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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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:
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
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
Hide 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
Arm/Group Title Arm A Arm B Arm C (Cohort 1) Arm C (Cohort 2) Arm C (Cohort 3) Arm D Total
Hide 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
Hide 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
1.Primary Outcome
Title Event-free Survival (EFS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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
Hide Description Median and range of bortezomib clearance during Induction II.
Time Frame Day 8 of Induction II
Hide Outcome Measure Data
Hide 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
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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
Hide Description Median and range of sorafenib steady state concentration for Induction I.
Time Frame Up to 30 days
Hide Outcome Measure Data
Hide 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
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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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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
Hide 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
Hide 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
Hide 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
Hide 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
Hide 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
Hide 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
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
Hide 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%) 
Hide 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
Hide 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%)