Protocol Index	

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IP RESEARCH PRO00035985 EA9181 NCT04530565 ARM C INTENSIFICATION SHAH	

Types:      Research Oncology Treatment
Synonyms:  

Cycle 1	Repeat 1 time	Cycle length: 7 days	Day 1	Perform every 1 day x1		Provider Communication
  	ONC PROVIDER COMMUNICATION 27	Interval: Until discontinued	Occurrences: --	Comments:	Please refer to Study Protocol for any questions or discrepancies. See Schedule of Events Calendar for sequence of diagnostic tests, examinations, and treatment administration: See Safety Parameters-for Toxicity Management and Dose Modification Guidelines: Protocol Access hyperlink:    EA9181-Shah
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: Until discontinued	Occurrences: --	Comments:	Dose Modifications and Management for HDMTX Treatment:  Refer to Section XXX (****TITLE****) Management of AEs Associated with ****STUDY DRUG****
Protocol Access Hyperlink:   EA9181-Shah
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: Once	Occurrences: --	Comments:	Patients are allowed to proceed to intensification immediately after morphologic CR or CRi was confirmed. There is no need to wait for molecular MRD results if an adequate sample had been submitted for MRD molecular test.
		  	ONC PROVIDER COMMUNICATION 18	Interval: Once	Occurrences: --	Comments:	High dose methotrexate is to be administered after MRD testing (quantitative BCR/ABL PCR) from a bone marrow sample was taken. Treatment with methotrexate can be prescribed up to 14 days after MRD test was drawn.
		  	ONC PROVIDER COMMUNICATION 19	Interval: Once	Occurrences: --	Comments:	Avoid using NSAIDs, trimethoprim/sulfamethoxazole, penicillin, probenecid, IV contrast media, proton pump inhibitors, phenytoin and fosphenytoin on the same day of methotrexate. TKI can be withheld on the day of high dose methotrexate administration per investigator discretion, but must resume upon clearance of methotrexate blood levels.
		  	ONC PROVIDER COMMUNICATION 29	Interval: --	Occurrences: --	Comments:	BSA should be capped at 2.3m2 for all drug-dosing
			Provider Communication
  	ONC PROVIDER COMMUNICATION 25	Interval: Until discontinued	Occurrences: --	Comments:	Sulfamethoxazole/Trimethoprim prophylaxis should be held prior to methotrexate and should not be restarted until methotrexate level is BELOW 0.05.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 5	Interval: Once	Occurrences: --	Comments:	Use baseline weight to calculate dose. Adjust dose for weight gains/losses of greater than or equal to 10%.
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: Once	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: Once	Occurrences: --		  	MAGNESIUM LEVEL	Interval: Once	Occurrences: --			Labs
  	PH, URINALYSIS	Interval: Every 8 hours	Occurrences: --	Comments:	Draw prior to starting Methotrexate and PRN until pH GREATER than 7.  Then draw urine pH every day until MTX is LESS than 0.05
			Nursing Orders
  	TREATMENT CONDITIONS 7	Interval: Once	Occurrences: --	Comments:	HOLD and notify provider if ANC LESS than 1000; Platelets LESS than 100,000.
			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: Once	Occurrences: --	Comments:	1) Obtain weight and height on date of admission. Obtain weight every 8 hours. 
2) Strict I&O's every 8 hours. 
3) Check urine output every 4 hours . 
4) Check Urine pH every 8 hours. 
5) NO carbonated beverages or fruit juices.
			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.			Pre-Hydration
  	sodium bicarbonate 150 mEq in dextrose 5% 1,000 mL infusion	Dose: 150 mL/hr	Route: intravenous	continuous	Start: S			Ingredients:	Name	Type	Dose	Selected	Adds Vol.	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	1,000 mL	Yes	Yes	DEXTROSE 10 % IN WATER (D10W) INTRAVENOUS SOLUTION	Base	1,000 mL	No	Yes	DEXTROSE 5 % AND 0.2 % SODIUM CHLORIDE INTRAVENOUS SOLUTION	Base	1,000 mL	No	Yes	DEXTROSE 5 % AND 0.45 % SODIUM CHLORIDE INTRAVENOUS SOLUTION	Base	1,000 mL	No	Yes	DEXTROSE 5 % AND 0.9 % SODIUM CHLORIDE INTRAVENOUS SOLUTION	Base	1,000 mL	No	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	1,000 mL	No	Yes	SODIUM CHLORIDE 0.45 % INTRAVENOUS SOLUTION	Base	1,000 mL	No	Yes	LACTATED RINGERS INTRAVENOUS SOLUTION	Base	1,000 mL	No	Yes	MVI,ADULT NO.4 WITH VIT K 3300 UNIT-150 MCG/10 ML INTRAVENOUS SOLUTION	Additives	10 mL	No	No	POTASSIUM CHLORIDE 2 MEQ/ML INTRAVENOUS SOLUTION	Additives	20 mEq	No	Yes	THIAMINE HCL (VITAMIN B1) 100 MG/ML INJECTION SOLUTION	Additives	100 mg	No	Yes	FOLIC ACID 5 MG/ML INJECTION SOLUTION	Additives	1 mg	No	Yes	MAGNESIUM SULFATE 500 MG/ML (50 %) INJECTION SOLUTION	Additives	 	No	Yes	CALCIUM GLUCONATE 100 MG/ML (10 %) INTRAVENOUS SOLUTION	Additives	 	No	Yes	PHYTONADIONE (VITAMIN K1) SUBCUTANEOUS	Additives	 	No	No	ASCORBIC ACID (VITAMIN C) 500 MG/ML INJECTION SOLUTION	Additives	500 mg	No	No	POTASSIUM ACETATE 2 MEQ/ML INTRAVENOUS SOLUTION	Additives	 	No	Yes	POTASSIUM PHOSPHATES-MBASIC AND DIBASIC 3 MMOL/ML INTRAVENOUS SOLUTION	Additives	 	No	Yes	SODIUM BICARBONATE 1 MEQ/ML (8.4 %) INTRAVENOUS SOLUTION	Additives	150 mEq	Yes	Yes	SODIUM PHOSPHATE 3 MMOL/ML INTRAVENOUS SOLUTION	Additives	 	No	Yes	SODIUM ACETATE 2 MEQ/ML INTRAVENOUS SOLUTION	Additives	 	No	Yes	ZINC SULFATE 1 MG/ML INTRAVENOUS SOLUTION	Additives	 	No	Yes	CYANOCOBALAMIN (VIT B-12) 1,000 MCG/ML INJECTION SOLUTION	Additives	 	No	Yes	SODIUM CHLORIDE 4 MEQ/ML INTRAVENOUS SOLUTION	Additives	 	No	Yes				Pre-Medications
  	fosaprepitant (EMEND) IVPB 150 mg	Dose: 150 mg	Route: intravenous	once over 30 Minutes for 1 dose	Start: S				  	ondansetron (ZOFRAN) 16 mg, dexamethasone (DECADRON) 12 mg in sodium chloride 0.9% 50 mL IVPB	Dose: 16 mg	Route: intravenous	once over 10 Minutes for 1 dose	Start: S			Ingredients:	Name	Type	Dose	Selected	Adds Vol.	ONDANSETRON HCL 2 MG/ML INTRAVENOUS SOLUTION	Medications	16 mg	Main Ingredient	No	DEXAMETHASONE SODIUM PHOSPHATE 10 MG/ML INJECTION SOLUTION	Medications	12 mg	Yes	No	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	50 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	50 mL	No	Yes				Nursing Orders
☑	ONC NURSING COMMUNICATION 10	Interval: Once	Occurrences: --	Comments:	Draw methotrexate level for 24 hours, 48 hours and 72 hours AFTER COMPLETION of methotrexate infusion and send STAT. Obtain level every 24 hours until methotrexate level is LESS than 0.05.

 Check STAT urine pH prior to starting Methotrexate and then every 8 hours. If urine pH is LESS than 7, administer 50 mEq sodium bicarbonate and recheck in 1 hour. If still LESS than 7, repeat 50 mEq sodium bicarbonate and recheck in 1 hour. If still LESS than 7, call provider. 

The syringe that the blood is sent to lab in needs to be COVERED (brown bag/paper towel) going to the lab.
			Medications
☐	furosemide (LASIX) injection 5 mg	Dose: 5 mg	Route: intravenous	once for 1 dose	Start: S	End: S  8:00 PM		Instructions:	Give if daily weight is GREATER THAN 0.5 kg above admission weight		☐	furosemide (LASIX) injection 10 mg	Dose: 10 mg	Route: intravenous	once for 1 dose	Start: S	End: S  8:00 PM		Instructions:	Give if daily weight is GREATER THAN 1.0 kg above admission weight		☐	furosemide (LASIX) injection 15 mg	Dose: 15 mg	Route: intravenous	once for 1 dose	Start: S	End: S  8:00 PM		Instructions:	Give if daily weight is GREATER THAN 1.5 kg above admission weight		☐	sodium bicarbonate tablet 3,250 mg	Dose: 3,250 mg	Route: oral	every 4 hours while awake	Start: S			Instructions:	Give until Methotrexate level is LESS THAN or EQUAL to 0.09 mmol			Provider Communication
  	ONC PROVIDER COMMUNICATION 20	Interval: Once	Occurrences: --	Comments:	Patient must have normal kidney function to receive this part of the protocol. If the current estimate creatinine clearance of a patient is GREATER than or EQUAL to 45mL/min but < 60mL/min, the dose of Methotrexate 2 g/m2IV in NS 500 ml over 2 hours should be administered. If the estimate creatinine clearance is below 45mL/min, do not administer methotrexate, wait a week and reexamine kidney function. If creatinine clearance is still below 45mL/min skip methotrexate and proceed to Step 3. Reducing the methotrexate dose to 2g/m2is also allowed if investigator suspects patient is expected to experience severe toxicity from the full dose.
		  	ONC PROVIDER COMMUNICATION 28	Interval: Until discontinued	Occurrences: --	Comments:	Please choose one of the following orders based on renal function (creatinine clearance):  
o For CrCl 45-60 mL/min, the methotrexate dose should be 2g/m2/dose.  
o For CrCl < 45 ml/min, HOLD methotrexate
			Chemotherapy
☑	methotrexate PF 3 g/m2 in sodium chloride 0.9% 500 mL chemo IVPB	Dose: 3 g/m2	Route: intravenous	once over 2 Hours for 1 dose	Start: S			Ingredients:	Name	Type	Dose	Selected	Adds Vol.	METHOTREXATE SODIUM (PF) 25 MG/ML INJECTION SOLUTION	Medications	3 g/m2	Main Ingredient	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	500 mL	No	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	500 mL	Yes	Yes			☑	methotrexate Preservative Free 2 g/m2 in sodium chloride 0.9% 500 mL chemo IVPB	Dose: 2 g/m2	Route: intravenous	once over 2 Hours for 1 dose	Start: S			Ingredients:	Name	Type	Dose	Selected	Adds Vol.	METHOTREXATE SODIUM (PF) 25 MG/ML INJECTION SOLUTION	Medications	2 g/m2	Main Ingredient	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	500 mL	No	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	500 mL	Yes	Yes				Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: Until discontinued	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 83	Interval: Until discontinued	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 4	Interval: Until discontinued	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	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	Start: S				  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					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.				Day 2	Perform every 1 day x1		Provider Communication
  	ONC PROVIDER COMMUNICATION 21	Interval: Once	Occurrences: --	Comments:	Guidelines at 24 hours: If methotrexate level is less than 10 umol/L continue leucovorin at current dosing. If methotrexate level is greater than 10 µmol/L at 24 hours or if creatinine increases greater than 50% of the pre- methotrexate level increase leucovorin to 100 mg/m2IV in 100 ml D5W every three hours until methotrexate level is less than 0.05 µmol/L.
		  	ONC PROVIDER COMMUNICATION 22	Interval: Once	Occurrences: --	Comments:	Guidelines at 48 hours: If methotrexate level is greater than 1 µmol/L at 48 hours or if creatinine increases greater than 50% of the pre- methotrexate level increase leucovorin to 100 mg/m2 IV in 100 ml D5W every three hours until methotrexate level is less than 0.05 µmol/L.
			Labs
  	BASIC METABOLIC PANEL	Interval: Once	Occurrences: --			Labs
  	METHOTREXATE LEVEL	Interval: Once	Occurrences: --	Comments:	Schedule MTX levels DAILY beginning EXACTLY 24 hours AFTER completion of MTX infusion until MTX level is LESS THAN 0.05 umol/L.
			Labs
  	PH, URINALYSIS	Interval: Every 8 hours	Occurrences: --	Comments:	Draw prior to starting Methotrexate and PRN until pH GREATER than 7.  Then draw urine pH every day until MTX is LESS than 0.05
			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.			Pre-Medications
  	ondansetron (ZOFRAN) IV 16 mg	Dose: 16 mg	Route: intravenous	once for 1 dose	Start: S					Nursing Orders
☑	ONC NURSING COMMUNICATION 10	Interval: Once	Occurrences: --	Comments:	Draw methotrexate level for 24 hours, 48 hours and 72 hours AFTER COMPLETION of methotrexate infusion and send STAT. Obtain level every 24 hours until methotrexate level is LESS than 0.05.

 Check STAT urine pH prior to starting Methotrexate and then every 8 hours. If urine pH is LESS than 7, administer 50 mEq sodium bicarbonate and recheck in 1 hour. If still LESS than 7, repeat 50 mEq sodium bicarbonate and recheck in 1 hour. If still LESS than 7, call provider. 

The syringe that the blood is sent to lab in needs to be COVERED (brown bag/paper towel) going to the lab.
			Medications
☐	furosemide (LASIX) injection 5 mg	Dose: 5 mg	Route: intravenous	once for 1 dose	Start: S	End: S  8:00 PM		Instructions:	Give if daily weight is GREATER THAN 0.5 kg above admission weight		☐	furosemide (LASIX) injection 10 mg	Dose: 10 mg	Route: intravenous	once for 1 dose	Start: S	End: S  8:00 PM		Instructions:	Give if daily weight is GREATER THAN 1.0 kg above admission weight		☐	furosemide (LASIX) injection 15 mg	Dose: 15 mg	Route: intravenous	once for 1 dose	Start: S	End: S  8:00 PM		Instructions:	Give if daily weight is GREATER THAN 1.5 kg above admission weight		☐	sodium bicarbonate tablet 3,250 mg	Dose: 3,250 mg	Route: oral	every 4 hours while awake	Start: S			Instructions:	Give until Methotrexate level is LESS THAN or EQUAL to 0.09 mmol			Supportive Care
  	leucovorin 10 mg/m2 in sodium chloride 0.9% 100 mL IVPB	Dose: 10 mg/m2	Route: intravenous	every 6 hours over 15 Minutes	Start: S			Instructions:	Start 22-24 hours after COMPLETION of methotrexate infusion and continue every 6 hours until methotrexate serum concentration is LESS than 0.05 micromol/L	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	LEUCOVORIN CALCIUM 350 MG SOLUTION FOR INJECTION	Medications	10 mg/m2	Main Ingredient	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes					Day 3	Perform every 1 day x1		Provider Communication
  	ONC PROVIDER COMMUNICATION 21	Interval: Once	Occurrences: --	Comments:	Guidelines at 24 hours: If methotrexate level is less than 10 umol/L continue leucovorin at current dosing. If methotrexate level is greater than 10 µmol/L at 24 hours or if creatinine increases greater than 50% of the pre- methotrexate level increase leucovorin to 100 mg/m2IV in 100 ml D5W every three hours until methotrexate level is less than 0.05 µmol/L.
		  	ONC PROVIDER COMMUNICATION 22	Interval: Once	Occurrences: --	Comments:	Guidelines at 48 hours: If methotrexate level is greater than 1 µmol/L at 48 hours or if creatinine increases greater than 50% of the pre- methotrexate level increase leucovorin to 100 mg/m2 IV in 100 ml D5W every three hours until methotrexate level is less than 0.05 µmol/L.
			Labs
  	BASIC METABOLIC PANEL	Interval: Once	Occurrences: --			Labs
  	METHOTREXATE LEVEL	Interval: Once	Occurrences: --	Comments:	Schedule MTX levels DAILY beginning EXACTLY 24 hours AFTER completion of MTX infusion until MTX level is LESS THAN 0.05 umol/L.
			Labs
  	PH, URINALYSIS	Interval: Every 8 hours	Occurrences: --	Comments:	Draw prior to starting Methotrexate and PRN until pH GREATER than 7.  Then draw urine pH every day until MTX is LESS than 0.05
			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 10	Interval: Once	Occurrences: --	Comments:	Draw methotrexate level for 24 hours, 48 hours and 72 hours AFTER COMPLETION of methotrexate infusion and send STAT. Obtain level every 24 hours until methotrexate level is LESS than 0.05.

 Check STAT urine pH prior to starting Methotrexate and then every 8 hours. If urine pH is LESS than 7, administer 50 mEq sodium bicarbonate and recheck in 1 hour. If still LESS than 7, repeat 50 mEq sodium bicarbonate and recheck in 1 hour. If still LESS than 7, call provider. 

The syringe that the blood is sent to lab in needs to be COVERED (brown bag/paper towel) going to the lab.
			Medications
☐	furosemide (LASIX) injection 5 mg	Dose: 5 mg	Route: intravenous	once for 1 dose	Start: S	End: S  8:00 PM		Instructions:	Give if daily weight is GREATER THAN 0.5 kg above admission weight		☐	furosemide (LASIX) injection 10 mg	Dose: 10 mg	Route: intravenous	once for 1 dose	Start: S	End: S  8:00 PM		Instructions:	Give if daily weight is GREATER THAN 1.0 kg above admission weight		☐	furosemide (LASIX) injection 15 mg	Dose: 15 mg	Route: intravenous	once for 1 dose	Start: S	End: S  8:00 PM		Instructions:	Give if daily weight is GREATER THAN 1.5 kg above admission weight		☐	sodium bicarbonate tablet 3,250 mg	Dose: 3,250 mg	Route: oral	every 4 hours while awake	Start: S			Instructions:	Give until Methotrexate level is LESS THAN or EQUAL to 0.09 mmol					
Cycle 2	Repeat 1 time	Cycle length: 7 days	Day 1	Perform every 1 day x1		Provider Communication
  	ONC PROVIDER COMMUNICATION 27	Interval: Until discontinued	Occurrences: --	Comments:	Please refer to Study Protocol for any questions or discrepancies. See Schedule of Events Calendar for sequence of diagnostic tests, examinations, and treatment administration: See Safety Parameters-for Toxicity Management and Dose Modification Guidelines: Protocol Access hyperlink:    EA9181-Shah
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: Until discontinued	Occurrences: --	Comments:	Dose Modifications and Management for HDMTX Treatment:  Refer to Section XXX (****TITLE****) Management of AEs Associated with ****STUDY DRUG****
Protocol Access Hyperlink:   EA9181-Shah
			Provider Communication
  	ONC PROVIDER COMMUNICATION 17	Interval: Once	Occurrences: --	Comments:	Patients are allowed to proceed to intensification immediately after morphologic CR or CRi was confirmed. There is no need to wait for molecular MRD results if an adequate sample had been submitted for MRD molecular test.
		  	ONC PROVIDER COMMUNICATION 18	Interval: Once	Occurrences: --	Comments:	High dose methotrexate is to be administered after MRD testing (quantitative BCR/ABL PCR) from a bone marrow sample was taken. Treatment with methotrexate can be prescribed up to 14 days after MRD test was drawn.
		  	ONC PROVIDER COMMUNICATION 19	Interval: Once	Occurrences: --	Comments:	Avoid using NSAIDs, trimethoprim/sulfamethoxazole, penicillin, probenecid, IV contrast media, proton pump inhibitors, phenytoin and fosphenytoin on the same day of methotrexate. TKI can be withheld on the day of high dose methotrexate administration per investigator discretion, but must resume upon clearance of methotrexate blood levels.
		  	ONC PROVIDER COMMUNICATION 29	Interval: --	Occurrences: --	Comments:	BSA should be capped at 2.3m2 for all drug-dosing
			Provider Communication
  	ONC PROVIDER COMMUNICATION 25	Interval: Until discontinued	Occurrences: --	Comments:	Sulfamethoxazole/Trimethoprim prophylaxis should be held prior to methotrexate and should not be restarted until methotrexate level is BELOW 0.05.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 5	Interval: Once	Occurrences: --	Comments:	Use baseline weight to calculate dose. Adjust dose for weight gains/losses of greater than or equal to 10%.
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: Once	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: Once	Occurrences: --		  	MAGNESIUM LEVEL	Interval: Once	Occurrences: --			Labs
  	PH, URINALYSIS	Interval: Every 8 hours	Occurrences: --	Comments:	Draw prior to starting Methotrexate and PRN until pH GREATER than 7.  Then draw urine pH every day until MTX is LESS than 0.05
			Nursing Orders
  	TREATMENT CONDITIONS 7	Interval: Once	Occurrences: --	Comments:	HOLD and notify provider if ANC LESS than 1000; Platelets LESS than 100,000.
			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: Once	Occurrences: --	Comments:	1) Obtain weight and height on date of admission. Obtain weight every 8 hours. 
2) Strict I&O's every 8 hours. 
3) Check urine output every 4 hours . 
4) Check Urine pH every 8 hours. 
5) NO carbonated beverages or fruit juices.
			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.			Pre-Hydration
  	sodium bicarbonate 150 mEq in dextrose 5% 1,000 mL infusion	Dose: 150 mL/hr	Route: intravenous	continuous	Start: S			Ingredients:	Name	Type	Dose	Selected	Adds Vol.	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	1,000 mL	Yes	Yes	DEXTROSE 10 % IN WATER (D10W) INTRAVENOUS SOLUTION	Base	1,000 mL	No	Yes	DEXTROSE 5 % AND 0.2 % SODIUM CHLORIDE INTRAVENOUS SOLUTION	Base	1,000 mL	No	Yes	DEXTROSE 5 % AND 0.45 % SODIUM CHLORIDE INTRAVENOUS SOLUTION	Base	1,000 mL	No	Yes	DEXTROSE 5 % AND 0.9 % SODIUM CHLORIDE INTRAVENOUS SOLUTION	Base	1,000 mL	No	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	1,000 mL	No	Yes	SODIUM CHLORIDE 0.45 % INTRAVENOUS SOLUTION	Base	1,000 mL	No	Yes	LACTATED RINGERS INTRAVENOUS SOLUTION	Base	1,000 mL	No	Yes	MVI,ADULT NO.4 WITH VIT K 3300 UNIT-150 MCG/10 ML INTRAVENOUS SOLUTION	Additives	10 mL	No	No	POTASSIUM CHLORIDE 2 MEQ/ML INTRAVENOUS SOLUTION	Additives	20 mEq	No	Yes	THIAMINE HCL (VITAMIN B1) 100 MG/ML INJECTION SOLUTION	Additives	100 mg	No	Yes	FOLIC ACID 5 MG/ML INJECTION SOLUTION	Additives	1 mg	No	Yes	MAGNESIUM SULFATE 500 MG/ML (50 %) INJECTION SOLUTION	Additives	 	No	Yes	CALCIUM GLUCONATE 100 MG/ML (10 %) INTRAVENOUS SOLUTION	Additives	 	No	Yes	PHYTONADIONE (VITAMIN K1) SUBCUTANEOUS	Additives	 	No	No	ASCORBIC ACID (VITAMIN C) 500 MG/ML INJECTION SOLUTION	Additives	500 mg	No	No	POTASSIUM ACETATE 2 MEQ/ML INTRAVENOUS SOLUTION	Additives	 	No	Yes	POTASSIUM PHOSPHATES-MBASIC AND DIBASIC 3 MMOL/ML INTRAVENOUS SOLUTION	Additives	 	No	Yes	SODIUM BICARBONATE 1 MEQ/ML (8.4 %) INTRAVENOUS SOLUTION	Additives	150 mEq	Yes	Yes	SODIUM PHOSPHATE 3 MMOL/ML INTRAVENOUS SOLUTION	Additives	 	No	Yes	SODIUM ACETATE 2 MEQ/ML INTRAVENOUS SOLUTION	Additives	 	No	Yes	ZINC SULFATE 1 MG/ML INTRAVENOUS SOLUTION	Additives	 	No	Yes	CYANOCOBALAMIN (VIT B-12) 1,000 MCG/ML INJECTION SOLUTION	Additives	 	No	Yes	SODIUM CHLORIDE 4 MEQ/ML INTRAVENOUS SOLUTION	Additives	 	No	Yes				Pre-Medications
  	fosaprepitant (EMEND) IVPB 150 mg	Dose: 150 mg	Route: intravenous	once over 30 Minutes for 1 dose	Start: S				  	ondansetron (ZOFRAN) 16 mg, dexamethasone (DECADRON) 12 mg in sodium chloride 0.9% 50 mL IVPB	Dose: 16 mg	Route: intravenous	once over 10 Minutes for 1 dose	Start: S			Ingredients:	Name	Type	Dose	Selected	Adds Vol.	ONDANSETRON HCL 2 MG/ML INTRAVENOUS SOLUTION	Medications	16 mg	Main Ingredient	No	DEXAMETHASONE SODIUM PHOSPHATE 10 MG/ML INJECTION SOLUTION	Medications	12 mg	Yes	No	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	50 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	50 mL	No	Yes				Nursing Orders
☑	ONC NURSING COMMUNICATION 10	Interval: Once	Occurrences: --	Comments:	Draw methotrexate level for 24 hours, 48 hours and 72 hours AFTER COMPLETION of methotrexate infusion and send STAT. Obtain level every 24 hours until methotrexate level is LESS than 0.05.

 Check STAT urine pH prior to starting Methotrexate and then every 8 hours. If urine pH is LESS than 7, administer 50 mEq sodium bicarbonate and recheck in 1 hour. If still LESS than 7, repeat 50 mEq sodium bicarbonate and recheck in 1 hour. If still LESS than 7, call provider. 

The syringe that the blood is sent to lab in needs to be COVERED (brown bag/paper towel) going to the lab.
			Medications
☐	furosemide (LASIX) injection 5 mg	Dose: 5 mg	Route: intravenous	once for 1 dose	Start: S	End: S  8:00 PM		Instructions:	Give if daily weight is GREATER THAN 0.5 kg above admission weight		☐	furosemide (LASIX) injection 10 mg	Dose: 10 mg	Route: intravenous	once for 1 dose	Start: S	End: S  8:00 PM		Instructions:	Give if daily weight is GREATER THAN 1.0 kg above admission weight		☐	furosemide (LASIX) injection 15 mg	Dose: 15 mg	Route: intravenous	once for 1 dose	Start: S	End: S  8:00 PM		Instructions:	Give if daily weight is GREATER THAN 1.5 kg above admission weight		☐	sodium bicarbonate tablet 3,250 mg	Dose: 3,250 mg	Route: oral	every 4 hours while awake	Start: S			Instructions:	Give until Methotrexate level is LESS THAN or EQUAL to 0.09 mmol			Provider Communication
  	ONC PROVIDER COMMUNICATION 20	Interval: Once	Occurrences: --	Comments:	Patient must have normal kidney function to receive this part of the protocol. If the current estimate creatinine clearance of a patient is GREATER than or EQUAL to 45mL/min but < 60mL/min, the dose of Methotrexate 2 g/m2IV in NS 500 ml over 2 hours should be administered. If the estimate creatinine clearance is below 45mL/min, do not administer methotrexate, wait a week and reexamine kidney function. If creatinine clearance is still below 45mL/min skip methotrexate and proceed to Step 3. Reducing the methotrexate dose to 2g/m2is also allowed if investigator suspects patient is expected to experience severe toxicity from the full dose.
		  	ONC PROVIDER COMMUNICATION 28	Interval: Until discontinued	Occurrences: --	Comments:	Please choose one of the following orders based on renal function (creatinine clearance):  
o For CrCl 45-60 mL/min, the methotrexate dose should be 2g/m2/dose.  
o For CrCl < 45 ml/min, HOLD methotrexate
			Chemotherapy
☑	methotrexate PF 3 g/m2 in sodium chloride 0.9% 500 mL chemo IVPB	Dose: 3 g/m2	Route: intravenous	once over 2 Hours for 1 dose	Start: S			Ingredients:	Name	Type	Dose	Selected	Adds Vol.	METHOTREXATE SODIUM (PF) 25 MG/ML INJECTION SOLUTION	Medications	3 g/m2	Main Ingredient	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	500 mL	No	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	500 mL	Yes	Yes			☑	methotrexate Preservative Free 2 g/m2 in sodium chloride 0.9% 500 mL chemo IVPB	Dose: 2 g/m2	Route: intravenous	once over 2 Hours for 1 dose	Start: S			Ingredients:	Name	Type	Dose	Selected	Adds Vol.	METHOTREXATE SODIUM (PF) 25 MG/ML INJECTION SOLUTION	Medications	2 g/m2	Main Ingredient	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	500 mL	No	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	500 mL	Yes	Yes				Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: Until discontinued	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 83	Interval: Until discontinued	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 4	Interval: Until discontinued	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	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	Start: S				  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					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.				Day 2	Perform every 1 day x1		Provider Communication
  	ONC PROVIDER COMMUNICATION 21	Interval: Once	Occurrences: --	Comments:	Guidelines at 24 hours: If methotrexate level is less than 10 umol/L continue leucovorin at current dosing. If methotrexate level is greater than 10 µmol/L at 24 hours or if creatinine increases greater than 50% of the pre- methotrexate level increase leucovorin to 100 mg/m2IV in 100 ml D5W every three hours until methotrexate level is less than 0.05 µmol/L.
		  	ONC PROVIDER COMMUNICATION 22	Interval: Once	Occurrences: --	Comments:	Guidelines at 48 hours: If methotrexate level is greater than 1 µmol/L at 48 hours or if creatinine increases greater than 50% of the pre- methotrexate level increase leucovorin to 100 mg/m2 IV in 100 ml D5W every three hours until methotrexate level is less than 0.05 µmol/L.
			Labs
  	BASIC METABOLIC PANEL	Interval: Once	Occurrences: --			Labs
  	METHOTREXATE LEVEL	Interval: Once	Occurrences: --	Comments:	Schedule MTX levels DAILY beginning EXACTLY 24 hours AFTER completion of MTX infusion until MTX level is LESS THAN 0.05 umol/L.
			Labs
  	PH, URINALYSIS	Interval: Every 8 hours	Occurrences: --	Comments:	Draw prior to starting Methotrexate and PRN until pH GREATER than 7.  Then draw urine pH every day until MTX is LESS than 0.05
			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.			Pre-Medications
  	ondansetron (ZOFRAN) IV 16 mg	Dose: 16 mg	Route: intravenous	once for 1 dose	Start: S					Nursing Orders
☑	ONC NURSING COMMUNICATION 10	Interval: Once	Occurrences: --	Comments:	Draw methotrexate level for 24 hours, 48 hours and 72 hours AFTER COMPLETION of methotrexate infusion and send STAT. Obtain level every 24 hours until methotrexate level is LESS than 0.05.

 Check STAT urine pH prior to starting Methotrexate and then every 8 hours. If urine pH is LESS than 7, administer 50 mEq sodium bicarbonate and recheck in 1 hour. If still LESS than 7, repeat 50 mEq sodium bicarbonate and recheck in 1 hour. If still LESS than 7, call provider. 

The syringe that the blood is sent to lab in needs to be COVERED (brown bag/paper towel) going to the lab.
			Medications
☐	furosemide (LASIX) injection 5 mg	Dose: 5 mg	Route: intravenous	once for 1 dose	Start: S	End: S  8:00 PM		Instructions:	Give if daily weight is GREATER THAN 0.5 kg above admission weight		☐	furosemide (LASIX) injection 10 mg	Dose: 10 mg	Route: intravenous	once for 1 dose	Start: S	End: S  8:00 PM		Instructions:	Give if daily weight is GREATER THAN 1.0 kg above admission weight		☐	furosemide (LASIX) injection 15 mg	Dose: 15 mg	Route: intravenous	once for 1 dose	Start: S	End: S  8:00 PM		Instructions:	Give if daily weight is GREATER THAN 1.5 kg above admission weight		☐	sodium bicarbonate tablet 3,250 mg	Dose: 3,250 mg	Route: oral	every 4 hours while awake	Start: S			Instructions:	Give until Methotrexate level is LESS THAN or EQUAL to 0.09 mmol			Supportive Care
  	leucovorin 10 mg/m2 in sodium chloride 0.9% 100 mL IVPB	Dose: 10 mg/m2	Route: intravenous	every 6 hours over 15 Minutes	Start: S			Instructions:	Start 22-24 hours after COMPLETION of methotrexate infusion and continue every 6 hours until methotrexate serum concentration is LESS than 0.05 micromol/L	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	LEUCOVORIN CALCIUM 350 MG SOLUTION FOR INJECTION	Medications	10 mg/m2	Main Ingredient	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	100 mL	Yes	Yes					Day 3	Perform every 1 day x1		Provider Communication
  	ONC PROVIDER COMMUNICATION 21	Interval: Once	Occurrences: --	Comments:	Guidelines at 24 hours: If methotrexate level is less than 10 umol/L continue leucovorin at current dosing. If methotrexate level is greater than 10 µmol/L at 24 hours or if creatinine increases greater than 50% of the pre- methotrexate level increase leucovorin to 100 mg/m2IV in 100 ml D5W every three hours until methotrexate level is less than 0.05 µmol/L.
		  	ONC PROVIDER COMMUNICATION 22	Interval: Once	Occurrences: --	Comments:	Guidelines at 48 hours: If methotrexate level is greater than 1 µmol/L at 48 hours or if creatinine increases greater than 50% of the pre- methotrexate level increase leucovorin to 100 mg/m2 IV in 100 ml D5W every three hours until methotrexate level is less than 0.05 µmol/L.
			Labs
  	BASIC METABOLIC PANEL	Interval: Once	Occurrences: --			Labs
  	METHOTREXATE LEVEL	Interval: Once	Occurrences: --	Comments:	Schedule MTX levels DAILY beginning EXACTLY 24 hours AFTER completion of MTX infusion until MTX level is LESS THAN 0.05 umol/L.
			Labs
  	PH, URINALYSIS	Interval: Every 8 hours	Occurrences: --	Comments:	Draw prior to starting Methotrexate and PRN until pH GREATER than 7.  Then draw urine pH every day until MTX is LESS than 0.05
			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 10	Interval: Once	Occurrences: --	Comments:	Draw methotrexate level for 24 hours, 48 hours and 72 hours AFTER COMPLETION of methotrexate infusion and send STAT. Obtain level every 24 hours until methotrexate level is LESS than 0.05.

 Check STAT urine pH prior to starting Methotrexate and then every 8 hours. If urine pH is LESS than 7, administer 50 mEq sodium bicarbonate and recheck in 1 hour. If still LESS than 7, repeat 50 mEq sodium bicarbonate and recheck in 1 hour. If still LESS than 7, call provider. 

The syringe that the blood is sent to lab in needs to be COVERED (brown bag/paper towel) going to the lab.
			Medications
☐	furosemide (LASIX) injection 5 mg	Dose: 5 mg	Route: intravenous	once for 1 dose	Start: S	End: S  8:00 PM		Instructions:	Give if daily weight is GREATER THAN 0.5 kg above admission weight		☐	furosemide (LASIX) injection 10 mg	Dose: 10 mg	Route: intravenous	once for 1 dose	Start: S	End: S  8:00 PM		Instructions:	Give if daily weight is GREATER THAN 1.0 kg above admission weight		☐	furosemide (LASIX) injection 15 mg	Dose: 15 mg	Route: intravenous	once for 1 dose	Start: S	End: S  8:00 PM		Instructions:	Give if daily weight is GREATER THAN 1.5 kg above admission weight		☐	sodium bicarbonate tablet 3,250 mg	Dose: 3,250 mg	Route: oral	every 4 hours while awake	Start: S			Instructions:	Give until Methotrexate level is LESS THAN or EQUAL to 0.09 mmol