-Medications
  	ondansetron (ZOFRAN) IV 8 mg	Dose: 8 mg	Route: intravenous	once for 1 dose	Start: S					Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Chemotherapy
  	NAB-PACLItaxel (ABRAXANE) chemo infusion 260 mg/m2 (Treatment Plan)	Dose: 260 mg/m2	Route: intravenous	once over 30 Minutes for 1 dose			Offset: 2.5 Hours			Supportive Care
  	pegfilgrastim (NEULASTA) on-body injection kit 6 mg	Dose: 6 mg	Route: subcutaneous	once for 1 dose			Offset: 3 Hours	Instructions:	After completion of Abraxane infusion.  Apply to intact, nonirritated skin on the back of the arm or abdomen (only use the back of the arm if caregiver is available to monitor On-body injection status).			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled				Days 2,3,4,5	Perform every 1 day x4		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled				Days 8,15	Perform every 7 days x2		Provider Communication
  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	CRC & Treating Team to Order fasting glucose if clinically indicated.
					
Cycle 2	Repeat 1 time	Cycle length: 21 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	Treatment conditions and management for Nab-paclitaxel: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11.  
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22. 
			Nursing Orders
  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	HOLD and notify provider if 
o ANC LESS than 1000; 
o Platelets LESS than 100,000; 
o Total bilirubin GREATER than 1.5X ULN; 
o AST GREATER than 10X ULN.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Nursing Orders
  	ONC NURSING COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	Physical exam will include vital sign (blood pressure, oral or temporal temperature, pulse, and respiratory rate) and weight measurements.
		  	MEASURE WEIGHT	Interval: --	Occurrences: --		  	ONC NURSING COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect ECOG performance status.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect  AEs and SAEs.
		  	ONC NURSING COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect concomitant medications.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	CRC & Treating Team to Order as clinically indicated:  
o MUGA Scan or ECHO. 
o 12-Lead EKG. 
o Urinalysis. 
			Labs
  	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		  	FASTING GLUCOSE LEVEL	Interval: --	Occurrences: --			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Pre-Medications
  	ondansetron (ZOFRAN) IV 8 mg	Dose: 8 mg	Route: intravenous	once for 1 dose	Start: S					Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Chemotherapy
  	NAB-PACLItaxel (ABRAXANE) chemo infusion 260 mg/m2 (Treatment Plan)	Dose: 260 mg/m2	Route: intravenous	once over 30 Minutes for 1 dose			Offset: 2.5 Hours			Supportive Care
  	pegfilgrastim (NEULASTA) on-body injection kit 6 mg	Dose: 6 mg	Route: subcutaneous	once for 1 dose			Offset: 3 Hours	Instructions:	After completion of Abraxane infusion.  Apply to intact, nonirritated skin on the back of the arm or abdomen (only use the back of the arm if caregiver is available to monitor On-body injection status).			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled				Days 2,3,4,5	Perform every 1 day x4		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 3	Repeat 1 time	Cycle length: 21 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	Treatment conditions and management for Nab-paclitaxel: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11.  
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22. 
			Nursing Orders
  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	HOLD and notify provider if 
o ANC LESS than 1000; 
o Platelets LESS than 100,000; 
o Total bilirubin GREATER than 1.5X ULN; 
o AST GREATER than 10X ULN.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Nursing Orders
  	ONC NURSING COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	Physical exam will include vital sign (blood pressure, oral or temporal temperature, pulse, and respiratory rate) and weight measurements.
		  	MEASURE WEIGHT	Interval: --	Occurrences: --		  	ONC NURSING COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect ECOG performance status.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect  AEs and SAEs.
		  	ONC NURSING COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect concomitant medications.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	CRC & Treating Team to Order as clinically indicated:  
o MUGA Scan or ECHO. 
o 12-Lead EKG. 
o Urinalysis. 
			Procedures
  	BIOPSY	Interval: --	Occurrences: --	Comments:	Core biopsy
			Labs
  	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		  	FASTING GLUCOSE LEVEL	Interval: --	Occurrences: --			Labs
  	HEMOGLOBIN A1C	Interval: --	Occurrences: --			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Imaging
☑	CT CHEST W CONTRAST ABDOMEN W CONTRAST PELVIS W CONTRAST	Interval: --	Occurrences: --	Comments:	If baseline bone scan is negative, bone scans may be repeated every 4 cycles. Scans should be performed within 7 days prior to scheduled visit.
		☐	MRI CHEST WO CONTRAST	Interval: --	Occurrences: --		☐	MRI ABDOMEN WO CONTRAST	Interval: --	Occurrences: --		☐	MRI PELVIS WO CONTRAST	Interval: --	Occurrences: --			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Pre-Medications
  	ondansetron (ZOFRAN) IV 8 mg	Dose: 8 mg	Route: intravenous	once for 1 dose	Start: S					Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Chemotherapy
  	NAB-PACLItaxel (ABRAXANE) chemo infusion 260 mg/m2 (Treatment Plan)	Dose: 260 mg/m2	Route: intravenous	once over 30 Minutes for 1 dose			Offset: 2.5 Hours			Supportive Care
  	pegfilgrastim (NEULASTA) on-body injection kit 6 mg	Dose: 6 mg	Route: subcutaneous	once for 1 dose			Offset: 3 Hours	Instructions:	After completion of Abraxane infusion.  Apply to intact, nonirritated skin on the back of the arm or abdomen (only use the back of the arm if caregiver is available to monitor On-body injection status).			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled				Days 2,3,4,5	Perform every 1 day x4		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 4	Repeat 1 time	Cycle length: 21 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	Treatment conditions and management for Nab-paclitaxel: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11.  
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22. 
			Nursing Orders
  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	HOLD and notify provider if 
o ANC LESS than 1000; 
o Platelets LESS than 100,000; 
o Total bilirubin GREATER than 1.5X ULN; 
o AST GREATER than 10X ULN.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Nursing Orders
  	ONC NURSING COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	Physical exam will include vital sign (blood pressure, oral or temporal temperature, pulse, and respiratory rate) and weight measurements.
		  	MEASURE WEIGHT	Interval: --	Occurrences: --		  	ONC NURSING COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect ECOG performance status.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect  AEs and SAEs.
		  	ONC NURSING COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect concomitant medications.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	CRC & Treating Team to Order as clinically indicated:  
o MUGA Scan or ECHO. 
o 12-Lead EKG. 
o Urinalysis. 
			Labs
  	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		  	FASTING GLUCOSE LEVEL	Interval: --	Occurrences: --			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Pre-Medications
  	ondansetron (ZOFRAN) IV 8 mg	Dose: 8 mg	Route: intravenous	once for 1 dose	Start: S					Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Chemotherapy
  	NAB-PACLItaxel (ABRAXANE) chemo infusion 260 mg/m2 (Treatment Plan)	Dose: 260 mg/m2	Route: intravenous	once over 30 Minutes for 1 dose			Offset: 2.5 Hours			Supportive Care
  	pegfilgrastim (NEULASTA) on-body injection kit 6 mg	Dose: 6 mg	Route: subcutaneous	once for 1 dose			Offset: 3 Hours	Instructions:	After completion of Abraxane infusion.  Apply to intact, nonirritated skin on the back of the arm or abdomen (only use the back of the arm if caregiver is available to monitor On-body injection status).			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled				Days 2,3,4,5	Perform every 1 day x4		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 5	Repeat 1 time	Cycle length: 21 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	Treatment conditions and management for Nab-paclitaxel: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11.  
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22. 
			Nursing Orders
  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	HOLD and notify provider if 
o ANC LESS than 1000; 
o Platelets LESS than 100,000; 
o Total bilirubin GREATER than 1.5X ULN; 
o AST GREATER than 10X ULN.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Nursing Orders
  	ONC NURSING COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	Physical exam will include vital sign (blood pressure, oral or temporal temperature, pulse, and respiratory rate) and weight measurements.
		  	MEASURE WEIGHT	Interval: --	Occurrences: --		  	ONC NURSING COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect ECOG performance status.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect  AEs and SAEs.
		  	ONC NURSING COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect concomitant medications.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	CRC & Treating Team to Order as clinically indicated:  
o MUGA Scan or ECHO. 
o 12-Lead EKG. 
o Urinalysis. 
			Labs
  	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		  	FASTING GLUCOSE LEVEL	Interval: --	Occurrences: --			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Imaging
☑	CT CHEST W CONTRAST ABDOMEN W CONTRAST PELVIS W CONTRAST	Interval: --	Occurrences: --	Comments:	If baseline bone scan is negative, bone scans may be repeated every 4 cycles. Scans should be performed within 7 days prior to scheduled visit.
		☐	MRI CHEST WO CONTRAST	Interval: --	Occurrences: --		☐	MRI ABDOMEN WO CONTRAST	Interval: --	Occurrences: --		☐	MRI PELVIS WO CONTRAST	Interval: --	Occurrences: --			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Pre-Medications
  	ondansetron (ZOFRAN) IV 8 mg	Dose: 8 mg	Route: intravenous	once for 1 dose	Start: S					Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Chemotherapy
  	NAB-PACLItaxel (ABRAXANE) chemo infusion 260 mg/m2 (Treatment Plan)	Dose: 260 mg/m2	Route: intravenous	once over 30 Minutes for 1 dose			Offset: 2.5 Hours			Supportive Care
  	pegfilgrastim (NEULASTA) on-body injection kit 6 mg	Dose: 6 mg	Route: subcutaneous	once for 1 dose			Offset: 3 Hours	Instructions:	After completion of Abraxane infusion.  Apply to intact, nonirritated skin on the back of the arm or abdomen (only use the back of the arm if caregiver is available to monitor On-body injection status).			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled				Days 2,3,4,5	Perform every 1 day x4		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 6	Repeat 1 time	Cycle length: 21 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	Treatment conditions and management for Nab-paclitaxel: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11.  
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22. 
			Nursing Orders
  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	HOLD and notify provider if 
o ANC LESS than 1000; 
o Platelets LESS than 100,000; 
o Total bilirubin GREATER than 1.5X ULN; 
o AST GREATER than 10X ULN.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Nursing Orders
  	ONC NURSING COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	Physical exam will include vital sign (blood pressure, oral or temporal temperature, pulse, and respiratory rate) and weight measurements.
		  	MEASURE WEIGHT	Interval: --	Occurrences: --		  	ONC NURSING COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect ECOG performance status.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect  AEs and SAEs.
		  	ONC NURSING COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect concomitant medications.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	CRC & Treating Team to Order as clinically indicated:  
o MUGA Scan or ECHO. 
o 12-Lead EKG. 
o Urinalysis. 
			Labs
  	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		  	FASTING GLUCOSE LEVEL	Interval: --	Occurrences: --			Labs
  	HEMOGLOBIN A1C	Interval: --	Occurrences: --			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Pre-Medications
  	ondansetron (ZOFRAN) IV 8 mg	Dose: 8 mg	Route: intravenous	once for 1 dose	Start: S					Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Chemotherapy
  	NAB-PACLItaxel (ABRAXANE) chemo infusion 260 mg/m2 (Treatment Plan)	Dose: 260 mg/m2	Route: intravenous	once over 30 Minutes for 1 dose			Offset: 2.5 Hours			Supportive Care
  	pegfilgrastim (NEULASTA) on-body injection kit 6 mg	Dose: 6 mg	Route: subcutaneous	once for 1 dose			Offset: 3 Hours	Instructions:	After completion of Abraxane infusion.  Apply to intact, nonirritated skin on the back of the arm or abdomen (only use the back of the arm if caregiver is available to monitor On-body injection status).			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled				Days 2,3,4,5	Perform every 1 day x4		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 7	Repeat 1 time	Cycle length: 21 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	Treatment conditions and management for Nab-paclitaxel: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11.  
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22. 
			Nursing Orders
  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	HOLD and notify provider if 
o ANC LESS than 1000; 
o Platelets LESS than 100,000; 
o Total bilirubin GREATER than 1.5X ULN; 
o AST GREATER than 10X ULN.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Nursing Orders
  	ONC NURSING COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	Physical exam will include vital sign (blood pressure, oral or temporal temperature, pulse, and respiratory rate) and weight measurements.
		  	MEASURE WEIGHT	Interval: --	Occurrences: --		  	ONC NURSING COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect ECOG performance status.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect  AEs and SAEs.
		  	ONC NURSING COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect concomitant medications.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	CRC & Treating Team to Order as clinically indicated:  
o MUGA Scan or ECHO. 
o 12-Lead EKG. 
o Urinalysis. 
			Labs
  	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		  	FASTING GLUCOSE LEVEL	Interval: --	Occurrences: --			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Imaging
☑	CT CHEST W CONTRAST ABDOMEN W CONTRAST PELVIS W CONTRAST	Interval: --	Occurrences: --	Comments:	If baseline bone scan is negative, bone scans may be repeated every 4 cycles. Scans should be performed within 7 days prior to scheduled visit.
		☐	MRI CHEST WO CONTRAST	Interval: --	Occurrences: --		☐	MRI ABDOMEN WO CONTRAST	Interval: --	Occurrences: --		☐	MRI PELVIS WO CONTRAST	Interval: --	Occurrences: --			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Pre-Medications
  	ondansetron (ZOFRAN) IV 8 mg	Dose: 8 mg	Route: intravenous	once for 1 dose	Start: S					Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Chemotherapy
  	NAB-PACLItaxel (ABRAXANE) chemo infusion 260 mg/m2 (Treatment Plan)	Dose: 260 mg/m2	Route: intravenous	once over 30 Minutes for 1 dose			Offset: 2.5 Hours			Supportive Care
  	pegfilgrastim (NEULASTA) on-body injection kit 6 mg	Dose: 6 mg	Route: subcutaneous	once for 1 dose			Offset: 3 Hours	Instructions:	After completion of Abraxane infusion.  Apply to intact, nonirritated skin on the back of the arm or abdomen (only use the back of the arm if caregiver is available to monitor On-body injection status).			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled				Days 2,3,4,5	Perform every 1 day x4		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 8	Repeat 1 time	Cycle length: 21 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	Treatment conditions and management for Nab-paclitaxel: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11.  
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22. 
			Nursing Orders
  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	HOLD and notify provider if 
o ANC LESS than 1000; 
o Platelets LESS than 100,000; 
o Total bilirubin GREATER than 1.5X ULN; 
o AST GREATER than 10X ULN.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Nursing Orders
  	ONC NURSING COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	Physical exam will include vital sign (blood pressure, oral or temporal temperature, pulse, and respiratory rate) and weight measurements.
		  	MEASURE WEIGHT	Interval: --	Occurrences: --		  	ONC NURSING COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect ECOG performance status.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect  AEs and SAEs.
		  	ONC NURSING COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect concomitant medications.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	CRC & Treating Team to Order as clinically indicated:  
o MUGA Scan or ECHO. 
o 12-Lead EKG. 
o Urinalysis. 
			Labs
  	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		  	FASTING GLUCOSE LEVEL	Interval: --	Occurrences: --			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Pre-Medications
  	ondansetron (ZOFRAN) IV 8 mg	Dose: 8 mg	Route: intravenous	once for 1 dose	Start: S					Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Chemotherapy
  	NAB-PACLItaxel (ABRAXANE) chemo infusion 260 mg/m2 (Treatment Plan)	Dose: 260 mg/m2	Route: intravenous	once over 30 Minutes for 1 dose			Offset: 2.5 Hours			Supportive Care
  	pegfilgrastim (NEULASTA) on-body injection kit 6 mg	Dose: 6 mg	Route: subcutaneous	once for 1 dose			Offset: 3 Hours	Instructions:	After completion of Abraxane infusion.  Apply to intact, nonirritated skin on the back of the arm or abdomen (only use the back of the arm if caregiver is available to monitor On-body injection status).			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled				Days 2,3,4,5	Perform every 1 day x4		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 9	Repeat 1 time	Cycle length: 21 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	Treatment conditions and management for Nab-paclitaxel: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11.  
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22. 
			Nursing Orders
  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	HOLD and notify provider if 
o ANC LESS than 1000; 
o Platelets LESS than 100,000; 
o Total bilirubin GREATER than 1.5X ULN; 
o AST GREATER than 10X ULN.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Nursing Orders
  	ONC NURSING COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	Physical exam will include vital sign (blood pressure, oral or temporal temperature, pulse, and respiratory rate) and weight measurements.
		  	MEASURE WEIGHT	Interval: --	Occurrences: --		  	ONC NURSING COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect ECOG performance status.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect  AEs and SAEs.
		  	ONC NURSING COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect concomitant medications.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	CRC & Treating Team to Order as clinically indicated:  
o MUGA Scan or ECHO. 
o 12-Lead EKG. 
o Urinalysis. 
			Labs
  	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		  	FASTING GLUCOSE LEVEL	Interval: --	Occurrences: --			Labs
  	HEMOGLOBIN A1C	Interval: --	Occurrences: --			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Imaging
☑	CT CHEST W CONTRAST ABDOMEN W CONTRAST PELVIS W CONTRAST	Interval: --	Occurrences: --	Comments:	If baseline bone scan is negative, bone scans may be repeated every 4 cycles. Scans should be performed within 7 days prior to scheduled visit.
		☐	MRI CHEST WO CONTRAST	Interval: --	Occurrences: --		☐	MRI ABDOMEN WO CONTRAST	Interval: --	Occurrences: --		☐	MRI PELVIS WO CONTRAST	Interval: --	Occurrences: --			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Pre-Medications
  	ondansetron (ZOFRAN) IV 8 mg	Dose: 8 mg	Route: intravenous	once for 1 dose	Start: S					Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Chemotherapy
  	NAB-PACLItaxel (ABRAXANE) chemo infusion 260 mg/m2 (Treatment Plan)	Dose: 260 mg/m2	Route: intravenous	once over 30 Minutes for 1 dose			Offset: 2.5 Hours			Supportive Care
  	pegfilgrastim (NEULASTA) on-body injection kit 6 mg	Dose: 6 mg	Route: subcutaneous	once for 1 dose			Offset: 3 Hours	Instructions:	After completion of Abraxane infusion.  Apply to intact, nonirritated skin on the back of the arm or abdomen (only use the back of the arm if caregiver is available to monitor On-body injection status).			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled				Days 2,3,4,5	Perform every 1 day x4		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 10	Repeat 1 time	Cycle length: 21 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	Treatment conditions and management for Nab-paclitaxel: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11.  
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22. 
			Nursing Orders
  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	HOLD and notify provider if 
o ANC LESS than 1000; 
o Platelets LESS than 100,000; 
o Total bilirubin GREATER than 1.5X ULN; 
o AST GREATER than 10X ULN.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Nursing Orders
  	ONC NURSING COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	Physical exam will include vital sign (blood pressure, oral or temporal temperature, pulse, and respiratory rate) and weight measurements.
		  	MEASURE WEIGHT	Interval: --	Occurrences: --		  	ONC NURSING COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect ECOG performance status.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect  AEs and SAEs.
		  	ONC NURSING COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect concomitant medications.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	CRC & Treating Team to Order as clinically indicated:  
o MUGA Scan or ECHO. 
o 12-Lead EKG. 
o Urinalysis. 
			Labs
  	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		  	FASTING GLUCOSE LEVEL	Interval: --	Occurrences: --			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Pre-Medications
  	ondansetron (ZOFRAN) IV 8 mg	Dose: 8 mg	Route: intravenous	once for 1 dose	Start: S					Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Chemotherapy
  	NAB-PACLItaxel (ABRAXANE) chemo infusion 260 mg/m2 (Treatment Plan)	Dose: 260 mg/m2	Route: intravenous	once over 30 Minutes for 1 dose			Offset: 2.5 Hours			Supportive Care
  	pegfilgrastim (NEULASTA) on-body injection kit 6 mg	Dose: 6 mg	Route: subcutaneous	once for 1 dose			Offset: 3 Hours	Instructions:	After completion of Abraxane infusion.  Apply to intact, nonirritated skin on the back of the arm or abdomen (only use the back of the arm if caregiver is available to monitor On-body injection status).			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled				Days 2,3,4,5	Perform every 1 day x4		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 11	Repeat 1 time	Cycle length: 21 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	Treatment conditions and management for Nab-paclitaxel: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11.  
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22. 
			Nursing Orders
  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	HOLD and notify provider if 
o ANC LESS than 1000; 
o Platelets LESS than 100,000; 
o Total bilirubin GREATER than 1.5X ULN; 
o AST GREATER than 10X ULN.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Nursing Orders
  	ONC NURSING COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	Physical exam will include vital sign (blood pressure, oral or temporal temperature, pulse, and respiratory rate) and weight measurements.
		  	MEASURE WEIGHT	Interval: --	Occurrences: --		  	ONC NURSING COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect ECOG performance status.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect  AEs and SAEs.
		  	ONC NURSING COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect concomitant medications.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	CRC & Treating Team to Order as clinically indicated:  
o MUGA Scan or ECHO. 
o 12-Lead EKG. 
o Urinalysis. 
			Labs
  	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		  	FASTING GLUCOSE LEVEL	Interval: --	Occurrences: --			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Imaging
☑	CT CHEST W CONTRAST ABDOMEN W CONTRAST PELVIS W CONTRAST	Interval: --	Occurrences: --	Comments:	If baseline bone scan is negative, bone scans may be repeated every 4 cycles. Scans should be performed within 7 days prior to scheduled visit.
		☐	MRI CHEST WO CONTRAST	Interval: --	Occurrences: --		☐	MRI ABDOMEN WO CONTRAST	Interval: --	Occurrences: --		☐	MRI PELVIS WO CONTRAST	Interval: --	Occurrences: --			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Pre-Medications
  	ondansetron (ZOFRAN) IV 8 mg	Dose: 8 mg	Route: intravenous	once for 1 dose	Start: S					Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Chemotherapy
  	NAB-PACLItaxel (ABRAXANE) chemo infusion 260 mg/m2 (Treatment Plan)	Dose: 260 mg/m2	Route: intravenous	once over 30 Minutes for 1 dose			Offset: 2.5 Hours			Supportive Care
  	pegfilgrastim (NEULASTA) on-body injection kit 6 mg	Dose: 6 mg	Route: subcutaneous	once for 1 dose			Offset: 3 Hours	Instructions:	After completion of Abraxane infusion.  Apply to intact, nonirritated skin on the back of the arm or abdomen (only use the back of the arm if caregiver is available to monitor On-body injection status).			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled				Days 2,3,4,5	Perform every 1 day x4		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 12	Repeat 1 time	Cycle length: 21 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	Treatment conditions and management for Nab-paclitaxel: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11.  
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22. 
			Nursing Orders
  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	HOLD and notify provider if 
o ANC LESS than 1000; 
o Platelets LESS than 100,000; 
o Total bilirubin GREATER than 1.5X ULN; 
o AST GREATER than 10X ULN.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Nursing Orders
  	ONC NURSING COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	Physical exam will include vital sign (blood pressure, oral or temporal temperature, pulse, and respiratory rate) and weight measurements.
		  	MEASURE WEIGHT	Interval: --	Occurrences: --		  	ONC NURSING COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect ECOG performance status.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect  AEs and SAEs.
		  	ONC NURSING COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect concomitant medications.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	CRC & Treating Team to Order as clinically indicated:  
o MUGA Scan or ECHO. 
o 12-Lead EKG. 
o Urinalysis. 
			Labs
  	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		  	FASTING GLUCOSE LEVEL	Interval: --	Occurrences: --			Labs
  	HEMOGLOBIN A1C	Interval: --	Occurrences: --			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Pre-Medications
  	ondansetron (ZOFRAN) IV 8 mg	Dose: 8 mg	Route: intravenous	once for 1 dose	Start: S					Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Chemotherapy
  	NAB-PACLItaxel (ABRAXANE) chemo infusion 260 mg/m2 (Treatment Plan)	Dose: 260 mg/m2	Route: intravenous	once over 30 Minutes for 1 dose			Offset: 2.5 Hours			Supportive Care
  	pegfilgrastim (NEULASTA) on-body injection kit 6 mg	Dose: 6 mg	Route: subcutaneous	once for 1 dose			Offset: 3 Hours	Instructions:	After completion of Abraxane infusion.  Apply to intact, nonirritated skin on the back of the arm or abdomen (only use the back of the arm if caregiver is available to monitor On-body injection status).			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled				Days 2,3,4,5	Perform every 1 day x4		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 13	Repeat 1 time	Cycle length: 21 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	Treatment conditions and management for Nab-paclitaxel: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11.  
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22. 
			Nursing Orders
  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	HOLD and notify provider if 
o ANC LESS than 1000; 
o Platelets LESS than 100,000; 
o Total bilirubin GREATER than 1.5X ULN; 
o AST GREATER than 10X ULN.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Nursing Orders
  	ONC NURSING COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	Physical exam will include vital sign (blood pressure, oral or temporal temperature, pulse, and respiratory rate) and weight measurements.
		  	MEASURE WEIGHT	Interval: --	Occurrences: --		  	ONC NURSING COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect ECOG performance status.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect  AEs and SAEs.
		  	ONC NURSING COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect concomitant medications.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	CRC & Treating Team to Order as clinically indicated:  
o MUGA Scan or ECHO. 
o 12-Lead EKG. 
o Urinalysis. 
			Labs
  	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		  	FASTING GLUCOSE LEVEL	Interval: --	Occurrences: --			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Imaging
☑	CT CHEST W CONTRAST ABDOMEN W CONTRAST PELVIS W CONTRAST	Interval: --	Occurrences: --	Comments:	If baseline bone scan is negative, bone scans may be repeated every 4 cycles. Scans should be performed within 7 days prior to scheduled visit.
		☐	MRI CHEST WO CONTRAST	Interval: --	Occurrences: --		☐	MRI ABDOMEN WO CONTRAST	Interval: --	Occurrences: --		☐	MRI PELVIS WO CONTRAST	Interval: --	Occurrences: --			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Pre-Medications
  	ondansetron (ZOFRAN) IV 8 mg	Dose: 8 mg	Route: intravenous	once for 1 dose	Start: S					Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Chemotherapy
  	NAB-PACLItaxel (ABRAXANE) chemo infusion 260 mg/m2 (Treatment Plan)	Dose: 260 mg/m2	Route: intravenous	once over 30 Minutes for 1 dose			Offset: 2.5 Hours			Supportive Care
  	pegfilgrastim (NEULASTA) on-body injection kit 6 mg	Dose: 6 mg	Route: subcutaneous	once for 1 dose			Offset: 3 Hours	Instructions:	After completion of Abraxane infusion.  Apply to intact, nonirritated skin on the back of the arm or abdomen (only use the back of the arm if caregiver is available to monitor On-body injection status).			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled				Days 2,3,4,5	Perform every 1 day x4		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 14	Repeat 1 time	Cycle length: 21 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	Treatment conditions and management for Nab-paclitaxel: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11.  
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22. 
			Nursing Orders
  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	HOLD and notify provider if 
o ANC LESS than 1000; 
o Platelets LESS than 100,000; 
o Total bilirubin GREATER than 1.5X ULN; 
o AST GREATER than 10X ULN.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Nursing Orders
  	ONC NURSING COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	Physical exam will include vital sign (blood pressure, oral or temporal temperature, pulse, and respiratory rate) and weight measurements.
		  	MEASURE WEIGHT	Interval: --	Occurrences: --		  	ONC NURSING COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect ECOG performance status.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect  AEs and SAEs.
		  	ONC NURSING COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect concomitant medications.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	CRC & Treating Team to Order as clinically indicated:  
o MUGA Scan or ECHO. 
o 12-Lead EKG. 
o Urinalysis. 
			Labs
  	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		  	FASTING GLUCOSE LEVEL	Interval: --	Occurrences: --			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Pre-Medications
  	ondansetron (ZOFRAN) IV 8 mg	Dose: 8 mg	Route: intravenous	once for 1 dose	Start: S					Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Chemotherapy
  	NAB-PACLItaxel (ABRAXANE) chemo infusion 260 mg/m2 (Treatment Plan)	Dose: 260 mg/m2	Route: intravenous	once over 30 Minutes for 1 dose			Offset: 2.5 Hours			Supportive Care
  	pegfilgrastim (NEULASTA) on-body injection kit 6 mg	Dose: 6 mg	Route: subcutaneous	once for 1 dose			Offset: 3 Hours	Instructions:	After completion of Abraxane infusion.  Apply to intact, nonirritated skin on the back of the arm or abdomen (only use the back of the arm if caregiver is available to monitor On-body injection status).			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled				Days 2,3,4,5	Perform every 1 day x4		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 15	Repeat 1 time	Cycle length: 21 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	Treatment conditions and management for Nab-paclitaxel: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11.  
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22. 
			Nursing Orders
  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	HOLD and notify provider if 
o ANC LESS than 1000; 
o Platelets LESS than 100,000; 
o Total bilirubin GREATER than 1.5X ULN; 
o AST GREATER than 10X ULN.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Nursing Orders
  	ONC NURSING COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	Physical exam will include vital sign (blood pressure, oral or temporal temperature, pulse, and respiratory rate) and weight measurements.
		  	MEASURE WEIGHT	Interval: --	Occurrences: --		  	ONC NURSING COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect ECOG performance status.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect  AEs and SAEs.
		  	ONC NURSING COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect concomitant medications.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	CRC & Treating Team to Order as clinically indicated:  
o MUGA Scan or ECHO. 
o 12-Lead EKG. 
o Urinalysis. 
			Labs
  	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		  	FASTING GLUCOSE LEVEL	Interval: --	Occurrences: --			Labs
  	HEMOGLOBIN A1C	Interval: --	Occurrences: --			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Imaging
☑	CT CHEST W CONTRAST ABDOMEN W CONTRAST PELVIS W CONTRAST	Interval: --	Occurrences: --	Comments:	If baseline bone scan is negative, bone scans may be repeated every 4 cycles. Scans should be performed within 7 days prior to scheduled visit.
		☐	MRI CHEST WO CONTRAST	Interval: --	Occurrences: --		☐	MRI ABDOMEN WO CONTRAST	Interval: --	Occurrences: --		☐	MRI PELVIS WO CONTRAST	Interval: --	Occurrences: --			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Pre-Medications
  	ondansetron (ZOFRAN) IV 8 mg	Dose: 8 mg	Route: intravenous	once for 1 dose	Start: S					Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Chemotherapy
  	NAB-PACLItaxel (ABRAXANE) chemo infusion 260 mg/m2 (Treatment Plan)	Dose: 260 mg/m2	Route: intravenous	once over 30 Minutes for 1 dose			Offset: 2.5 Hours			Supportive Care
  	pegfilgrastim (NEULASTA) on-body injection kit 6 mg	Dose: 6 mg	Route: subcutaneous	once for 1 dose			Offset: 3 Hours	Instructions:	After completion of Abraxane infusion.  Apply to intact, nonirritated skin on the back of the arm or abdomen (only use the back of the arm if caregiver is available to monitor On-body injection status).			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled				Days 2,3,4,5	Perform every 1 day x4		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 16	Repeat 1 time	Cycle length: 21 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	Treatment conditions and management for Nab-paclitaxel: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11.  
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22. 
			Nursing Orders
  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	HOLD and notify provider if 
o ANC LESS than 1000; 
o Platelets LESS than 100,000; 
o Total bilirubin GREATER than 1.5X ULN; 
o AST GREATER than 10X ULN.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Nursing Orders
  	ONC NURSING COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	Physical exam will include vital sign (blood pressure, oral or temporal temperature, pulse, and respiratory rate) and weight measurements.
		  	MEASURE WEIGHT	Interval: --	Occurrences: --		  	ONC NURSING COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect ECOG performance status.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect  AEs and SAEs.
		  	ONC NURSING COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect concomitant medications.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	CRC & Treating Team to Order as clinically indicated:  
o MUGA Scan or ECHO. 
o 12-Lead EKG. 
o Urinalysis. 
			Labs
  	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		  	FASTING GLUCOSE LEVEL	Interval: --	Occurrences: --			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Pre-Medications
  	ondansetron (ZOFRAN) IV 8 mg	Dose: 8 mg	Route: intravenous	once for 1 dose	Start: S					Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Chemotherapy
  	NAB-PACLItaxel (ABRAXANE) chemo infusion 260 mg/m2 (Treatment Plan)	Dose: 260 mg/m2	Route: intravenous	once over 30 Minutes for 1 dose			Offset: 2.5 Hours			Supportive Care
  	pegfilgrastim (NEULASTA) on-body injection kit 6 mg	Dose: 6 mg	Route: subcutaneous	once for 1 dose			Offset: 3 Hours	Instructions:	After completion of Abraxane infusion.  Apply to intact, nonirritated skin on the back of the arm or abdomen (only use the back of the arm if caregiver is available to monitor On-body injection status).			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled				Days 2,3,4,5	Perform every 1 day x4		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 17	Repeat 1 time	Cycle length: 21 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	Treatment conditions and management for Nab-paclitaxel: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11.  
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22. 
			Nursing Orders
  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	HOLD and notify provider if 
o ANC LESS than 1000; 
o Platelets LESS than 100,000; 
o Total bilirubin GREATER than 1.5X ULN; 
o AST GREATER than 10X ULN.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Nursing Orders
  	ONC NURSING COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	Physical exam will include vital sign (blood pressure, oral or temporal temperature, pulse, and respiratory rate) and weight measurements.
		  	MEASURE WEIGHT	Interval: --	Occurrences: --		  	ONC NURSING COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect ECOG performance status.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect  AEs and SAEs.
		  	ONC NURSING COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect concomitant medications.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	CRC & Treating Team to Order as clinically indicated:  
o MUGA Scan or ECHO. 
o 12-Lead EKG. 
o Urinalysis. 
			Labs
  	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		  	FASTING GLUCOSE LEVEL	Interval: --	Occurrences: --			Labs
  	HEMOGLOBIN A1C	Interval: --	Occurrences: --			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Imaging
☑	CT CHEST W CONTRAST ABDOMEN W CONTRAST PELVIS W CONTRAST	Interval: --	Occurrences: --	Comments:	If baseline bone scan is negative, bone scans may be repeated every 4 cycles. Scans should be performed within 7 days prior to scheduled visit.
		☐	MRI CHEST WO CONTRAST	Interval: --	Occurrences: --		☐	MRI ABDOMEN WO CONTRAST	Interval: --	Occurrences: --		☐	MRI PELVIS WO CONTRAST	Interval: --	Occurrences: --			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Pre-Medications
  	ondansetron (ZOFRAN) IV 8 mg	Dose: 8 mg	Route: intravenous	once for 1 dose	Start: S					Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Chemotherapy
  	NAB-PACLItaxel (ABRAXANE) chemo infusion 260 mg/m2 (Treatment Plan)	Dose: 260 mg/m2	Route: intravenous	once over 30 Minutes for 1 dose			Offset: 2.5 Hours			Supportive Care
  	pegfilgrastim (NEULASTA) on-body injection kit 6 mg	Dose: 6 mg	Route: subcutaneous	once for 1 dose			Offset: 3 Hours	Instructions:	After completion of Abraxane infusion.  Apply to intact, nonirritated skin on the back of the arm or abdomen (only use the back of the arm if caregiver is available to monitor On-body injection status).			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled				Days 2,3,4,5	Perform every 1 day x4		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	o If L-NMMA is discontinued for any reason other than progression, nab-paclitaxel and alpelisib to be continued until progression. 
o If Alpelisib is discontinued for any reason other than progression, L-NMMA and nab-paclitaxel to be continued until progression. 
o If Nab-paclitaxel is discontinued for any reason, alpelisib and L-NMMA can be continued if subject derives clinical benefit. 
o If both Alpelisib and L-NMMA are medications discontinued for any reason other than progression, nab-paclitaxel should be continued until progression or toxicity requiring discontinuation.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 18	Interval: --	Occurrences: --	Comments:	Dose Modifications and Management for Alpelisib:  Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf.  
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 19	Interval: --	Occurrences: --	Comments:	Treatment Conditions and Management for L-NMMA: Toxicities Management, Treatment Interventions, Dose Modifications: see Protocol Hyperlink: HMCC-BR22-001 CHANG_Niravath -Alpelisib L-NMMA V5 16June2022 TC.pdf. 
Please refer to Protocol Sections for: 
o Dose Limiting Toxicities (DLT)- Definition, Management and Treatment Interventions see Section 4.1 Overall Design Pg 9-11. 
o Toxicity Management, Interventions, and Dose Modifications see Section 6.1.2 Dosing and Administration Pg. 17-22.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	Proposed Dose Levels for Alpelisib as Determined by Dose Limiting Toxicities (DLT).
o The dose escalation will be guided by the Bayesian optimal interval (BOIN) design with the target DLT rate of 30%. Eligible patients will enter the study in cohorts of three with the first cohort treated at Dose 0. 
o To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to the rule displayed in Table 6, and repeat this process until the number of patients treated at the current dose reaches 6 and the decision according to Table 5 is to stay at the current dose, or the maximum sample size of 18 is reached. The RP2D will be defined as the highest dose administered at which 6 patients are treated with no more than 2 experiencing DLT. The patients treated at the RP2D will be rolled over to phase II for further evaluation of efficacy and toxicity.

Dose level	Alpelisib Dose
-2		200 mg for Days 1-21
-1		250 mg for Days 1-10
0		250 mg for Days 1-21 - Starting Dose
1		300 mg for Days 1-21
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: --	Occurrences: --	Comments:	Dose Escalation/De-escalation rule (Table 6 in protocol) with Dose Limiting Toxicities (DLT).
Cohort 1 | Cohort 2  | Corresponding Response 
0	 | 1	         | Escalate the Alpelisib dose  	
1	 | 2	         | Stay at same Alpelisib dose 
2	 | 3 or more   | De-escalate the Alpelisib dose 
3	 | 4 or more   | Eliminate current/higher doses from trial use
			Line Care
  	sodium chloride 0.9% flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Line Care
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mg/dL; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	MEASURE BLOOD PRESSURE	Interval: --	Occurrences: --	Comments:	Blood pressure to be taken pre-dose, 1 hour (±10 minutes) into infusion, and at end of infusion.
			Chemotherapy
  	INV-L-NMMA (HMCC-BR22-001/Pro00030489/Chang) 20 mg/kg in sodium chloride 0.9% 100 mL infusion	Dose: 20 mg/kg	Route: intravenous	once over 2 Hours for 1 dose			Offset: 30 Minutes	Instructions:	Contains active study drug L-NMMA in NS, total volume 100 mL. Prepared bag is stable for 4 hours when refrigerated. Infuse intravenously over 2 hours.
Caution: New Drug-Limited by Federal (USA) Law to Investigational use.
	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	INV-L-NMMA 50 MG/ML INTRAVENOUS SOLN (HMCC-BR22-001/PRO00030489/CHANG)	Medications	20 mg/kg	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes				Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Confirm patient is taking home Alpelisib and supportive meds (Amlodipine, Metformin, and Cetirizine) as prescribed.
			Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only - itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 - MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms - shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Cetirizine 10 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	cetirizine (ZyrTEC) tablet 10 mg	Dose: 10 mg	Route: oral	once PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
EOT	Repeat 1 time	Cycle length: 1 day	Day 1	Perform every 1 day x1		Nursing Orders
  	ONC NURSING COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	Physical exam will include vital sign (blood pressure, oral or temporal temperature, pulse, and respiratory rate) and weight measurements.
		  	MEASURE WEIGHT	Interval: --	Occurrences: --		  	ONC NURSING COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect ECOG performance status.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect  AEs and SAEs.
		  	ONC NURSING COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	CRC and treatment team to collect concomitant medications.
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Imaging
☑	CT CHEST W CONTRAST ABDOMEN W CONTRAST PELVIS W CONTRAST	Interval: --	Occurrences: --	Comments:	If baseline bone scan is negative, bone scans may be repeated every 4 cycles. Scans should be performed within 7 days prior to scheduled visit.
		☐	MRI CHEST WO CONTRAST	Interval: --	Occurrences: --		☐	MRI ABDOMEN WO CONTRAST	Interval: --	Occurrences: --		☐	MRI PELVIS WO CONTRAST	Interval: --	Occurrences: --