Bortezomib and Sorafenib Tosylate in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

• ClinicalTrials.gov Identifier: NCT01371981
• Recruitment Status: Active, not recruiting
• First Posted: June 13, 2011
• Results First Posted: July 7, 2020
• Last Update Posted: July 7, 2020
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Acute Myeloid Leukemia; Leukemia Cutis; Myeloid Neoplasm; Myeloid Sarcoma
• Interventions: Drug: Asparaginase; Drug: Bortezomib; Drug: Cytarabine; Drug: Daunorubicin Hydrochloride; Drug: Etoposide; Other: Laboratory Biomarker Analysis; Drug: Mitoxantrone Hydrochloride; Other: Pharmacological Study; Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Drug: Sorafenib Tosylate
• Enrollment: 1645

Participant Flow

Recruitment Details
Pre-assignment Details	Results in the Participant Flow table summarize final (or analysis) arm assignment. Therefore, results for patients on Arms A, B, and D do not include any patient who transferred to Arm C.

Arm/Group Title	Arm A	Arm B	Arm C (Cohort 1)	Arm C (Cohort 2)	Arm C (Cohort 3)	Arm D
Arm/Group Description	INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days 1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days 2,9. SCT: pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis.	IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis.	IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year.	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INT I: Pts receive cytarabine IT and AE as in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year.	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO days 11-28. IND II: Pts receive cytarabine IT day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours days 1-5, sorafenib tosylate PO days 9-36. INT I: Pts receive cytarabine IT & AE as in Arm A, INT II, & sorafenib tosylate PO daily days 6-28. INT II: Pts receive cytarabine IT day 1, MA as in Arm A, IND II (HR patients), & sorafenib tosylate PO days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily days -5 to -2. Pts undergo allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for 1 year.	INDUCTION I: Patients with unknown FLT3/ITD status prior to study enrollment receive cytarabine IT and ADE chemotherapy as in Arm A, Induction I. If patients are determined to be HR FLT3/ITD+ no later than the end of Induction I they will be eligible to participate in Arm C.
Period Title: Overall Study
Started	580	591	12	33	47	382
Completed	396	399	6	12	15	368
Not Completed	184	192	6	21	32	14
Reason Not Completed
Adverse Event	12	17	0	4	1	0
Death	22	16	0	0	2	2
Lack of Efficacy	69	61	4	8	5	0
Physician Decision	48	63	1	7	14	3
Withdrawal by Subject	12	19	1	2	10	3
Ineligible	19	13	0	0	0	4
Did not start treatment	2	3	0	0	0	2

Baseline Characteristics

Arm/Group Title		Arm A	Arm B	Arm C (Cohort 1)	Arm C (Cohort 2)	Arm C (Cohort 3)	Arm D	Total
Arm/Group Description		INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis.	IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis.	IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year.	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year.	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO days 11-28. IND II: Pts receive cytarabine IT day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours days 1-5, sorafenib tosylate PO days 9-36. INT I: Pts receive cytarabine IT & AE as in Arm A, INT II, & sorafenib tosylate PO daily days 6-28. INT II: Pts receive cytarabine IT day 1, MA as in Arm A, IND II (HR patients), & sorafenib tosylate PO days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily days -5 to -2. Pts undergo allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for 1 year.	INDUCTION I: Patients with unknown FLT3/ITD status prior to study enrollment receive cytarabine IT and ADE chemotherapy as in Arm A, Induction I. If patients are determined to be HR FLT3/ITD+ no later than the end of Induction I they will be eligible to participate in Arm C.	Total of all reporting groups
Overall Number of Baseline Participants		580	591	12	33	47	382	1645
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	580 participants	591 participants	12 participants	33 participants	47 participants	382 participants	1645 participants
		9.5940 (6.6172)	9.4322 (6.6408)	11.7930 (4.9715)	12.4961 (5.0103)	11.7907 (5.0134)	9.1600 (6.6186)	9.5721 (6.5691)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	580 participants	591 participants	12 participants	33 participants	47 participants	382 participants	1645 participants
	Female	304 52.4%	305 51.6%	8 66.7%	18 54.5%	20 42.6%	203 53.1%	858 52.2%
	Male	276 47.6%	286 48.4%	4 33.3%	15 45.5%	27 57.4%	179 46.9%	787 47.8%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	580 participants	591 participants	12 participants	33 participants	47 participants	382 participants	1645 participants
	Hispanic or Latino	107 18.4%	106 17.9%	1 8.3%	5 15.2%	3 6.4%	80 20.9%	302 18.4%
	Not Hispanic or Latino	457 78.8%	465 78.7%	10 83.3%	28 84.8%	36 76.6%	273 71.5%	1269 77.1%
	Unknown or Not Reported	16 2.8%	20 3.4%	1 8.3%	0 0.0%	8 17.0%	29 7.6%	74 4.5%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	580 participants	591 participants	12 participants	33 participants	47 participants	382 participants	1645 participants
	American Indian or Alaska Native	3 0.5%	6 1.0%	0 0.0%	0 0.0%	1 2.1%	2 0.5%	12 0.7%
	Asian	27 4.7%	28 4.7%	0 0.0%	2 6.1%	1 2.1%	21 5.5%	79 4.8%
	Native Hawaiian or Other Pacific Islander	3 0.5%	6 1.0%	0 0.0%	0 0.0%	0 0.0%	4 1.0%	13 0.8%
	Black or African American	76 13.1%	70 11.8%	4 33.3%	3 9.1%	5 10.6%	40 10.5%	198 12.0%
	White	411 70.9%	413 69.9%	7 58.3%	27 81.8%	33 70.2%	257 67.3%	1148 69.8%
	More than one race	0 0.0%	1 0.2%	0 0.0%	0 0.0%	1 2.1%	6 1.6%	8 0.5%
	Unknown or Not Reported	60 10.3%	67 11.3%	1 8.3%	1 3.0%	6 12.8%	52 13.6%	187 11.4%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	580 participants	591 participants	12 participants	33 participants	47 participants	382 participants	1645 participants
United States		514	515	11	29	41	334	1444
Canada		31	43	1	3	5	24	107
Australia		23	29	0	1	1	15	69
New Zealand		12	4	0	0	0	9	25

Outcome Measures

1. Primary Outcome

Title	Event-free Survival (EFS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations
Description	The Kaplan-Meier method will be used to estimate 3-year EFS, defined as the time from study entry until induction failure, relapse, secondary malignancy, or death.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients ineligible, did not start treatment, or on Arm D are excluded from analyses of EFS. Arm D patients who were not eligible for Arm C by the end of induction I were declared off study per protocol; thus, no outcome data were collected for Arm D patients. Arms A and B are limited to patients without high allelic ratio FLT3/ITD+ mutations.

Arm/Group Title	Arm A	Arm B
Arm/Group Description:	INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis.	IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis.
Overall Number of Participants Analyzed	540	552
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of patients
	45.64; (41.34 to 49.83)	46.95; (42.69 to 51.09)

2. Primary Outcome

Title	EFS for Patients on Arm C, Cohort 1
Description	The Kaplan-Meier method will be used to estimate 3-year EFS, defined as the time from study entry until induction failure, relapse, secondary malignancy, or death.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients ineligible, did not start treatment, or on Arm D are excluded from analyses of EFS. Arm D patients who were not eligible for Arm C by the end of induction I were declared off study per protocol; thus, no outcome data were collected for Arm D patients.

Arm/Group Title	Arm C (Cohort 1)
Arm/Group Description:	IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year.
Overall Number of Participants Analyzed	12
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of patients
	25.00; (6.01 to 50.48)

3. Primary Outcome

Title	EFS for Patients on Arm C, Cohort 2
Description	The Kaplan-Meier method will be used to estimate 3-year EFS, defined as the time from study entry until induction failure, relapse, secondary malignancy, or death.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients ineligible, did not start treatment, or on Arm D are excluded from analyses of EFS. Arm D patients who were not eligible for Arm C by the end of induction I were declared off study per protocol; thus, no outcome data were collected for Arm D patients.

Arm/Group Title	Arm C (Cohort 2)
Arm/Group Description:	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year.
Overall Number of Participants Analyzed	33
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of patients
	56.12; (37.33 to 71.28)

4. Primary Outcome

Title	EFS for Patients on Arm C, Cohort 3
Description	The Kaplan-Meier method will be used to estimate 3-year EFS, defined as the time from study entry until induction failure, relapse, secondary malignancy, or death.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients ineligible, did not start treatment, or on Arm D are excluded from analyses of EFS. Arm D patients who were not eligible for Arm C by the end of induction I were declared off study per protocol; thus, no outcome data were collected for Arm D patients.

Arm/Group Title	Arm C (Cohort 3)
Arm/Group Description:	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO days 11-28. IND II: Pts receive cytarabine IT day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours days 1-5, sorafenib tosylate PO days 9-36. INT I: Pts receive cytarabine IT & AE as in Arm A, INT II, & sorafenib tosylate PO daily days 6-28. INT II: Pts receive cytarabine IT day 1, MA as in Arm A, IND II (HR patients), & sorafenib tosylate PO days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily days -5 to -2. Pts undergo allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for 1 year.
Overall Number of Participants Analyzed	47
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of patients
	58.18; (42.30 to 71.11)

5. Secondary Outcome

Title	Overall Survival (OS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations
Description	The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients ineligible, did not start treatment, or on Arm D are excluded from analyses of OS. Arm D patients who were not eligible for Arm C by the end of induction I were declared off study per protocol; thus, no outcome data were collected for Arm D patients. Arms A and B are limited to patients without high allelic ratio FLT3/ITD+ mutations.

Arm/Group Title	Arm A	Arm B
Arm/Group Description:	INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis.	IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis.
Overall Number of Participants Analyzed	540	552
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of patients
	65.04; (60.75 to 68.98)	68.45; (64.33 to 72.21)

6. Secondary Outcome

Title	OS for Patients on Arm C, Cohort 1
Description	The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients ineligible, did not start treatment, or on Arm D are excluded from analyses of OS. Arm D patients who were not eligible for Arm C by the end of induction I were declared off study per protocol; thus, no outcome data were collected for Arm D patients.

Arm/Group Title	Arm C (Cohort 1)
Arm/Group Description:	IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year.
Overall Number of Participants Analyzed	12
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of patients
	41.67; (15.25 to 66.53)

7. Secondary Outcome

Title	OS for Patients on Arm C, Cohort 2
Description	The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients ineligible, did not start treatment, or on Arm D are excluded from analyses of OS. Arm D patients who were not eligible for Arm C by the end of induction I were declared off study per protocol; thus, no outcome data were collected for Arm D patients.

Arm/Group Title	Arm C (Cohort 2)
Arm/Group Description:	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year.
Overall Number of Participants Analyzed	33
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of patients
	64.77; (45.37 to 78.77)

8. Secondary Outcome

Title	OS for Patients on Arm C, Cohort 3
Description	The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients ineligible, did not start treatment, or on Arm D are excluded from analyses of OS. Arm D patients who were not eligible for Arm C by the end of induction I were declared off study per protocol; thus, no outcome data were collected for Arm D patients.

Arm/Group Title	Arm C (Cohort 3)
Arm/Group Description:	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO days 11-28. IND II: Pts receive cytarabine IT day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours days 1-5, sorafenib tosylate PO days 9-36. INT I: Pts receive cytarabine IT & AE as in Arm A, INT II, & sorafenib tosylate PO daily days 6-28. INT II: Pts receive cytarabine IT day 1, MA as in Arm A, IND II (HR patients), & sorafenib tosylate PO days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily days -5 to -2. Pts undergo allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for 1 year.
Overall Number of Participants Analyzed	47
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of patients
	61.84; (44.09 to 75.42)

9. Secondary Outcome

Title	Relapse Rate for Patients Without High Allelic Ratio FLT3/ITD+ Mutations
Description	Cumulative incidence estimates 3 year relapse rate defined as time from study entry to induction failure or relapse where deaths or secondary malignancies are competing events.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Patients ineligible, did not start treatment, or on Arms C or D are excluded. Arm D patients who were not eligible for Arm C by the end of induction I were declared off study per protocol; thus, no outcome data were collected for Arm D patients. Results are limited to patients on Arms A and B without high allelic ratio FLT3/ITD+ mutations.

Arm/Group Title	Arm A	Arm B
Arm/Group Description:	INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis.	IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis.
Overall Number of Participants Analyzed	540	552
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of patients
	46.67; (42.36 to 50.86)	46.65; (42.39 to 50.80)

10. Secondary Outcome

Title	Proportion of Patients Experiencing Grade 3 or Higher Non-hematologic Toxicities and Infections While on Protocol Therapy
Description	The proportion of patients experiencing at least one grade 3 or higher non-hematologic toxicity and infection while on protocol therapy will be estimated along with the corresponding 95% confidence interval determined using a binomial exact method. Toxicity will be assessed by Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Patients ineligible or who did not start treatment are excluded from results.

Arm/Group Title	Arm A	Arm B	Arm C (Cohort 1)	Arm C (Cohort 2)	Arm C (Cohort 3)	Arm D
Arm/Group Description:	INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis.	IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis.	IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year.	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year.	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO days 11-28. IND II: Pts receive cytarabine IT day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours days 1-5, sorafenib tosylate PO days 9-36. INT I: Pts receive cytarabine IT & AE as in Arm A, INT II, & sorafenib tosylate PO daily days 6-28. INT II: Pts receive cytarabine IT day 1, MA as in Arm A, IND II (HR patients), & sorafenib tosylate PO days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily days -5 to -2. Pts undergo allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for 1 year.	INDUCTION I: Patients with unknown FLT3/ITD status prior to study enrollment receive cytarabine IT and ADE chemotherapy as in Arm A, Induction I. If patients are determined to be HR FLT3/ITD+ no later than the end of Induction I they will be eligible to participate in Arm C.
Overall Number of Participants Analyzed	559	575	12	33	47	376
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Proportion of patients
	0.8819; (0.8522 to 0.9075)	0.9217; (0.8967 to 0.9423)	0.9167; (0.6152 to 0.9979)	0.9394; (0.7977 to 0.9926)	0.9149; (0.7962 to 0.9763)	0.0239; (0.0110 to 0.0450)

11. Secondary Outcome

Title	Proportion of High Risk Children Without HR FLT3/ITD+ Converting From Positive MRD at End of Induction I to Negative MRD at the End of Induction II
Description	The proportion of high risk children without HR FLT3/ITD+ converting from positive MRD at end of Induction I to negative MRD at the end of Induction II will be estimated as well as the corresponding 95% confidence interval determined using a binomial exact method.
Time Frame	Up to 8 weeks

Outcome Measure Data

Analysis Population Description

Patients ineligible, did not start treatment, on Arms C, D are excluded from results. Complete MRD results were not collected for Arm D patients due to being declared off study at end of induction I. Results limited to High Risk patients without high allelic ratio FLT3/ITD+ mutations and with evaluable MRD data from end of Induction I and II.

Arm/Group Title	Arm A	Arm B
Arm/Group Description:	INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis.	IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis.
Overall Number of Participants Analyzed	76	84
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Proportion of patients
	0.5000; (0.3830 to 0.6170)	0.5238; (0.4119 to 0.6340)

12. Secondary Outcome

Title	Total Scale Score From Parent-reported Pediatric Quality of Life Inventory Module
Description	Results represent the total scale scores from the parent report of the PedsQL™ 4.0 Generic Core Scales for timepoint 1 (up to 14 days from start of therapy). Items are reverse-scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. Therefore, a higher number is a better outcome. The total score is the sum of all the items divided by the number of items answered on all the scales. "Scores on a scale" is used for a unit of measure.
Time Frame	Up to 14 days

Outcome Measure Data

Analysis Population Description

Patients ineligible or who did not start treatment are excluded from results. Patients on Arms C (cohort 3) or Arm D are excluded due to enrolling post quality of life study accrual completion. Results are limited to only patients with an evaluable total scale score.

Arm/Group Title	Arm A	Arm B	Arm C (Cohort 1)	Arm C (Cohort 2)
Arm/Group Description:	INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis.	IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis.	IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year.	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year.
Overall Number of Participants Analyzed	228	195	8	16
Mean (Inter-Quartile Range); Unit of Measure: Scores on a scale
	68.3; (55.7 to 81.5)	67.8; (52.2 to 83.7)	71.3; (58.7 to 87.5)	61.6; (46.2 to 81.0)

13. Secondary Outcome

Title	Total Scale Score From Parent-reported Cancer Module
Description	Results represent the total scale scores from the parent report of the PedsQL™ 3.0 Cancer Module for timepoint 1 (up to 14 days from start of therapy). Items are reverse-scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. Therefore, a higher number is a better outcome. The total score is the sum of all the items divided by the number of items answered on all the scales. "Scores on a scale" is used for a unit of measure.
Time Frame	Up to 14 days

Outcome Measure Data

Analysis Population Description

Patients ineligible or who did not start treatment are excluded from results. Patients on Arms C (cohort 3) or Arm D are excluded due to enrolling post quality of life study accrual completion. Results are limited to only patients with an evaluable total scale score.

Arm/Group Title	Arm A	Arm B	Arm C (Cohort 1)	Arm C (Cohort 2)
Arm/Group Description:	INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis.	IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis.	IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year.	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year.
Overall Number of Participants Analyzed	230	193	8	16
Mean (Inter-Quartile Range); Unit of Measure: Scores on a scale
	66.2; (53.7 to 78.7)	65.8; (53.7 to 77.9)	74.9; (69.0 to 81.7)	63.7; (56.9 to 74.0)

14. Secondary Outcome

Title	Total Scale Score From Parent-reported Multidimensional Fatigue Scale Module
Description	Results represent the total scale scores from the parent report of the PedsQL™ Multidimensional Fatigue Scale for timepoint 1 (up to 14 days from start of therapy). Items are reverse-scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. Therefore, a higher number is a better outcome. The total score is the sum of all the items divided by the number of items answered on all the scales. "Scores on a scale" is used for a unit of measure.
Time Frame	Up to 14 days

Outcome Measure Data

Analysis Population Description

Patients ineligible or who did not start treatment are excluded from results. Patients on Arms C (cohort 3) or Arm D are excluded due to enrolling post quality of life study accrual completion. Results are limited to only patients with an evaluable total scale score.

Arm/Group Title	Arm A	Arm B	Arm C (Cohort 1)	Arm C (Cohort 2)
Arm/Group Description:	INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis.	IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis.	IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year.	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year.
Overall Number of Participants Analyzed	226	194	8	16
Mean (Inter-Quartile Range); Unit of Measure: Scores on a scale
	60.5; (45.8 to 75.0)	58.1; (44.4 to 73.6)	71.2; (52.8 to 87.5)	48.2; (30.6 to 64.6)

15. Secondary Outcome

Title	Bortezomib Clearance
Description	Median and range of bortezomib clearance during Induction II.
Time Frame	Day 8 of Induction II

Outcome Measure Data

Analysis Population Description

Only eligible patients on Arm B with evaluable Bortezomib PK clearance data during Induction II are reported.

Arm/Group Title	Arm B
Arm/Group Description:	IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis.
Overall Number of Participants Analyzed	53
Median (Full Range); Unit of Measure: Liters/hour/m^2
	8.42; (3.52 to 12.70)

16. Secondary Outcome

Title	Sorafenib Steady State Concentration
Description	Median and range of sorafenib steady state concentration for Induction I.
Time Frame	Up to 30 days

Outcome Measure Data

Analysis Population Description

Data reported from Arm C were collected and analyzed regardless of the cohort as pre-specified in the study protocol. Only eligible patients on Arm C with evaluable Sorafenib steady state concentration data during Induction I are reported.

Arm/Group Title	Arm C
Arm/Group Description:	Arm C (Cohort 1) IND II:cytarabine IT; cytarabine IV; daunorubicin hydrochloride IV; etoposide IV; sorafenib tosylate PO INT I:cytarabine IT; AE chemotherapy as Arm A, Intensification II; sorafenib tosylate PO INT II:cytarabine IT; MA chemotherapy as Arm A, Induction II (HR patients); sorafenib tosylate PO. SCT (HR pts w/ matched family [MFD] or unrelated donor): fludarabine phosphate IV; busulfan IV; allogeneic SCT; GVHD prophylaxis. MAINTENANCE:sorafenib tosylate PO Arm C (Cohort 2 and 3) IND I:cytarabine IT; ADE as Arm A, IND I; sorafenib tosylate PO IND II:cytarabine IT; cytarabine IV; daunorubicin hydrochloride IV; etoposide IV; sorafenib tosylate PO INT I:cytarabine IT; AE as Arm A, INT II, & sorafenib tosylate PO INT II:cytarabine IT; MA as Arm A, IND II (HR patients); sorafenib tosylate PO. SCT (HR pts w/ matched family [MFD] or unrelated donor): fludarabine phosphate IV; busulfan IV; allogeneic SCT; GVHD prophylaxis. MAINTENANCE:sorafenib tosylate PO
Overall Number of Participants Analyzed	23
Median (Full Range); Unit of Measure: Nanogram/Milliliter
	1090.0; (290.0 to 4740.0)

17. Secondary Outcome

Title	Change in Shortening Fraction
Description	Mean percentage change in shortening fraction from baseline to the end of Induction I will be determined for eligible patients enrolled on Arms A, B and C.
Time Frame	Up to 4 weeks

Outcome Measure Data

Analysis Population Description

Patients ineligible, did not start treatment, or on Arm D are excluded from results. Shortening fraction data were not collected at end of Induction I for patients enrolled to Arm D. Results are limited to patients with evaluable shortening fraction data from study entry and at end of Induction I .

Arm/Group Title	Arm A	Arm B	Arm C (Cohort 1)	Arm C (Cohort 2)	Arm C (Cohort 3)
Arm/Group Description:	INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis.	IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis.	IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year.	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year.	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO days 11-28. IND II: Pts receive cytarabine IT day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours days 1-5, sorafenib tosylate PO days 9-36. INT I: Pts receive cytarabine IT & AE as in Arm A, INT II, & sorafenib tosylate PO daily days 6-28. INT II: Pts receive cytarabine IT day 1, MA as in Arm A, IND II (HR patients), & sorafenib tosylate PO days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily days -5 to -2. Pts undergo allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for 1 year.
Overall Number of Participants Analyzed	499	503	9	32	41
Mean (Standard Error); Unit of Measure: Percentage change
	-1.8445 (5.2070)	-2.6298 (6.7797)	-2.2333 (4.7689)	-3.6700 (5.3115)	-3.4246 (4.8583)

18. Secondary Outcome

Title	Change in Ejection Fraction
Description	The mean percentage change in ejection fraction from baseline to the end of Induction I will be determined for eligible patients enrolled on Arms A, B and C.
Time Frame	Up to 4 weeks

Outcome Measure Data

Analysis Population Description

Patients ineligible, did not start treatment, or on Arm D are excluded from results. Ejection fraction data were not collected at end of Induction I for patients enrolled to Arm D. Results are limited to patients with evaluable ejection fraction data from study entry and at end of Induction I .

Arm/Group Title	Arm A	Arm B	Arm C (Cohort 1)	Arm C (Cohort 2)	Arm C (Cohort 3)
Arm/Group Description:	INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis.	IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis.	IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year.	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year.	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO days 11-28. IND II: Pts receive cytarabine IT day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours days 1-5, sorafenib tosylate PO days 9-36. INT I: Pts receive cytarabine IT & AE as in Arm A, INT II, & sorafenib tosylate PO daily days 6-28. INT II: Pts receive cytarabine IT day 1, MA as in Arm A, IND II (HR patients), & sorafenib tosylate PO days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily days -5 to -2. Pts undergo allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for 1 year.
Overall Number of Participants Analyzed	426	425	6	30	38
Mean (Standard Deviation); Unit of Measure: Percentage change
	-2.0272 (7.1843)	-2.3453 (7.6974)	-7.5000 (12.5340)	-5.1997 (7.0532)	-3.4624 (6.7516)

19. Secondary Outcome

Title	Serum Concentrations of GVHD Biomarker
Description	The mean serum concentration of the day 28 GVHD biomarker will be estimated as well as the corresponding 95% confidence interval.
Time Frame	Up to day 28 after SCT

Outcome Measure Data

Analysis Population Description

Data were never collected

Arm/Group Title	Arm A	Arm B	Arm C (Cohort 1)	Arm C (Cohort 2)	Arm C (Cohort 3)
Arm/Group Description:	INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis.	IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis.	IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year.	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year.	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO days 11-28. IND II: Pts receive cytarabine IT day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours days 1-5, sorafenib tosylate PO days 9-36. INT I: Pts receive cytarabine IT & AE as in Arm A, INT II, & sorafenib tosylate PO daily days 6-28. INT II: Pts receive cytarabine IT day 1, MA as in Arm A, IND II (HR patients), & sorafenib tosylate PO days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily days -5 to -2. Pts undergo allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for 1 year.
Overall Number of Participants Analyzed	0	0	0	0	0

No data displayed because Outcome Measure has zero total analyzed.

20. Other Pre-specified Outcome

Title	Course Duration
Description	Descriptive statistics will be used to summarize length of hospitalization time.
Time Frame	Up to 6 months

Outcome Measure Data Not Reported

21. Other Pre-specified Outcome

Title	Incidence of Treatment-related Mortality
Description	Cumulative incidence estimates that account for competing events will be used to estimate treatment-related mortality.
Time Frame	Up to 2 years

Outcome Measure Data Not Reported

22. Other Pre-specified Outcome

Title	Length of Hospitalization
Description	Descriptive statistics will be used to summarize length of hospitalization time.
Time Frame	Up to 6 months

Outcome Measure Data Not Reported

23. Other Pre-specified Outcome

Title	Remission Rate After 1 Course of Therapy
Description	The proportion of patients achieving remission after 1 course of therapy will be estimated along with a corresponding 95% confidence interval.
Time Frame	4 weeks

Outcome Measure Data Not Reported

24. Other Pre-specified Outcome

Title	Remission Rate After 2 Courses of Therapy
Description	The proportion of patients achieving remission after 2 courses of therapy will be estimated along with a corresponding 95% confidence interval.
Time Frame	8 weeks

Outcome Measure Data Not Reported

25. Other Pre-specified Outcome

Title	Time to Blood Count Recovery
Description	Cumulative incidence estimates that account for competing events will be used to estimate time to count recovery.
Time Frame	Up to 6 months

Outcome Measure Data Not Reported

Adverse Events

Time Frame	While patients were on protocol therapy (including up to 4 courses, stem cell transplant course, and 3 courses of maintenance therapy)) or up to 7 years in follow-up.
Adverse Event Reporting Description	Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.
Arm/Group Title	Arm A	Arm B	Arm C (Cohort 1)	Arm C (Cohort 2)	Arm C (Cohort 3)	Arm D
Arm/Group Description	INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis.	IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis.	IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year.	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year.	IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO days 11-28. IND II: Pts receive cytarabine IT day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours days 1-5, sorafenib tosylate PO days 9-36. INT I: Pts receive cytarabine IT & AE cin Arm A, INT II, & sorafenib tosylate PO daily days 6-28. INT II: Pts receive cytarabine IT day 1, MA as in Arm A, IND II (HR patients), & sorafenib tosylate PO days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily days -5 to -2. Pts undergo allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for 1 year.	INDUCTION I: Patients with unknown FLT3/ITD status prior to study enrollment receive cytarabine IT and ADE chemotherapy as in Arm A, Induction I. If patients are determined to be HR FLT3/ITD+ no later than the end of Induction I they will be eligible to participate in Arm C.
All-Cause Mortality
	Arm A	Arm B	Arm C (Cohort 1)	Arm C (Cohort 2)	Arm C (Cohort 3)	Arm D
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	198/559 (35.42%)	189/575 (32.87%)	7/12 (58.33%)	11/33 (33.33%)	16/47 (34.04%)	2/376 (0.53%)
Serious Adverse Events
	Arm A	Arm B	Arm C (Cohort 1)	Arm C (Cohort 2)	Arm C (Cohort 3)	Arm D
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	82/559 (14.67%)	305/575 (53.04%)	6/12 (50.00%)	16/33 (48.48%)	30/47 (63.83%)	2/376 (0.53%)
Blood and lymphatic system disorders
Anemia † [1]	0/559 (0.00%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Blood and lymphatic system disorders - Other, specify † [1]	1/559 (0.18%)	4/575 (0.70%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Bone marrow hypocellular † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Disseminated intravascular coagulation † [1]	3/559 (0.54%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Febrile neutropenia † [1]	0/559 (0.00%)	21/575 (3.65%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Hemolysis † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hemolytic uremic syndrome † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Leukocytosis † [1]	0/559 (0.00%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Cardiac disorders
Asystole † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Atrial fibrillation † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Atrial flutter † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Cardiac arrest † [1]	3/559 (0.54%)	4/575 (0.70%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Cardiac disorders - Other, specify † [1]	0/559 (0.00%)	7/575 (1.22%)	0/12 (0.00%)	1/33 (3.03%)	2/47 (4.26%)	0/376 (0.00%)
Chest pain - cardiac † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Heart failure † [1]	4/559 (0.72%)	15/575 (2.61%)	0/12 (0.00%)	1/33 (3.03%)	2/47 (4.26%)	0/376 (0.00%)
Left ventricular systolic dysfunction † [1]	3/559 (0.54%)	23/575 (4.00%)	0/12 (0.00%)	2/33 (6.06%)	4/47 (8.51%)	0/376 (0.00%)
Myocardial infarction † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Pericardial effusion † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Pericarditis † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Restrictive cardiomyopathy † [1]	0/559 (0.00%)	4/575 (0.70%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Right ventricular dysfunction † [1]	2/559 (0.36%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Sinus bradycardia † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Sinus tachycardia † [1]	0/559 (0.00%)	10/575 (1.74%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Supraventricular tachycardia † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Ventricular arrhythmia † [1]	0/559 (0.00%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Ventricular fibrillation † [1]	1/559 (0.18%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Ventricular tachycardia † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Endocrine disorders
Adrenal insufficiency † [1]	0/559 (0.00%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Endocrine disorders - Other, specify † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hypothyroidism † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Eye disorders
Eye disorders - Other, specify † [1]	1/559 (0.18%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Optic nerve disorder † [1]	0/559 (0.00%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Papilledema † [1]	0/559 (0.00%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Gastrointestinal disorders
Abdominal distension † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Abdominal pain † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Anal pain † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Ascites † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Colitis † [1]	0/559 (0.00%)	9/575 (1.57%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Colonic perforation † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Diarrhea † [1]	0/559 (0.00%)	9/575 (1.57%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Enterocolitis † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Esophagitis † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Gastric hemorrhage † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Gastritis † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Gastrointestinal disorders - Other, specify † [1]	0/559 (0.00%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Ileus † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	1/33 (3.03%)	1/47 (2.13%)	0/376 (0.00%)
Lower gastrointestinal hemorrhage † [1]	0/559 (0.00%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Mucositis oral † [1]	0/559 (0.00%)	3/575 (0.52%)	1/12 (8.33%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Nausea † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Oral pain † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Pancreatitis † [1]	0/559 (0.00%)	8/575 (1.39%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Small intestinal obstruction † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Typhlitis † [1]	2/559 (0.36%)	24/575 (4.17%)	0/12 (0.00%)	1/33 (3.03%)	1/47 (2.13%)	0/376 (0.00%)
Upper gastrointestinal hemorrhage † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Vomiting † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
General disorders
Chills † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Death NOS † [1]	38/559 (6.80%)	35/575 (6.09%)	1/12 (8.33%)	5/33 (15.15%)	6/47 (12.77%)	0/376 (0.00%)
Edema face † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Fever † [1]	0/559 (0.00%)	13/575 (2.26%)	0/12 (0.00%)	0/33 (0.00%)	3/47 (6.38%)	0/376 (0.00%)
Gait disturbance † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hypothermia † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Multi-organ failure † [1]	1/559 (0.18%)	8/575 (1.39%)	0/12 (0.00%)	0/33 (0.00%)	2/47 (4.26%)	0/376 (0.00%)
Non-cardiac chest pain † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Pain † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hepatobiliary disorders
Bile duct stenosis † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Cholecystitis † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Hepatic failure † [1]	2/559 (0.36%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hepatobiliary disorders - Other, specify † [1]	0/559 (0.00%)	4/575 (0.70%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Immune system disorders
Allergic reaction † [1]	1/559 (0.18%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Anaphylaxis † [1]	0/559 (0.00%)	5/575 (0.87%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Immune system disorders - Other, specify † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Infections and infestations
Anorectal infection † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Appendicitis † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Bladder infection † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Bronchial infection † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Catheter related infection † [1]	0/559 (0.00%)	5/575 (0.87%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Cecal infection † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Duodenal infection † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Encephalitis infection † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Enterocolitis infectious † [1]	1/559 (0.18%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Esophageal infection † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Infections and infestations - Other, specify † [1]	2/559 (0.36%)	13/575 (2.26%)	0/12 (0.00%)	2/33 (6.06%)	0/47 (0.00%)	0/376 (0.00%)
Lung infection † [1]	1/559 (0.18%)	13/575 (2.26%)	1/12 (8.33%)	2/33 (6.06%)	0/47 (0.00%)	0/376 (0.00%)
Lymph gland infection † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Meningitis † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Mucosal infection † [1]	0/559 (0.00%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Periorbital infection † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Sepsis † [1]	17/559 (3.04%)	50/575 (8.70%)	0/12 (0.00%)	1/33 (3.03%)	4/47 (8.51%)	0/376 (0.00%)
Skin infection † [1]	0/559 (0.00%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Soft tissue infection † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Tracheitis † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Upper respiratory infection † [1]	1/559 (0.18%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Urinary tract infection † [1]	1/559 (0.18%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Injury, poisoning and procedural complications
Infusion related reaction † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Postoperative hemorrhage † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Vascular access complication † [1]	0/559 (0.00%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Investigations
Activated partial thromboplastin time prolonged † [1]	0/559 (0.00%)	4/575 (0.70%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Alanine aminotransferase increased † [1]	0/559 (0.00%)	16/575 (2.78%)	0/12 (0.00%)	0/33 (0.00%)	2/47 (4.26%)	0/376 (0.00%)
Aspartate aminotransferase increased † [1]	1/559 (0.18%)	10/575 (1.74%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Blood bilirubin increased † [1]	2/559 (0.36%)	16/575 (2.78%)	0/12 (0.00%)	1/33 (3.03%)	1/47 (2.13%)	0/376 (0.00%)
Carbon monoxide diffusing capacity decreased † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Creatinine increased † [1]	0/559 (0.00%)	8/575 (1.39%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Ejection fraction decreased † [1]	2/559 (0.36%)	18/575 (3.13%)	0/12 (0.00%)	2/33 (6.06%)	4/47 (8.51%)	0/376 (0.00%)
Electrocardiogram QT corrected interval prolonged † [1]	1/559 (0.18%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Fibrinogen decreased † [1]	1/559 (0.18%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
GGT increased † [1]	0/559 (0.00%)	4/575 (0.70%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Investigations - Other, specify † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Lipase increased † [1]	0/559 (0.00%)	4/575 (0.70%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Lymphocyte count decreased † [1]	0/559 (0.00%)	5/575 (0.87%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Neutrophil count decreased † [1]	0/559 (0.00%)	8/575 (1.39%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Platelet count decreased † [1]	0/559 (0.00%)	7/575 (1.22%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Serum amylase increased † [1]	0/559 (0.00%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Urine output decreased † [1]	1/559 (0.18%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Weight loss † [1]	0/559 (0.00%)	0/575 (0.00%)	0/12 (0.00%)	1/33 (3.03%)	1/47 (2.13%)	0/376 (0.00%)
White blood cell decreased † [1]	0/559 (0.00%)	5/575 (0.87%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Metabolism and nutrition disorders
Acidosis † [1]	0/559 (0.00%)	4/575 (0.70%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Alkalosis † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Anorexia † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Dehydration † [1]	0/559 (0.00%)	3/575 (0.52%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Hypercalcemia † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hyperglycemia † [1]	1/559 (0.18%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hyperkalemia † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Hypernatremia † [1]	2/559 (0.36%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Hypertriglyceridemia † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hypoalbuminemia † [1]	0/559 (0.00%)	6/575 (1.04%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Hypocalcemia † [1]	0/559 (0.00%)	8/575 (1.39%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hypokalemia † [1]	1/559 (0.18%)	27/575 (4.70%)	0/12 (0.00%)	2/33 (6.06%)	1/47 (2.13%)	0/376 (0.00%)
Hypomagnesemia † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hyponatremia † [1]	0/559 (0.00%)	10/575 (1.74%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hypophosphatemia † [1]	1/559 (0.18%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Metabolism and nutrition disorders - Other, specify † [1]	2/559 (0.36%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Tumor lysis syndrome † [1]	1/559 (0.18%)	3/575 (0.52%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Back pain † [1]	0/559 (0.00%)	4/575 (0.70%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Neck pain † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Pain in extremity † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify † [1]	2/559 (0.36%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	1/376 (0.27%)
Nervous system disorders
Ataxia † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Central nervous system necrosis † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Cerebrospinal fluid leakage † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Cognitive disturbance † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Depressed level of consciousness † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Dizziness † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Dysesthesia † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Edema cerebral † [1]	1/559 (0.18%)	4/575 (0.70%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Encephalopathy † [1]	1/559 (0.18%)	5/575 (0.87%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Headache † [1]	0/559 (0.00%)	4/575 (0.70%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hydrocephalus † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hypersomnia † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Intracranial hemorrhage † [1]	2/559 (0.36%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	1/376 (0.27%)
Leukoencephalopathy † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Nervous system disorders - Other, specify † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Neuralgia † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Paresthesia † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Peripheral sensory neuropathy † [1]	0/559 (0.00%)	14/575 (2.43%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Reversible posterior leukoencephalopathy syndrome † [1]	0/559 (0.00%)	4/575 (0.70%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Seizure † [1]	1/559 (0.18%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Somnolence † [1]	0/559 (0.00%)	4/575 (0.70%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Syncope † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Psychiatric disorders
Agitation † [1]	0/559 (0.00%)	2/575 (0.35%)	1/12 (8.33%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Anxiety † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Delirium † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Renal and urinary disorders
Acute kidney injury † [1]	5/559 (0.89%)	15/575 (2.61%)	0/12 (0.00%)	3/33 (9.09%)	3/47 (6.38%)	0/376 (0.00%)
Cystitis noninfective † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hematuria † [1]	0/559 (0.00%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Proteinuria † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Renal and urinary disorders - Other, specify † [1]	1/559 (0.18%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome † [1]	3/559 (0.54%)	15/575 (2.61%)	0/12 (0.00%)	2/33 (6.06%)	0/47 (0.00%)	0/376 (0.00%)
Apnea † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Aspiration † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Atelectasis † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Bronchopulmonary hemorrhage † [1]	3/559 (0.54%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Bronchospasm † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Cough † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Dyspnea † [1]	1/559 (0.18%)	12/575 (2.09%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Epistaxis † [1]	0/559 (0.00%)	7/575 (1.22%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Hypoxia † [1]	3/559 (0.54%)	55/575 (9.57%)	1/12 (8.33%)	3/33 (9.09%)	3/47 (6.38%)	0/376 (0.00%)
Laryngeal edema † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Laryngeal mucositis † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Mediastinal hemorrhage † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Pharyngeal mucositis † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Pleural effusion † [1]	0/559 (0.00%)	8/575 (1.39%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Pneumonitis † [1]	0/559 (0.00%)	9/575 (1.57%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Productive cough † [1]	0/559 (0.00%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Pulmonary edema † [1]	3/559 (0.54%)	12/575 (2.09%)	0/12 (0.00%)	0/33 (0.00%)	2/47 (4.26%)	0/376 (0.00%)
Pulmonary hypertension † [1]	1/559 (0.18%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Respiratory failure † [1]	10/559 (1.79%)	22/575 (3.83%)	0/12 (0.00%)	2/33 (6.06%)	2/47 (4.26%)	0/376 (0.00%)
Respiratory, thoracic and mediastinal disorders - Other, specify † [1]	1/559 (0.18%)	6/575 (1.04%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Sore throat † [1]	0/559 (0.00%)	1/575 (0.17%)	1/12 (8.33%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Stridor † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Tracheal mucositis † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Wheezing † [1]	0/559 (0.00%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Skin and subcutaneous tissue disorders
Erythroderma † [1]	0/559 (0.00%)	0/575 (0.00%)	1/12 (8.33%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Pain of skin † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Palmar-plantar erythrodysesthesia syndrome † [1]	0/559 (0.00%)	1/575 (0.17%)	1/12 (8.33%)	1/33 (3.03%)	1/47 (2.13%)	0/376 (0.00%)
Pruritus † [1]	0/559 (0.00%)	1/575 (0.17%)	1/12 (8.33%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Rash maculo-papular † [1]	0/559 (0.00%)	10/575 (1.74%)	1/12 (8.33%)	2/33 (6.06%)	3/47 (6.38%)	0/376 (0.00%)
Skin and subcutaneous tissue disorders - Other, specify † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Toxic epidermal necrolysis † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Urticaria † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Vascular disorders
Capillary leak syndrome † [1]	0/559 (0.00%)	5/575 (0.87%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Flushing † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hypertension † [1]	0/559 (0.00%)	10/575 (1.74%)	0/12 (0.00%)	1/33 (3.03%)	1/47 (2.13%)	0/376 (0.00%)
Hypotension † [1]	7/559 (1.25%)	47/575 (8.17%)	1/12 (8.33%)	3/33 (9.09%)	3/47 (6.38%)	0/376 (0.00%)
Peripheral ischemia † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Thromboembolic event † [1]	3/559 (0.54%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
† Indicates events were collected by systematic assessment; [1] Adeers submitted
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Arm A	Arm B	Arm C (Cohort 1)	Arm C (Cohort 2)	Arm C (Cohort 3)	Arm D
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	506/559 (90.52%)	529/575 (92.00%)	12/12 (100.00%)	32/33 (96.97%)	41/47 (87.23%)	7/376 (1.86%)
Blood and lymphatic system disorders
Anemia † [1]	4/559 (0.72%)	5/575 (0.87%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Blood and lymphatic system disorders - Other, specify † [1]	3/559 (0.54%)	1/575 (0.17%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Bone marrow hypocellular † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Disseminated intravascular coagulation † [1]	3/559 (0.54%)	3/575 (0.52%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Febrile neutropenia † [1]	212/559 (37.92%)	175/575 (30.43%)	6/12 (50.00%)	8/33 (24.24%)	12/47 (25.53%)	2/376 (0.53%)
Leukocytosis † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Lymph node pain † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Thrombotic thrombocytopenic purpura † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Cardiac disorders
Asystole † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Cardiac arrest † [1]	4/559 (0.72%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Cardiac disorders - Other, specify † [1]	8/559 (1.43%)	16/575 (2.78%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Chest pain - cardiac † [1]	1/559 (0.18%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Heart failure † [1]	21/559 (3.76%)	22/575 (3.83%)	1/12 (8.33%)	2/33 (6.06%)	0/47 (0.00%)	0/376 (0.00%)
Left ventricular systolic dysfunction † [1]	30/559 (5.37%)	28/575 (4.87%)	1/12 (8.33%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Pericardial effusion † [1]	4/559 (0.72%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Pulmonary valve disease † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Restrictive cardiomyopathy † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Right ventricular dysfunction † [1]	3/559 (0.54%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Sinus bradycardia † [1]	1/559 (0.18%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Sinus tachycardia † [1]	13/559 (2.33%)	7/575 (1.22%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Supraventricular tachycardia † [1]	2/559 (0.36%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Tricuspid valve disease † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Ventricular arrhythmia † [1]	2/559 (0.36%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Ventricular fibrillation † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Ventricular tachycardia † [1]	1/559 (0.18%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Congenital, familial and genetic disorders
Congenital, familial and genetic disorders - Other, specify † [1]	0/559 (0.00%)	0/575 (0.00%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Ear and labyrinth disorders
Hearing impaired † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Endocrine disorders
Adrenal insufficiency † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Endocrine disorders - Other, specify † [1]	0/559 (0.00%)	0/575 (0.00%)	1/12 (8.33%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Eye disorders
Blurred vision † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Eye disorders - Other, specify † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Eye pain † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Periorbital edema † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Vitreous hemorrhage † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Gastrointestinal disorders
Abdominal distension † [1]	3/559 (0.54%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Abdominal pain † [1]	28/559 (5.01%)	26/575 (4.52%)	1/12 (8.33%)	4/33 (12.12%)	5/47 (10.64%)	0/376 (0.00%)
Anal mucositis † [1]	3/559 (0.54%)	1/575 (0.17%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Anal pain † [1]	7/559 (1.25%)	4/575 (0.70%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Anal ulcer † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Ascites † [1]	3/559 (0.54%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Colitis † [1]	20/559 (3.58%)	15/575 (2.61%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Constipation † [1]	2/559 (0.36%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Dental caries † [1]	2/559 (0.36%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Diarrhea † [1]	37/559 (6.62%)	48/575 (8.35%)	1/12 (8.33%)	5/33 (15.15%)	4/47 (8.51%)	1/376 (0.27%)
Duodenal ulcer † [1]	0/559 (0.00%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Dysphagia † [1]	0/559 (0.00%)	0/575 (0.00%)	1/12 (8.33%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Enterocolitis † [1]	2/559 (0.36%)	8/575 (1.39%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Esophageal hemorrhage † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Esophageal pain † [1]	1/559 (0.18%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Esophageal ulcer † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Esophagitis † [1]	4/559 (0.72%)	2/575 (0.35%)	1/12 (8.33%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Gastric hemorrhage † [1]	0/559 (0.00%)	0/575 (0.00%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Gastric ulcer † [1]	0/559 (0.00%)	0/575 (0.00%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Gastritis † [1]	1/559 (0.18%)	4/575 (0.70%)	0/12 (0.00%)	0/33 (0.00%)	2/47 (4.26%)	0/376 (0.00%)
Gastrointestinal disorders - Other, specify † [1]	2/559 (0.36%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Gastrointestinal fistula † [1]	0/559 (0.00%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Gastrointestinal pain † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Gingival pain † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Ileal perforation † [1]	0/559 (0.00%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Ileus † [1]	5/559 (0.89%)	10/575 (1.74%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Lower gastrointestinal hemorrhage † [1]	2/559 (0.36%)	0/575 (0.00%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Malabsorption † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Mucositis oral † [1]	115/559 (20.57%)	92/575 (16.00%)	4/12 (33.33%)	10/33 (30.30%)	11/47 (23.40%)	0/376 (0.00%)
Nausea † [1]	40/559 (7.16%)	40/575 (6.96%)	1/12 (8.33%)	4/33 (12.12%)	3/47 (6.38%)	0/376 (0.00%)
Oral hemorrhage † [1]	2/559 (0.36%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Oral pain † [1]	11/559 (1.97%)	5/575 (0.87%)	0/12 (0.00%)	1/33 (3.03%)	3/47 (6.38%)	0/376 (0.00%)
Pancreatitis † [1]	2/559 (0.36%)	5/575 (0.87%)	0/12 (0.00%)	2/33 (6.06%)	1/47 (2.13%)	0/376 (0.00%)
Proctitis † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Rectal mucositis † [1]	2/559 (0.36%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Rectal pain † [1]	7/559 (1.25%)	4/575 (0.70%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Retroperitoneal hemorrhage † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Small intestinal mucositis † [1]	2/559 (0.36%)	1/575 (0.17%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Small intestinal obstruction † [1]	2/559 (0.36%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Toothache † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Typhlitis † [1]	36/559 (6.44%)	22/575 (3.83%)	0/12 (0.00%)	1/33 (3.03%)	2/47 (4.26%)	0/376 (0.00%)
Upper gastrointestinal hemorrhage † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Vomiting † [1]	21/559 (3.76%)	23/575 (4.00%)	0/12 (0.00%)	4/33 (12.12%)	2/47 (4.26%)	1/376 (0.27%)
General disorders
Edema face † [1]	2/559 (0.36%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Edema limbs † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Edema trunk † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Fatigue † [1]	4/559 (0.72%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Fever † [1]	53/559 (9.48%)	94/575 (16.35%)	2/12 (16.67%)	5/33 (15.15%)	7/47 (14.89%)	0/376 (0.00%)
General disorders and administration site conditions - Other, specify † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Localized edema † [1]	2/559 (0.36%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Multi-organ failure † [1]	7/559 (1.25%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Non-cardiac chest pain † [1]	1/559 (0.18%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Pain † [1]	13/559 (2.33%)	13/575 (2.26%)	1/12 (8.33%)	1/33 (3.03%)	4/47 (8.51%)	0/376 (0.00%)
Hepatobiliary disorders
Cholecystitis † [1]	1/559 (0.18%)	2/575 (0.35%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Gallbladder necrosis † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hepatic failure † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hepatobiliary disorders - Other, specify † [1]	2/559 (0.36%)	1/575 (0.17%)	0/12 (0.00%)	1/33 (3.03%)	2/47 (4.26%)	0/376 (0.00%)
Portal hypertension † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Immune system disorders
Allergic reaction † [1]	7/559 (1.25%)	8/575 (1.39%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Anaphylaxis † [1]	10/559 (1.79%)	4/575 (0.70%)	0/12 (0.00%)	2/33 (6.06%)	0/47 (0.00%)	0/376 (0.00%)
Autoimmune disorder † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Immune system disorders - Other, specify † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Serum sickness † [1]	0/559 (0.00%)	0/575 (0.00%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Infections and infestations
Abdominal infection † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Anorectal infection † [1]	6/559 (1.07%)	4/575 (0.70%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Appendicitis † [1]	6/559 (1.07%)	9/575 (1.57%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Bladder infection † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Bone infection † [1]	5/559 (0.89%)	1/575 (0.17%)	1/12 (8.33%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Bronchial infection † [1]	1/559 (0.18%)	5/575 (0.87%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Catheter related infection † [1]	14/559 (2.50%)	16/575 (2.78%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Cecal infection † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Conjunctivitis † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Device related infection † [1]	0/559 (0.00%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Encephalitis infection † [1]	1/559 (0.18%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Endocarditis infective † [1]	1/559 (0.18%)	2/575 (0.35%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Endophthalmitis † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Enterocolitis infectious † [1]	31/559 (5.55%)	29/575 (5.04%)	0/12 (0.00%)	2/33 (6.06%)	1/47 (2.13%)	1/376 (0.27%)
Esophageal infection † [1]	2/559 (0.36%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Eye infection † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Gallbladder infection † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Gum infection † [1]	0/559 (0.00%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Hepatic infection † [1]	4/559 (0.72%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hepatitis viral † [1]	1/559 (0.18%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Infections and infestations - Other, specify † [1]	275/559 (49.19%)	293/575 (50.96%)	6/12 (50.00%)	19/33 (57.58%)	16/47 (34.04%)	0/376 (0.00%)
Infective myositis † [1]	4/559 (0.72%)	1/575 (0.17%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Joint infection † [1]	0/559 (0.00%)	0/575 (0.00%)	2/12 (16.67%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Kidney infection † [1]	1/559 (0.18%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Lip infection † [1]	0/559 (0.00%)	4/575 (0.70%)	1/12 (8.33%)	0/33 (0.00%)	2/47 (4.26%)	0/376 (0.00%)
Lung infection † [1]	60/559 (10.73%)	72/575 (12.52%)	3/12 (25.00%)	8/33 (24.24%)	6/47 (12.77%)	1/376 (0.27%)
Lymph gland infection † [1]	2/559 (0.36%)	7/575 (1.22%)	0/12 (0.00%)	1/33 (3.03%)	1/47 (2.13%)	0/376 (0.00%)
Meningitis † [1]	2/559 (0.36%)	1/575 (0.17%)	1/12 (8.33%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Mucosal infection † [1]	6/559 (1.07%)	3/575 (0.52%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Nail infection † [1]	1/559 (0.18%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Otitis externa † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Otitis media † [1]	1/559 (0.18%)	3/575 (0.52%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Papulopustular rash † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Paronychia † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Pelvic infection † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Penile infection † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Periorbital infection † [1]	2/559 (0.36%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Peritoneal infection † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Pharyngitis † [1]	1/559 (0.18%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Pleural infection † [1]	2/559 (0.36%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Salivary gland infection † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Scrotal infection † [1]	1/559 (0.18%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Sepsis † [1]	88/559 (15.74%)	72/575 (12.52%)	0/12 (0.00%)	3/33 (9.09%)	3/47 (6.38%)	1/376 (0.27%)
Sinusitis † [1]	11/559 (1.97%)	17/575 (2.96%)	1/12 (8.33%)	1/33 (3.03%)	1/47 (2.13%)	0/376 (0.00%)
Skin infection † [1]	36/559 (6.44%)	26/575 (4.52%)	1/12 (8.33%)	0/33 (0.00%)	3/47 (6.38%)	0/376 (0.00%)
Small intestine infection † [1]	1/559 (0.18%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Soft tissue infection † [1]	8/559 (1.43%)	10/575 (1.74%)	1/12 (8.33%)	2/33 (6.06%)	1/47 (2.13%)	0/376 (0.00%)
Splenic infection † [1]	2/559 (0.36%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Tooth infection † [1]	2/559 (0.36%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Tracheitis † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Upper respiratory infection † [1]	13/559 (2.33%)	24/575 (4.17%)	1/12 (8.33%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Urinary tract infection † [1]	18/559 (3.22%)	20/575 (3.48%)	0/12 (0.00%)	1/33 (3.03%)	1/47 (2.13%)	0/376 (0.00%)
Vaginal infection † [1]	1/559 (0.18%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Vulval infection † [1]	4/559 (0.72%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Wound infection † [1]	1/559 (0.18%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Injury, poisoning and procedural complications
Infusion related reaction † [1]	4/559 (0.72%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Injury, poisoning and procedural complications - Other, specify † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Tracheal obstruction † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Vascular access complication † [1]	3/559 (0.54%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Venous injury † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Wound dehiscence † [1]	0/559 (0.00%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Investigations
Activated partial thromboplastin time prolonged † [1]	6/559 (1.07%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Alanine aminotransferase increased † [1]	84/559 (15.03%)	79/575 (13.74%)	0/12 (0.00%)	7/33 (21.21%)	14/47 (29.79%)	2/376 (0.53%)
Alkaline phosphatase increased † [1]	1/559 (0.18%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Aspartate aminotransferase increased † [1]	56/559 (10.02%)	63/575 (10.96%)	0/12 (0.00%)	5/33 (15.15%)	7/47 (14.89%)	1/376 (0.27%)
Blood bilirubin increased † [1]	25/559 (4.47%)	20/575 (3.48%)	1/12 (8.33%)	3/33 (9.09%)	5/47 (10.64%)	0/376 (0.00%)
CPK increased † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Cardiac troponin I increased † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Cholesterol high † [1]	0/559 (0.00%)	0/575 (0.00%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Creatinine increased † [1]	1/559 (0.18%)	10/575 (1.74%)	1/12 (8.33%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Ejection fraction decreased † [1]	22/559 (3.94%)	29/575 (5.04%)	1/12 (8.33%)	4/33 (12.12%)	0/47 (0.00%)	0/376 (0.00%)
Electrocardiogram QT corrected interval prolonged † [1]	153/559 (27.37%)	175/575 (30.43%)	3/12 (25.00%)	10/33 (30.30%)	14/47 (29.79%)	0/376 (0.00%)
Fibrinogen decreased † [1]	1/559 (0.18%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
GGT increased † [1]	16/559 (2.86%)	19/575 (3.30%)	0/12 (0.00%)	3/33 (9.09%)	1/47 (2.13%)	0/376 (0.00%)
INR increased † [1]	1/559 (0.18%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Investigations - Other, specify † [1]	3/559 (0.54%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Lipase increased † [1]	10/559 (1.79%)	9/575 (1.57%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Neutrophil count decreased † [1]	188/559 (33.63%)	193/575 (33.57%)	3/12 (25.00%)	7/33 (21.21%)	5/47 (10.64%)	0/376 (0.00%)
Platelet count decreased † [1]	4/559 (0.72%)	7/575 (1.22%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Serum amylase increased † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Urine output decreased † [1]	1/559 (0.18%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Weight gain † [1]	1/559 (0.18%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Weight loss † [1]	12/559 (2.15%)	7/575 (1.22%)	0/12 (0.00%)	2/33 (6.06%)	0/47 (0.00%)	0/376 (0.00%)
White blood cell decreased † [1]	2/559 (0.36%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Metabolism and nutrition disorders
Acidosis † [1]	5/559 (0.89%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Alkalosis † [1]	5/559 (0.89%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Anorexia † [1]	123/559 (22.00%)	130/575 (22.61%)	5/12 (41.67%)	7/33 (21.21%)	11/47 (23.40%)	0/376 (0.00%)
Dehydration † [1]	12/559 (2.15%)	6/575 (1.04%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Glucose intolerance † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hypercalcemia † [1]	2/559 (0.36%)	5/575 (0.87%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	0/376 (0.00%)
Hyperglycemia † [1]	59/559 (10.55%)	59/575 (10.26%)	3/12 (25.00%)	6/33 (18.18%)	6/47 (12.77%)	1/376 (0.27%)
Hyperkalemia † [1]	17/559 (3.04%)	10/575 (1.74%)	1/12 (8.33%)	3/33 (9.09%)	2/47 (4.26%)	0/376 (0.00%)
Hypermagnesemia † [1]	3/559 (0.54%)	3/575 (0.52%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hypernatremia † [1]	2/559 (0.36%)	9/575 (1.57%)	1/12 (8.33%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hypertriglyceridemia † [1]	5/559 (0.89%)	4/575 (0.70%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hyperuricemia † [1]	1/559 (0.18%)	1/575 (0.17%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Hypoalbuminemia † [1]	14/559 (2.50%)	19/575 (3.30%)	0/12 (0.00%)	1/33 (3.03%)	2/47 (4.26%)	1/376 (0.27%)
Hypocalcemia † [1]	31/559 (5.55%)	29/575 (5.04%)	3/12 (25.00%)	3/33 (9.09%)	1/47 (2.13%)	1/376 (0.27%)
Hypoglycemia † [1]	1/559 (0.18%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Hypokalemia † [1]	149/559 (26.65%)	152/575 (26.43%)	5/12 (41.67%)	9/33 (27.27%)	9/47 (19.15%)	0/376 (0.00%)
Hypomagnesemia † [1]	5/559 (0.89%)	4/575 (0.70%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Hyponatremia † [1]	34/559 (6.08%)	28/575 (4.87%)	2/12 (16.67%)	5/33 (15.15%)	2/47 (4.26%)	0/376 (0.00%)
Hypophosphatemia † [1]	39/559 (6.98%)	42/575 (7.30%)	1/12 (8.33%)	3/33 (9.09%)	7/47 (14.89%)	0/376 (0.00%)
Iron overload † [1]	2/559 (0.36%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Metabolism and nutrition disorders - Other, specify † [1]	1/559 (0.18%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Tumor lysis syndrome † [1]	9/559 (1.61%)	12/575 (2.09%)	0/12 (0.00%)	0/33 (0.00%)	1/47 (2.13%)	1/376 (0.27%)
Musculoskeletal and connective tissue disorders
Arthralgia † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	2/33 (6.06%)	1/47 (2.13%)	0/376 (0.00%)
Avascular necrosis † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Back pain † [1]	8/559 (1.43%)	7/575 (1.22%)	1/12 (8.33%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Bone pain † [1]	2/559 (0.36%)	1/575 (0.17%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Buttock pain † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	2/47 (4.26%)	0/376 (0.00%)
Chest wall pain † [1]	3/559 (0.54%)	0/575 (0.00%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Flank pain † [1]	2/559 (0.36%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Generalized muscle weakness † [1]	1/559 (0.18%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Musculoskeletal and connective tissue disorder - Other, specify † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Myalgia † [1]	0/559 (0.00%)	2/575 (0.35%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Myositis † [1]	4/559 (0.72%)	3/575 (0.52%)	1/12 (8.33%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Neck pain † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Pain in extremity † [1]	6/559 (1.07%)	5/575 (0.87%)	2/12 (16.67%)	1/33 (3.03%)	1/47 (2.13%)	0/376 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify † [1]	24/559 (4.29%)	13/575 (2.26%)	0/12 (0.00%)	1/33 (3.03%)	0/47 (0.00%)	0/376 (0.00%)
Nervous system disorders
Aphonia † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Cognitive disturbance † [1]	1/559 (0.18%)	1/575 (0.17%)	1/12 (8.33%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Depressed level of consciousness † [1]	2/559 (0.36%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Dizziness † [1]	0/559 (0.00%)	1/575 (0.17%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Encephalopathy † [1]	1/559 (0.18%)	0/575 (0.00%)	0/12 (0.00%)	0/33 (0.00%)	0/47 (0.00%)	0/376 (0.00%)
Headache † [1]	22/559 (3.94%)	16/575 (2.78%)	1/12 (8.33%)	2/33 (6.06%)	0/47 (0.00%)