Bortezomib and Sorafenib Tosylate in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Active, not recruiting
CT.gov ID
NCT01371981
Collaborator
(none)
1,645
220
6
195.4
7.5
0
Study Details
Study Description
Brief Summary
This randomized phase III trial studies how well bortezomib and sorafenib tosylate work in treating patients with newly diagnosed acute myeloid leukemia. Bortezomib and sorafenib tosylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib and sorafenib tosylate together with combination chemotherapy may be an effective treatment for acute myeloid leukemia.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
PRIMARY OBJECTIVES:
-
To compare event-free survival (EFS) and overall survival (OS) in patients with de novo acute myeloid leukemia (AML) without high allelic ratio fms-like tyrosine kinase (FLT3)/internal tandem duplications (ITD)+ mutations who are randomized to standard therapy versus bortezomib/standard combination therapy.
-
To determine the feasibility of combining bortezomib with standard chemotherapy in patients with de novo AML.
-
To compare the OS and EFS of high-risk patients treated with intensive Induction II with historical controls from AAML03P1 and AAML0531.
-
To determine the feasibility of administering sorafenib (sorafenib tosylate) with standard chemotherapy and in a one year maintenance phase in patients with de novo high allelic ratio FLT3/ITD+ AML.
SECONDARY OBJECTIVES:
-
To assess the anti-leukemic activity of sorafenib in patients with de novo high allelic ratio FLT3/ITD+ AML.
-
To compare the percentage of patients converting from positive minimal residual disease (MRD) to negative MRD after Intensive Induction II with historical controls from AAML03P1 and AAML0531.
-
To compare OS, disease-free survival (DFS), cumulative incidence of relapse, and treatment-related mortality from end of Intensification I between patients allocated to best allogenic donor stem cell transplant (SCT) and comparable patients on AAML0531 who did not receive allogenic donor SCT.
-
To compare OS, DFS, cumulative incidence of relapse, treatment-related mortality, and severe toxicity between patients allocated to matched family donor SCT on AAML1031 and AAML0531.
-
To assess the health-related quality of life (HRQOL) of patients treated with chemotherapy and stem cell transplant (SCT) for AML.
-
To evaluate bortezomib pharmacokinetics (PK) in patients receiving the combination regimen.
-
To obtain sorafenib and metabolite steady state pharmacokinetics and pharmacokinetic-pharmacodynamic data in subjects with FLT3/ITD receiving sorafenib.
-
To compare the changes in shortening fraction/ejection fraction over time between patients treated with and without dexrazoxane.
-
To refine the use of minimal-residual disease (MRD) detection with 4-color flow cytometry.
-
To evaluate the prognostic significance of molecular MRD and its contribution to risk identification with multidimensional flow cytometry (MDF)-based MRD in patients with translocations amenable to quantitative real time (RT)-polymerase chain reaction (PCR) (e.g., t[8;21], inv[16], t[9;11], Wilms tumor 1 [WT1] expression).
-
To determine the leukemic involvement of the hematopoietic early progenitor cell and its role in defining response to therapy.
-
To define the leukemic stem cell population in patients with AML. XIII. To determine the prevalence and prognostic significance of molecular abnormalities of WT1, runt-related transcription factor (RUNX)1, mixed-lineage leukemia (MLL)-partial tandem duplication (PTD), tet methylcytosine dioxygenase 2 (TET2), Cbl proto-oncogene, E3 ubiquitin protein ligase (c-CBL), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), and other novel AML-associated genes in pediatric AML.
-
Correlate the expression of cluster of differentiation (CD)74 antigen as well as proteasome beta 5-subunit (PSMB5) gene expression and mutation with response to bortezomib.
-
To evaluate the changes in protein expression and unfolded protein response (UPR) in patients with AML.
-
To determine the expression level of wild-type FLT3, and correlate with outcome and in vitro sensitivity to FLT3 inhibition.
-
To collect biology specimens at diagnosis, treatment time points, and relapse for future biology studies XVIII. To create a pediatric-specific algorithm to predict the occurrence of grade 2-4 acute graft-versus-host disease (GVHD) prior to its clinical manifestations using a combination of pre-transplant clinical variables and serum GVHD biomarker concentrations in the first weeks after SCT.
OUTLINE: This is a dose-escalation study of sorafenib tosylate. Patients are randomized to Arm A or B or offered treatment on 1 of 6 arms. (Arms A and B are closed to new patient enrollment as of 02/04/2016)
Arm A:
INDUCTION I: Patients receive cytarabine intrathecally (IT) on day 1 and ADE chemotherapy comprising cytarabine intravenously (IV) over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5; and etoposide IV over 1-2 hours on days 1-5.
INDUCTION II: Patients with low risk (LR) receive cytarabine IT and ADE chemotherapy as in Induction I. Patients with high risk (HR) receive cytarabine IT on day 1 and MA chemotherapy comprising high-dose cytarabine IV over 1-3 hours on days 1-4, and mitoxantrone IV over 15-30 minutes on days 3-6. Patients who achieve complete remission (CR) proceed to Intensification I (beginning on day 37). Patients with refractory disease are off protocol therapy.
INTENSIFICATION I: Patients receive cytarabine IT on day 1 and AE chemotherapy comprising high-dose cytarabine IV over 1-3 hours, and etoposide IV over 1-2 hours on days 1-5. Patients who achieve CR proceed to Intensification II or stem cell transplantation (SCT) beginning on day 34. Patients with refractory disease are off protocol therapy.
INTENSIFICATION II: Patients with LR receive cytarabine IT on day 1 and MA chemotherapy as in Induction II. Patients with HR and no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9 and asparaginase intramuscularly (IM) on days 2 and 9.
STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family [MFD] or unrelated donor):
CONDITIONING REGIMEN: Patients 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.
TRANSPLANTATION: Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO beginning on day -2 and continuing until day 98 (matched sibling donor) or day 180 (with taper) (other related/unrelated donors or cord blood) and methotrexate IV on days 1, 3, and 6 (matched sibling/cord blood donors) or days 1, 3, 6, and 11 (other related/unrelated donors). Patients with unrelated donors also receive antithymocyte globulin IV over 6-8 hours on days -3 to -1.
Arm B:
INDUCTION I: Patients 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, and 8.
INDUCTION II: Patients with LR receive cytarabine IT, ADE chemotherapy, and bortezomib as in Induction I. Patients with HR receive cytarabine IT and MA chemotherapy as in Induction II, Arm A (HR patients) and bortezomib IV on days 1, 4, and 8.
INTENSIFICATION I: Patients receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and bortezomib IV on days 1, 4, and 8. Patients who achieve CR proceed to Intensification II or stem cell transplantation (SCT) beginning on day 34. Patients with refractory disease are off protocol therapy.
INTENSIFICATION II: Patients with LR receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), and bortezomib IV on days 1, 4, and 8. Patients with HR and no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9 and asparaginase intramuscularly (IM) on days 2 and 9.
STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family [MFD] or unrelated donor):
CONDITIONING REGIMEN: Patients 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.
TRANSPLANTATION: Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO beginning on day -2 and continuing until day 98 (matched sibling donor) or day 180 (with taper) (other related/unrelated donors or cord blood) and methotrexate IV on days 1, 3, and 6 (matched sibling/cord blood donors) or days 1, 3, 6, and 11 (other related/unrelated donors). Patients with unrelated donors also receive antithymocyte globulin IV over 6-8 hours on days -3 to -1.
ARM C (COHORT 1):
INDUCTION II: Patients 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, and sorafenib tosylate PO on days 9-36.
INTENSIFICATION I: Patients receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28.
INTENSIFICATION II: Patients receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), and sorafenib tosylate PO on days 7-34.
STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family [MFD] or unrelated donor):
CONDITIONING REGIMEN: Patients 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.
TRANSPLANTATION: Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO beginning on day -2 and continuing until day 98 (matched sibling donor) or day 180 (with taper) (other related/unrelated donors or cord blood) and methotrexate IV on days 1, 3, and 6 (matched sibling/cord blood donors) or days 1, 3, 6, and 11 (other related/unrelated donors). Patients with unrelated donors also receive antithymocyte globulin IV over 6-8 hours on days -3 to -1.
MAINTENANCE: Patients receive sorafenib tosylate PO starting on day 40-100 after completion of intensification II or SCT for one year.
ARM C (COHORT 2):
INDUCTION I: Patients receive cytarabine IT and ADE chemotherapy as in Arm A, Induction I and sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including in Induction I and concurrently with chemotherapy).
INDUCTION II: Patients 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, and sorafenib tosylate PO on days 9-36.
INTENSIFICATION I: Patients receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28.
INTENSIFICATION II: Patients receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), and sorafenib tosylate PO on days 7-34.
STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family [MFD] or unrelated donor):
CONDITIONING REGIMEN: Patients 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.
TRANSPLANTATION: Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO beginning on day -2 and continuing until day 98 (matched sibling donor) or day 180 (with taper) (other related/unrelated donors or cord blood) and methotrexate IV on days 1, 3, and 6 (matched sibling/cord blood donors) or days 1, 3, 6, and 11 (other related/unrelated donors). Patients with unrelated donors also receive antithymocyte globulin IV over 6-8 hours on days -3 to -1.
MAINTENANCE: Patients receive sorafenib tosylate PO starting on day 40-100 after completion of intensification II or SCT for one year.
ARM C (COHORT 3):
INDUCTION I: Patients receive cytarabine IT and ADE chemotherapy as in Arm A, Induction I and sorafenib tosylate PO on days 11-28.
INDUCTION II: Patients 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, and sorafenib tosylate PO on days 9-36.
INTENSIFICATION I: Patients receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28.
INTENSIFICATION II: Patients receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), and sorafenib tosylate PO on days 7-34.
STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family [MFD] or unrelated donor):
CONDITIONING REGIMEN: Patients 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.
TRANSPLANTATION: Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO beginning on day -2 and continuing until day 98 (matched sibling donor) or day 180 (with taper) (other related/unrelated donors or cord blood) and methotrexate IV on days 1, 3, and 6 (matched sibling/cord blood donors) or days 1, 3, 6, and 11 (other related/unrelated donors). Patients with unrelated donors also receive antithymocyte globulin IV over 6-8 hours on days -3 to -1.
MAINTENANCE: Patients receive sorafenib tosylate PO starting on day 40-100 after completion of intensification II or SCT for one year.
ARM D:
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.
After completion of study therapy, patients are followed up monthly for 6 months, every 2 months for 6 months, every 4 months for 1 year, every 6 months for 1 year, and then yearly thereafter.
Study Design
Study Type:
Interventional
Actual Enrollment
:
1645 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase III Randomized Trial for Patients With De Novo AML Using Bortezomib and Sorafenib (NSC# 681239, NSC# 724772) for Patients With High Allelic Ratio FLT3/ITD
Actual Study Start Date
:
Jun 20, 2011
Actual Primary Completion Date
:
Mar 31, 2019
Anticipated Study Completion Date
:
Sep 30, 2027
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm A See Detailed Description |
Drug: Asparaginase
Given IM
Other Names:
Drug: Cytarabine
Given IT or IV
Other Names:
Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mitoxantrone Hydrochloride
Given IV
Other Names:
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Names:
Other: Questionnaire Administration
Ancillary studies
|
| Experimental: Arm B See Detailed Description |
Drug: Asparaginase
Given IM
Other Names:
Drug: Bortezomib
Given IV
Other Names:
Drug: Cytarabine
Given IT or IV
Other Names:
Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mitoxantrone Hydrochloride
Given IV
Other Names:
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Names:
Other: Questionnaire Administration
Ancillary studies
|
| Experimental: Arm C (Cohort 1) See Detailed Description |
Drug: Asparaginase
Given IM
Other Names:
Drug: Cytarabine
Given IT or IV
Other Names:
Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mitoxantrone Hydrochloride
Given IV
Other Names:
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Names:
Other: Questionnaire Administration
Ancillary studies
Drug: Sorafenib Tosylate
Given PO
Other Names:
|
| Experimental: Arm C (Cohort 2) See Detailed Description. |
Drug: Asparaginase
Given IM
Other Names:
Drug: Cytarabine
Given IT or IV
Other Names:
Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mitoxantrone Hydrochloride
Given IV
Other Names:
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Names:
Other: Questionnaire Administration
Ancillary studies
Drug: Sorafenib Tosylate
Given PO
Other Names:
|
| Experimental: Arm C (Cohort 3) See Detailed Description. Different dose. |
Drug: Asparaginase
Given IM
Other Names:
Drug: Cytarabine
Given IT or IV
Other Names:
Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mitoxantrone Hydrochloride
Given IV
Other Names:
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Names:
Other: Questionnaire Administration
Ancillary studies
Drug: Sorafenib Tosylate
Given PO
Other Names:
|
| Experimental: Arm D See Detailed Description. May reassigned to Arm C. |
Drug: Cytarabine
Given IT or IV
Other Names:
Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Names:
Other: Questionnaire Administration
Ancillary studies
|
Outcome Measures
Primary Outcome Measures
- Event-free Survival (EFS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations [Up to 3 years]
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.
- EFS for Patients on Arm C, Cohort 1 [Up to 3 years]
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.
- EFS for Patients on Arm C, Cohort 2 [Up to 3 years]
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.
- EFS for Patients on Arm C, Cohort 3 [Up to 3 years]
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.
Secondary Outcome Measures
- Overall Survival (OS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations [Up to 3 years]
The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.
- OS for Patients on Arm C, Cohort 1 [Up to 3 years]
The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.
- OS for Patients on Arm C, Cohort 2 [Up to 3 years]
The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.
- OS for Patients on Arm C, Cohort 3 [Up to 3 years]
The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.
- Relapse Rate for Patients Without High Allelic Ratio FLT3/ITD+ Mutations [Up to 3 years]
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.
- Proportion of Patients Experiencing Grade 3 or Higher Non-hematologic Toxicities and Infections While on Protocol Therapy [Up to 2 years]
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).
- 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 [Up to 8 weeks]
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.
- Total Scale Score From Parent-reported Pediatric Quality of Life Inventory Module [Up to 14 days]
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.
- Total Scale Score From Parent-reported Cancer Module [Up to 14 days]
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.
- Total Scale Score From Parent-reported Multidimensional Fatigue Scale Module [Up to 14 days]
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.
- Bortezomib Clearance [Day 8 of Induction II]
Median and range of bortezomib clearance during Induction II.
- Sorafenib Steady State Concentration [Up to 30 days]
Median and range of sorafenib steady state concentration for Induction I.
- Change in Shortening Fraction [Up to 4 weeks]
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.
- Change in Ejection Fraction [Up to 4 weeks]
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.
- Serum Concentrations of GVHD Biomarker [Up to day 28 after SCT]
The mean serum concentration of the day 28 GVHD biomarker will be estimated as well as the corresponding 95% confidence interval.
Other Outcome Measures
- Course Duration [Up to 6 months]
Descriptive statistics will be used to summarize length of hospitalization time.
- Incidence of Treatment-related Mortality [Up to 2 years]
Cumulative incidence estimates that account for competing events will be used to estimate treatment-related mortality.
- Length of Hospitalization [Up to 6 months]
Descriptive statistics will be used to summarize length of hospitalization time.
- Remission Rate After 1 Course of Therapy [4 weeks]
The proportion of patients achieving remission after 1 course of therapy will be estimated along with a corresponding 95% confidence interval.
- Remission Rate After 2 Courses of Therapy [8 weeks]
The proportion of patients achieving remission after 2 courses of therapy will be estimated along with a corresponding 95% confidence interval.
- Time to Blood Count Recovery [Up to 6 months]
Cumulative incidence estimates that account for competing events will be used to estimate time to count recovery.
Eligibility Criteria
Criteria
Ages Eligible for Study:
N/A
to 29 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Patients must be newly diagnosed with de novo acute myelogenous leukemia
-
Patients with previously untreated primary AML who meet the customary criteria for AML with >= 20% bone marrow blasts as set out in the 2008 World Health Organization (WHO) Myeloid Neoplasm Classification are eligible
-
Attempts to obtain bone marrow either by aspirate or biopsy must be made unless clinically prohibitive; in cases where it is clinically prohibitive, peripheral blood with an excess of 20% blasts and in which adequate flow cytometric and cytogenetics/fluorescent in situ hybridization (FISH) testing is feasible can be substituted for the marrow exam at diagnosis
-
Patients with < 20% bone marrow blasts are eligible if they have:
-
A karyotypic abnormality characteristic of de novo AML (t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22) or 11q23 abnormalities
-
The unequivocal presence of megakaryoblasts, or
-
Biopsy proven isolated myeloid sarcoma (myeloblastoma; chloroma, including leukemia cutis)
-
Patients with any performance status are eligible for enrollment
-
Prior therapy with hydroxyurea, all-trans retinoic acid (ATRA), corticosteroids (any route), and IT cytarabine given at diagnosis is allowed; hydroxyurea and ATRA must be discontinued prior to initiation of protocol therapy; patients who have previously received any other chemotherapy, radiation therapy or any other antileukemic therapy are not eligible for this protocol
Exclusion Criteria:
-
Patients with any of the following constitutional conditions are not eligible:
-
Fanconi anemia
-
Shwachman syndrome
-
Any other known bone marrow failure syndrome
-
Patients with constitutional trisomy 21 or with constitutional mosaicism of trisomy 21 Note: enrollment may occur pending results of clinically indicated studies to exclude these conditions
-
Patients with any of the following oncologic diagnoses are not eligible:
-
Any concurrent malignancy
-
Juvenile myelomonocytic leukemia (JMML)
-
Philadelphia chromosome positive AML
-
Biphenotypic or bilineal acute leukemia
-
Acute promyelocytic leukemia
-
Acute myeloid leukemia arising from myelodysplasia
-
Therapy-related myeloid neoplasms Note: enrollment may occur pending results of clinically indicated studies to exclude these conditions
-
Pregnancy and breast feeding
-
Female patients who are pregnant are ineligible
-
Lactating females are not eligible unless they have agreed not to breastfeed their infants
-
Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
-
Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Children's Hospital of Alabama | Birmingham | Alabama | United States | 35233 |
| 2 | University of Alabama at Birmingham Cancer Center | Birmingham | Alabama | United States | 35233 |
| 3 | USA Health Strada Patient Care Center | Mobile | Alabama | United States | 36604 |
| 4 | Banner Children's at Desert | Mesa | Arizona | United States | 85202 |
| 5 | Phoenix Childrens Hospital | Phoenix | Arizona | United States | 85016 |
| 6 | Banner University Medical Center - Tucson | Tucson | Arizona | United States | 85719 |
| 7 | Arkansas Children's Hospital | Little Rock | Arkansas | United States | 72202-3591 |
| 8 | University of Arkansas for Medical Sciences | Little Rock | Arkansas | United States | 72205 |
| 9 | Kaiser Permanente Downey Medical Center | Downey | California | United States | 90242 |
| 10 | City of Hope Comprehensive Cancer Center | Duarte | California | United States | 91010 |
| 11 | Loma Linda University Medical Center | Loma Linda | California | United States | 92354 |
| 12 | Miller Children's and Women's Hospital Long Beach | Long Beach | California | United States | 90806 |
| 13 | Children's Hospital Los Angeles | Los Angeles | California | United States | 90027 |
| 14 | Cedars Sinai Medical Center | Los Angeles | California | United States | 90048 |
| 15 | Valley Children's Hospital | Madera | California | United States | 93636 |
| 16 | UCSF Benioff Children's Hospital Oakland | Oakland | California | United States | 94609 |
| 17 | Kaiser Permanente-Oakland | Oakland | California | United States | 94611 |
| 18 | Children's Hospital of Orange County | Orange | California | United States | 92868 |
| 19 | Lucile Packard Children's Hospital Stanford University | Palo Alto | California | United States | 94304 |
| 20 | Sutter Medical Center Sacramento | Sacramento | California | United States | 95816 |
| 21 | University of California Davis Comprehensive Cancer Center | Sacramento | California | United States | 95817 |
| 22 | Rady Children's Hospital - San Diego | San Diego | California | United States | 92123 |
| 23 | UCSF Medical Center-Parnassus | San Francisco | California | United States | 94143 |
| 24 | UCSF Medical Center-Mission Bay | San Francisco | California | United States | 94158 |
| 25 | Santa Barbara Cottage Hospital | Santa Barbara | California | United States | 93102 |
| 26 | Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center | Torrance | California | United States | 90502 |
| 27 | Children's Hospital Colorado | Aurora | Colorado | United States | 80045 |
| 28 | Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center | Denver | Colorado | United States | 80218 |
| 29 | Connecticut Children's Medical Center | Hartford | Connecticut | United States | 06106 |
| 30 | Yale University | New Haven | Connecticut | United States | 06520 |
| 31 | Alfred I duPont Hospital for Children | Wilmington | Delaware | United States | 19803 |
| 32 | MedStar Georgetown University Hospital | Washington | District of Columbia | United States | 20007 |
| 33 | Children's National Medical Center | Washington | District of Columbia | United States | 20010 |
| 34 | Broward Health Medical Center | Fort Lauderdale | Florida | United States | 33316 |
| 35 | Lee Memorial Health System | Fort Myers | Florida | United States | 33901 |
| 36 | Golisano Children's Hospital of Southwest Florida | Fort Myers | Florida | United States | 33908 |
| 37 | University of Florida Health Science Center - Gainesville | Gainesville | Florida | United States | 32610 |
| 38 | Memorial Regional Hospital/Joe DiMaggio Children's Hospital | Hollywood | Florida | United States | 33021 |
| 39 | Nemours Children's Clinic-Jacksonville | Jacksonville | Florida | United States | 32207 |
| 40 | University of Miami Miller School of Medicine-Sylvester Cancer Center | Miami | Florida | United States | 33136 |
| 41 | Nicklaus Children's Hospital | Miami | Florida | United States | 33155 |
| 42 | Miami Cancer Institute | Miami | Florida | United States | 33176 |
| 43 | AdventHealth Orlando | Orlando | Florida | United States | 32803 |
| 44 | Arnold Palmer Hospital for Children | Orlando | Florida | United States | 32806 |
| 45 | Nemours Children's Clinic - Orlando | Orlando | Florida | United States | 32806 |
| 46 | Orlando Health Cancer Institute | Orlando | Florida | United States | 32806 |
| 47 | Nemours Children's Hospital | Orlando | Florida | United States | 32827 |
| 48 | Nemours Children's Clinic - Pensacola | Pensacola | Florida | United States | 32504 |
| 49 | Johns Hopkins All Children's Hospital | Saint Petersburg | Florida | United States | 33701 |
| 50 | Tampa General Hospital | Tampa | Florida | United States | 33606 |
| 51 | Saint Joseph's Hospital/Children's Hospital-Tampa | Tampa | Florida | United States | 33607 |
| 52 | Saint Mary's Hospital | West Palm Beach | Florida | United States | 33407 |
| 53 | Children's Healthcare of Atlanta - Egleston | Atlanta | Georgia | United States | 30322 |
| 54 | Augusta University Medical Center | Augusta | Georgia | United States | 30912 |
| 55 | Memorial Health University Medical Center | Savannah | Georgia | United States | 31404 |
| 56 | University of Hawaii Cancer Center | Honolulu | Hawaii | United States | 96813 |
| 57 | Kapiolani Medical Center for Women and Children | Honolulu | Hawaii | United States | 96826 |
| 58 | Saint Luke's Cancer Institute - Boise | Boise | Idaho | United States | 83712 |
| 59 | Lurie Children's Hospital-Chicago | Chicago | Illinois | United States | 60611 |
| 60 | University of Illinois | Chicago | Illinois | United States | 60612 |
| 61 | University of Chicago Comprehensive Cancer Center | Chicago | Illinois | United States | 60637 |
| 62 | Loyola University Medical Center | Maywood | Illinois | United States | 60153 |
| 63 | Advocate Children's Hospital-Oak Lawn | Oak Lawn | Illinois | United States | 60453 |
| 64 | Advocate Children's Hospital-Park Ridge | Park Ridge | Illinois | United States | 60068 |
| 65 | Advocate Lutheran General Hospital | Park Ridge | Illinois | United States | 60068 |
| 66 | Southern Illinois University School of Medicine | Springfield | Illinois | United States | 62702 |
| 67 | Riley Hospital for Children | Indianapolis | Indiana | United States | 46202 |
| 68 | Saint Vincent Hospital and Health Care Center | Indianapolis | Indiana | United States | 46260 |
| 69 | Blank Children's Hospital | Des Moines | Iowa | United States | 50309 |
| 70 | University of Iowa/Holden Comprehensive Cancer Center | Iowa City | Iowa | United States | 52242 |
| 71 | University of Kentucky/Markey Cancer Center | Lexington | Kentucky | United States | 40536 |
| 72 | Norton Children's Hospital | Louisville | Kentucky | United States | 40202 |
| 73 | Tulane University Health Sciences Center | New Orleans | Louisiana | United States | 70112 |
| 74 | Children's Hospital New Orleans | New Orleans | Louisiana | United States | 70118 |
| 75 | Ochsner Medical Center Jefferson | New Orleans | Louisiana | United States | 70121 |
| 76 | Eastern Maine Medical Center | Bangor | Maine | United States | 04401 |
| 77 | Maine Children's Cancer Program | Scarborough | Maine | United States | 04074 |
| 78 | University of Maryland/Greenebaum Cancer Center | Baltimore | Maryland | United States | 21201 |
| 79 | Sinai Hospital of Baltimore | Baltimore | Maryland | United States | 21215 |
| 80 | Johns Hopkins University/Sidney Kimmel Cancer Center | Baltimore | Maryland | United States | 21287 |
| 81 | Walter Reed National Military Medical Center | Bethesda | Maryland | United States | 20889-5600 |
| 82 | Tufts Children's Hospital | Boston | Massachusetts | United States | 02111 |
| 83 | Massachusetts General Hospital Cancer Center | Boston | Massachusetts | United States | 02114 |
| 84 | Dana-Farber Cancer Institute | Boston | Massachusetts | United States | 02215 |
| 85 | Baystate Medical Center | Springfield | Massachusetts | United States | 01199 |
| 86 | UMass Memorial Medical Center - University Campus | Worcester | Massachusetts | United States | 01655 |
| 87 | C S Mott Children's Hospital | Ann Arbor | Michigan | United States | 48109 |
| 88 | Wayne State University/Karmanos Cancer Institute | Detroit | Michigan | United States | 48201 |
| 89 | Ascension Saint John Hospital | Detroit | Michigan | United States | 48236 |
| 90 | Michigan State University Clinical Center | East Lansing | Michigan | United States | 48824-7016 |
| 91 | Hurley Medical Center | Flint | Michigan | United States | 48503 |
| 92 | Helen DeVos Children's Hospital at Spectrum Health | Grand Rapids | Michigan | United States | 49503 |
| 93 | Bronson Methodist Hospital | Kalamazoo | Michigan | United States | 49007 |
| 94 | Beaumont Children's Hospital-Royal Oak | Royal Oak | Michigan | United States | 48073 |
| 95 | Children's Hospitals and Clinics of Minnesota - Minneapolis | Minneapolis | Minnesota | United States | 55404 |
| 96 | University of Minnesota/Masonic Cancer Center | Minneapolis | Minnesota | United States | 55455 |
| 97 | Mayo Clinic in Rochester | Rochester | Minnesota | United States | 55905 |
| 98 | University of Mississippi Medical Center | Jackson | Mississippi | United States | 39216 |
| 99 | Columbia Regional | Columbia | Missouri | United States | 65201 |
| 100 | Children's Mercy Hospitals and Clinics | Kansas City | Missouri | United States | 64108 |
| 101 | Washington University School of Medicine | Saint Louis | Missouri | United States | 63110 |
| 102 | Mercy Hospital Saint Louis | Saint Louis | Missouri | United States | 63141 |
| 103 | Children's Hospital and Medical Center of Omaha | Omaha | Nebraska | United States | 68114 |
| 104 | University of Nebraska Medical Center | Omaha | Nebraska | United States | 68198 |
| 105 | University Medical Center of Southern Nevada | Las Vegas | Nevada | United States | 89102 |
| 106 | Sunrise Hospital and Medical Center | Las Vegas | Nevada | United States | 89109 |
| 107 | Alliance for Childhood Diseases/Cure 4 the Kids Foundation | Las Vegas | Nevada | United States | 89135 |
| 108 | Summerlin Hospital Medical Center | Las Vegas | Nevada | United States | 89144 |
| 109 | Nevada Cancer Research Foundation NCORP | Las Vegas | Nevada | United States | 89169 |
| 110 | Dartmouth Hitchcock Medical Center | Lebanon | New Hampshire | United States | 03756 |
| 111 | Hackensack University Medical Center | Hackensack | New Jersey | United States | 07601 |
| 112 | Saint Barnabas Medical Center | Livingston | New Jersey | United States | 07039 |
| 113 | Morristown Medical Center | Morristown | New Jersey | United States | 07960 |
| 114 | Saint Peter's University Hospital | New Brunswick | New Jersey | United States | 08901 |
| 115 | Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital | New Brunswick | New Jersey | United States | 08903 |
| 116 | Newark Beth Israel Medical Center | Newark | New Jersey | United States | 07112 |
| 117 | Saint Joseph's Regional Medical Center | Paterson | New Jersey | United States | 07503 |
| 118 | Overlook Hospital | Summit | New Jersey | United States | 07902 |
| 119 | University of New Mexico Cancer Center | Albuquerque | New Mexico | United States | 87102 |
| 120 | Albany Medical Center | Albany | New York | United States | 12208 |
| 121 | Montefiore Medical Center - Moses Campus | Bronx | New York | United States | 10467 |
| 122 | Roswell Park Cancer Institute | Buffalo | New York | United States | 14263 |
| 123 | NYU Winthrop Hospital | Mineola | New York | United States | 11501 |
| 124 | The Steven and Alexandra Cohen Children's Medical Center of New York | New Hyde Park | New York | United States | 11040 |
| 125 | Laura and Isaac Perlmutter Cancer Center at NYU Langone | New York | New York | United States | 10016 |
| 126 | Mount Sinai Hospital | New York | New York | United States | 10029 |
| 127 | NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center | New York | New York | United States | 10032 |
| 128 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
| 129 | NYP/Weill Cornell Medical Center | New York | New York | United States | 10065 |
| 130 | University of Rochester | Rochester | New York | United States | 14642 |
| 131 | Stony Brook University Medical Center | Stony Brook | New York | United States | 11794 |
| 132 | State University of New York Upstate Medical University | Syracuse | New York | United States | 13210 |
| 133 | New York Medical College | Valhalla | New York | United States | 10595 |
| 134 | Mission Hospital | Asheville | North Carolina | United States | 28801 |
| 135 | UNC Lineberger Comprehensive Cancer Center | Chapel Hill | North Carolina | United States | 27599 |
| 136 | Carolinas Medical Center/Levine Cancer Institute | Charlotte | North Carolina | United States | 28203 |
| 137 | Novant Health Presbyterian Medical Center | Charlotte | North Carolina | United States | 28204 |
| 138 | Duke University Medical Center | Durham | North Carolina | United States | 27710 |
| 139 | Wake Forest University Health Sciences | Winston-Salem | North Carolina | United States | 27157 |
| 140 | Sanford Broadway Medical Center | Fargo | North Dakota | United States | 58122 |
| 141 | Children's Hospital Medical Center of Akron | Akron | Ohio | United States | 44308 |
| 142 | Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio | United States | 45229 |
| 143 | Rainbow Babies and Childrens Hospital | Cleveland | Ohio | United States | 44106 |
| 144 | Cleveland Clinic Foundation | Cleveland | Ohio | United States | 44195 |
| 145 | Nationwide Children's Hospital | Columbus | Ohio | United States | 43205 |
| 146 | Dayton Children's Hospital | Dayton | Ohio | United States | 45404 |
| 147 | ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital | Toledo | Ohio | United States | 43606 |
| 148 | Mercy Children's Hospital | Toledo | Ohio | United States | 43608 |
| 149 | University of Oklahoma Health Sciences Center | Oklahoma City | Oklahoma | United States | 73104 |
| 150 | Legacy Emanuel Children's Hospital | Portland | Oregon | United States | 97227 |
| 151 | Legacy Emanuel Hospital and Health Center | Portland | Oregon | United States | 97227 |
| 152 | Oregon Health and Science University | Portland | Oregon | United States | 97239 |
| 153 | Lehigh Valley Hospital - Muhlenberg | Bethlehem | Pennsylvania | United States | 18017 |
| 154 | Geisinger Medical Center | Danville | Pennsylvania | United States | 17822 |
| 155 | Penn State Children's Hospital | Hershey | Pennsylvania | United States | 17033 |
| 156 | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | United States | 19104 |
| 157 | Saint Christopher's Hospital for Children | Philadelphia | Pennsylvania | United States | 19134 |
| 158 | Children's Hospital of Pittsburgh of UPMC | Pittsburgh | Pennsylvania | United States | 15224 |
| 159 | Rhode Island Hospital | Providence | Rhode Island | United States | 02903 |
| 160 | Medical University of South Carolina | Charleston | South Carolina | United States | 29425 |
| 161 | Prisma Health Richland Hospital | Columbia | South Carolina | United States | 29203 |
| 162 | BI-LO Charities Children's Cancer Center | Greenville | South Carolina | United States | 29605 |
| 163 | Sanford USD Medical Center - Sioux Falls | Sioux Falls | South Dakota | United States | 57117-5134 |
| 164 | T C Thompson Children's Hospital | Chattanooga | Tennessee | United States | 37403 |
| 165 | East Tennessee Childrens Hospital | Knoxville | Tennessee | United States | 37916 |
| 166 | Vanderbilt University/Ingram Cancer Center | Nashville | Tennessee | United States | 37232 |
| 167 | Dell Children's Medical Center of Central Texas | Austin | Texas | United States | 78723 |
| 168 | Driscoll Children's Hospital | Corpus Christi | Texas | United States | 78411 |
| 169 | Medical City Dallas Hospital | Dallas | Texas | United States | 75230 |
| 170 | UT Southwestern/Simmons Cancer Center-Dallas | Dallas | Texas | United States | 75390 |
| 171 | El Paso Children's Hospital | El Paso | Texas | United States | 79905 |
| 172 | Brooke Army Medical Center | Fort Sam Houston | Texas | United States | 78234 |
| 173 | Cook Children's Medical Center | Fort Worth | Texas | United States | 76104 |
| 174 | Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center | Houston | Texas | United States | 77030 |
| 175 | Covenant Children's Hospital | Lubbock | Texas | United States | 79410 |
| 176 | Children's Hospital of San Antonio | San Antonio | Texas | United States | 78207 |
| 177 | Methodist Children's Hospital of South Texas | San Antonio | Texas | United States | 78229 |
| 178 | University of Texas Health Science Center at San Antonio | San Antonio | Texas | United States | 78229 |
| 179 | Scott and White Memorial Hospital | Temple | Texas | United States | 76508 |
| 180 | Primary Children's Hospital | Salt Lake City | Utah | United States | 84113 |
| 181 | University of Vermont and State Agricultural College | Burlington | Vermont | United States | 05405 |
| 182 | Inova Fairfax Hospital | Falls Church | Virginia | United States | 22042 |
| 183 | Children's Hospital of The King's Daughters | Norfolk | Virginia | United States | 23507 |
| 184 | Virginia Commonwealth University/Massey Cancer Center | Richmond | Virginia | United States | 23298 |
| 185 | Carilion Children's | Roanoke | Virginia | United States | 24014 |
| 186 | Seattle Children's Hospital | Seattle | Washington | United States | 98105 |
| 187 | Providence Sacred Heart Medical Center and Children's Hospital | Spokane | Washington | United States | 99204 |
| 188 | Mary Bridge Children's Hospital and Health Center | Tacoma | Washington | United States | 98405 |
| 189 | Madigan Army Medical Center | Tacoma | Washington | United States | 98431 |
| 190 | West Virginia University Charleston Division | Charleston | West Virginia | United States | 25304 |
| 191 | West Virginia University Healthcare | Morgantown | West Virginia | United States | 26506 |
| 192 | Saint Vincent Hospital Cancer Center Green Bay | Green Bay | Wisconsin | United States | 54301 |
| 193 | University of Wisconsin Carbone Cancer Center | Madison | Wisconsin | United States | 53792 |
| 194 | Marshfield Medical Center-Marshfield | Marshfield | Wisconsin | United States | 54449 |
| 195 | Children's Hospital of Wisconsin | Milwaukee | Wisconsin | United States | 53226 |
| 196 | John Hunter Children's Hospital | Hunter Regional Mail Centre | New South Wales | Australia | 2310 |
| 197 | Sydney Children's Hospital | Randwick | New South Wales | Australia | 2031 |
| 198 | The Children's Hospital at Westmead | Westmead | New South Wales | Australia | 2145 |
| 199 | Royal Brisbane and Women's Hospital | Herston | Queensland | Australia | 4029 |
| 200 | Royal Children's Hospital-Brisbane | Herston | Queensland | Australia | 4029 |
| 201 | Queensland Children's Hospital | South Brisbane | Queensland | Australia | 4101 |
| 202 | Royal Children's Hospital | Parkville | Victoria | Australia | 3052 |
| 203 | Princess Margaret Hospital for Children | Perth | Western Australia | Australia | 6008 |
| 204 | Alberta Children's Hospital | Calgary | Alberta | Canada | T3B 6A8 |
| 205 | University of Alberta Hospital | Edmonton | Alberta | Canada | T6G 2B7 |
| 206 | British Columbia Children's Hospital | Vancouver | British Columbia | Canada | V6H 3V4 |
| 207 | CancerCare Manitoba | Winnipeg | Manitoba | Canada | R3E 0V9 |
| 208 | Janeway Child Health Centre | Saint John's | Newfoundland and Labrador | Canada | A1B 3V6 |
| 209 | IWK Health Centre | Halifax | Nova Scotia | Canada | B3K 6R8 |
| 210 | McMaster Children's Hospital at Hamilton Health Sciences | Hamilton | Ontario | Canada | L8N 3Z5 |
| 211 | Kingston Health Sciences Centre | Kingston | Ontario | Canada | K7L 2V7 |
| 212 | Children's Hospital | London | Ontario | Canada | N6A 5W9 |
| 213 | Children's Hospital of Eastern Ontario | Ottawa | Ontario | Canada | K1H 8L1 |
| 214 | Hospital for Sick Children | Toronto | Ontario | Canada | M5G 1X8 |
| 215 | The Montreal Children's Hospital of the MUHC | Montreal | Quebec | Canada | H3H 1P3 |
| 216 | Centre Hospitalier Universitaire Sainte-Justine | Montreal | Quebec | Canada | H3T 1C5 |
| 217 | Centre Hospitalier Universitaire de Quebec | Quebec | Canada | G1V 4G2 | |
| 218 | Starship Children's Hospital | Grafton | Auckland | New Zealand | 1145 |
| 219 | Christchurch Hospital | Christchurch | New Zealand | 8011 | |
| 220 | San Jorge Children's Hospital | San Juan | Puerto Rico | 00912 |
Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Richard Aplenc, Children's Oncology Group
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.Responsible Party:
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01371981
Other Study ID Numbers:
- NCI-2011-02670
- NCI-2011-02670
- CDR0000701850
- AAML1031
- COG-AAML1031
- S12-02301
- AAML1031
- AAML1031
- U10CA180886
- U10CA098543
First Posted:
Jun 13, 2011
Last Update Posted:
Jul 28, 2022
Last Verified:
Jul 1, 2022
Studies a U.S. FDA-regulated Drug Product:
Yes
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | Results in the Participant Flow table summarize final (or analysis) arm assignment. Therefore, results for patients on Arms A, B, and D do not include any patient who transferred to Arm C. |
| Arm/Group Title | Arm A | Arm B | Arm C (Cohort 1) | Arm C (Cohort 2) | Arm C (Cohort 3) | Arm D |
|---|---|---|---|---|---|---|
| Arm/Group Description | INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days 1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days 2,9. SCT: pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. | IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. | IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year. | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INT I: Pts receive cytarabine IT and AE as in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year. | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO days 11-28. IND II: Pts receive cytarabine IT day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours days 1-5, sorafenib tosylate PO days 9-36. INT I: Pts receive cytarabine IT & AE as in Arm A, INT II, & sorafenib tosylate PO daily days 6-28. INT II: Pts receive cytarabine IT day 1, MA as in Arm A, IND II (HR patients), & sorafenib tosylate PO days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily days -5 to -2. Pts undergo allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for 1 year. | INDUCTION I: Patients with unknown FLT3/ITD status prior to study enrollment receive cytarabine IT and ADE chemotherapy as in Arm A, Induction I. If patients are determined to be HR FLT3/ITD+ no later than the end of Induction I they will be eligible to participate in Arm C. |
| Period Title: Overall Study | ||||||
| STARTED | 580 | 591 | 12 | 33 | 47 | 382 |
| COMPLETED | 396 | 399 | 6 | 12 | 15 | 368 |
| NOT COMPLETED | 184 | 192 | 6 | 21 | 32 | 14 |
Baseline Characteristics
| Arm/Group Title | Arm A | Arm B | Arm C (Cohort 1) | Arm C (Cohort 2) | Arm C (Cohort 3) | Arm D | Total |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. | IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. | IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year. | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year. | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO days 11-28. IND II: Pts receive cytarabine IT day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours days 1-5, sorafenib tosylate PO days 9-36. INT I: Pts receive cytarabine IT & AE as in Arm A, INT II, & sorafenib tosylate PO daily days 6-28. INT II: Pts receive cytarabine IT day 1, MA as in Arm A, IND II (HR patients), & sorafenib tosylate PO days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily days -5 to -2. Pts undergo allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for 1 year. | INDUCTION I: Patients with unknown FLT3/ITD status prior to study enrollment receive cytarabine IT and ADE chemotherapy as in Arm A, Induction I. If patients are determined to be HR FLT3/ITD+ no later than the end of Induction I they will be eligible to participate in Arm C. | Total of all reporting groups |
| Overall Participants | 580 | 591 | 12 | 33 | 47 | 382 | 1645 |
| Age (years) [Mean (Standard Deviation) ] | |||||||
| Mean (Standard Deviation) [years] |
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 (Count of 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) (Count of 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%
|
8
17%
|
29
7.6%
|
74
4.5%
|
| Race (NIH/OMB) (Count of Participants) | |||||||
| American Indian or Alaska Native |
3
0.5%
|
6
1%
|
0
0%
|
0
0%
|
1
2.1%
|
2
0.5%
|
12
0.7%
|
| Asian |
27
4.7%
|
28
4.7%
|
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%
|
4
1%
|
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%
|
| 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%
|
1
0.2%
|
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%
|
6
12.8%
|
52
13.6%
|
187
11.4%
|
| Region of Enrollment (participants) [Number] | |||||||
| United States |
514
88.6%
|
515
87.1%
|
11
91.7%
|
29
87.9%
|
41
87.2%
|
334
87.4%
|
1444
87.8%
|
| Canada |
31
5.3%
|
43
7.3%
|
1
8.3%
|
3
9.1%
|
5
10.6%
|
24
6.3%
|
107
6.5%
|
| Australia |
23
4%
|
29
4.9%
|
0
0%
|
1
3%
|
1
2.1%
|
15
3.9%
|
69
4.2%
|
| New Zealand |
12
2.1%
|
4
0.7%
|
0
0%
|
0
0%
|
0
0%
|
9
2.4%
|
25
1.5%
|
Outcome Measures
| Title | Event-free Survival (EFS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations |
|---|---|
| Description | The Kaplan-Meier method will be used to estimate 3-year EFS, defined as the time from study entry until induction failure, relapse, secondary malignancy, or death. |
| Time Frame | Up to 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients ineligible, did not start treatment, or on Arm D are excluded from analyses of EFS. Arm D patients who were not eligible for Arm C by the end of induction I were declared off study per protocol; thus, no outcome data were collected for Arm D patients. Arms A and B are limited to patients without high allelic ratio FLT3/ITD+ mutations. |
| Arm/Group Title | Arm A | Arm B |
|---|---|---|
| Arm/Group Description | INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. | IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. |
| Measure Participants | 540 | 552 |
| Number (95% Confidence Interval) [percentage of patients] |
45.64
|
46.95
|
| Title | EFS for Patients on Arm C, Cohort 1 |
|---|---|
| Description | The Kaplan-Meier method will be used to estimate 3-year EFS, defined as the time from study entry until induction failure, relapse, secondary malignancy, or death. |
| Time Frame | Up to 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients ineligible, did not start treatment, or on Arm D are excluded from analyses of EFS. Arm D patients who were not eligible for Arm C by the end of induction I were declared off study per protocol; thus, no outcome data were collected for Arm D patients. |
| Arm/Group Title | Arm C (Cohort 1) |
|---|---|
| Arm/Group Description | IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year. |
| Measure Participants | 12 |
| Number (95% Confidence Interval) [percentage of patients] |
25.00
|
| Title | EFS for Patients on Arm C, Cohort 2 |
|---|---|
| Description | The Kaplan-Meier method will be used to estimate 3-year EFS, defined as the time from study entry until induction failure, relapse, secondary malignancy, or death. |
| Time Frame | Up to 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients ineligible, did not start treatment, or on Arm D are excluded from analyses of EFS. Arm D patients who were not eligible for Arm C by the end of induction I were declared off study per protocol; thus, no outcome data were collected for Arm D patients. |
| Arm/Group Title | Arm C (Cohort 2) |
|---|---|
| Arm/Group Description | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year. |
| Measure Participants | 33 |
| Number (95% Confidence Interval) [percentage of patients] |
56.12
|
| Title | EFS for Patients on Arm C, Cohort 3 |
|---|---|
| Description | The Kaplan-Meier method will be used to estimate 3-year EFS, defined as the time from study entry until induction failure, relapse, secondary malignancy, or death. |
| Time Frame | Up to 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients ineligible, did not start treatment, or on Arm D are excluded from analyses of EFS. Arm D patients who were not eligible for Arm C by the end of induction I were declared off study per protocol; thus, no outcome data were collected for Arm D patients. |
| Arm/Group Title | Arm C (Cohort 3) |
|---|---|
| Arm/Group Description | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO days 11-28. IND II: Pts receive cytarabine IT day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours days 1-5, sorafenib tosylate PO days 9-36. INT I: Pts receive cytarabine IT & AE as in Arm A, INT II, & sorafenib tosylate PO daily days 6-28. INT II: Pts receive cytarabine IT day 1, MA as in Arm A, IND II (HR patients), & sorafenib tosylate PO days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily days -5 to -2. Pts undergo allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for 1 year. |
| Measure Participants | 47 |
| Number (95% Confidence Interval) [percentage of patients] |
58.18
|
| Title | Overall Survival (OS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations |
|---|---|
| Description | The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death. |
| Time Frame | Up to 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients ineligible, did not start treatment, or on Arm D are excluded from analyses of OS. Arm D patients who were not eligible for Arm C by the end of induction I were declared off study per protocol; thus, no outcome data were collected for Arm D patients. Arms A and B are limited to patients without high allelic ratio FLT3/ITD+ mutations. |
| Arm/Group Title | Arm A | Arm B |
|---|---|---|
| Arm/Group Description | INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. | IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. |
| Measure Participants | 540 | 552 |
| Number (95% Confidence Interval) [percentage of patients] |
65.04
|
68.45
|
| Title | OS for Patients on Arm C, Cohort 1 |
|---|---|
| Description | The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death. |
| Time Frame | Up to 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients ineligible, did not start treatment, or on Arm D are excluded from analyses of OS. Arm D patients who were not eligible for Arm C by the end of induction I were declared off study per protocol; thus, no outcome data were collected for Arm D patients. |
| Arm/Group Title | Arm C (Cohort 1) |
|---|---|
| Arm/Group Description | IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year. |
| Measure Participants | 12 |
| Number (95% Confidence Interval) [percentage of patients] |
41.67
|
| Title | OS for Patients on Arm C, Cohort 2 |
|---|---|
| Description | The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death. |
| Time Frame | Up to 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients ineligible, did not start treatment, or on Arm D are excluded from analyses of OS. Arm D patients who were not eligible for Arm C by the end of induction I were declared off study per protocol; thus, no outcome data were collected for Arm D patients. |
| Arm/Group Title | Arm C (Cohort 2) |
|---|---|
| Arm/Group Description | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year. |
| Measure Participants | 33 |
| Number (95% Confidence Interval) [percentage of patients] |
64.77
|
| Title | OS for Patients on Arm C, Cohort 3 |
|---|---|
| Description | The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death. |
| Time Frame | Up to 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients ineligible, did not start treatment, or on Arm D are excluded from analyses of OS. Arm D patients who were not eligible for Arm C by the end of induction I were declared off study per protocol; thus, no outcome data were collected for Arm D patients. |
| Arm/Group Title | Arm C (Cohort 3) |
|---|---|
| Arm/Group Description | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO days 11-28. IND II: Pts receive cytarabine IT day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours days 1-5, sorafenib tosylate PO days 9-36. INT I: Pts receive cytarabine IT & AE as in Arm A, INT II, & sorafenib tosylate PO daily days 6-28. INT II: Pts receive cytarabine IT day 1, MA as in Arm A, IND II (HR patients), & sorafenib tosylate PO days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily days -5 to -2. Pts undergo allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for 1 year. |
| Measure Participants | 47 |
| Number (95% Confidence Interval) [percentage of patients] |
61.84
|
| Title | Relapse Rate for Patients Without High Allelic Ratio FLT3/ITD+ Mutations |
|---|---|
| Description | Cumulative incidence estimates 3 year relapse rate defined as time from study entry to induction failure or relapse where deaths or secondary malignancies are competing events. |
| Time Frame | Up to 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients ineligible, did not start treatment, or on Arms C or D are excluded. Arm D patients who were not eligible for Arm C by the end of induction I were declared off study per protocol; thus, no outcome data were collected for Arm D patients. Results are limited to patients on Arms A and B without high allelic ratio FLT3/ITD+ mutations. |
| Arm/Group Title | Arm A | Arm B |
|---|---|---|
| Arm/Group Description | INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. | IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. |
| Measure Participants | 540 | 552 |
| Number (95% Confidence Interval) [percentage of patients] |
46.67
|
46.65
|
| Title | Proportion of Patients Experiencing Grade 3 or Higher Non-hematologic Toxicities and Infections While on Protocol Therapy |
|---|---|
| Description | The proportion of patients experiencing at least one grade 3 or higher non-hematologic toxicity and infection while on protocol therapy will be estimated along with the corresponding 95% confidence interval determined using a binomial exact method. Toxicity will be assessed by Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). |
| Time Frame | Up to 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients ineligible or who did not start treatment are excluded from results. |
| Arm/Group Title | Arm A | Arm B | Arm C (Cohort 1) | Arm C (Cohort 2) | Arm C (Cohort 3) | Arm D |
|---|---|---|---|---|---|---|
| Arm/Group Description | INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. | IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. | IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year. | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year. | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO days 11-28. IND II: Pts receive cytarabine IT day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours days 1-5, sorafenib tosylate PO days 9-36. INT I: Pts receive cytarabine IT & AE as in Arm A, INT II, & sorafenib tosylate PO daily days 6-28. INT II: Pts receive cytarabine IT day 1, MA as in Arm A, IND II (HR patients), & sorafenib tosylate PO days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily days -5 to -2. Pts undergo allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for 1 year. | INDUCTION I: Patients with unknown FLT3/ITD status prior to study enrollment receive cytarabine IT and ADE chemotherapy as in Arm A, Induction I. If patients are determined to be HR FLT3/ITD+ no later than the end of Induction I they will be eligible to participate in Arm C. |
| Measure Participants | 559 | 575 | 12 | 33 | 47 | 376 |
| Number (95% Confidence Interval) [Proportion of patients] |
0.8819
|
0.9217
|
0.9167
|
0.9394
|
0.9149
|
0.0239
|
| Title | Proportion of High Risk Children Without HR FLT3/ITD+ Converting From Positive MRD at End of Induction I to Negative MRD at the End of Induction II |
|---|---|
| Description | The proportion of high risk children without HR FLT3/ITD+ converting from positive MRD at end of Induction I to negative MRD at the end of Induction II will be estimated as well as the corresponding 95% confidence interval determined using a binomial exact method. |
| Time Frame | Up to 8 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients ineligible, did not start treatment, on Arms C, D are excluded from results. Complete MRD results were not collected for Arm D patients due to being declared off study at end of induction I. Results limited to High Risk patients without high allelic ratio FLT3/ITD+ mutations and with evaluable MRD data from end of Induction I and II. |
| Arm/Group Title | Arm A | Arm B |
|---|---|---|
| Arm/Group Description | INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. | IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. |
| Measure Participants | 76 | 84 |
| Number (95% Confidence Interval) [Proportion of patients] |
0.5000
|
0.5238
|
| Title | Total Scale Score From Parent-reported Pediatric Quality of Life Inventory Module |
|---|---|
| Description | Results represent the total scale scores from the parent report of the PedsQL™ 4.0 Generic Core Scales for timepoint 1 (up to 14 days from start of therapy). Items are reverse-scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. Therefore, a higher number is a better outcome. The total score is the sum of all the items divided by the number of items answered on all the scales. "Scores on a scale" is used for a unit of measure. |
| Time Frame | Up to 14 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients ineligible or who did not start treatment are excluded from results. Patients on Arms C (cohort 3) or Arm D are excluded due to enrolling post quality of life study accrual completion. Results are limited to only patients with an evaluable total scale score. |
| Arm/Group Title | Arm A | Arm B | Arm C (Cohort 1) | Arm C (Cohort 2) |
|---|---|---|---|---|
| Arm/Group Description | INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. | IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. | IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year. | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year. |
| Measure Participants | 228 | 195 | 8 | 16 |
| Mean (Inter-Quartile Range) [Scores on a scale] |
68.3
|
67.8
|
71.3
|
61.6
|
| Title | Total Scale Score From Parent-reported Cancer Module |
|---|---|
| Description | Results represent the total scale scores from the parent report of the PedsQL™ 3.0 Cancer Module for timepoint 1 (up to 14 days from start of therapy). Items are reverse-scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. Therefore, a higher number is a better outcome. The total score is the sum of all the items divided by the number of items answered on all the scales. "Scores on a scale" is used for a unit of measure. |
| Time Frame | Up to 14 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients ineligible or who did not start treatment are excluded from results. Patients on Arms C (cohort 3) or Arm D are excluded due to enrolling post quality of life study accrual completion. Results are limited to only patients with an evaluable total scale score. |
| Arm/Group Title | Arm A | Arm B | Arm C (Cohort 1) | Arm C (Cohort 2) |
|---|---|---|---|---|
| Arm/Group Description | INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. | IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. | IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year. | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year. |
| Measure Participants | 230 | 193 | 8 | 16 |
| Mean (Inter-Quartile Range) [Scores on a scale] |
66.2
|
65.8
|
74.9
|
63.7
|
| Title | Total Scale Score From Parent-reported Multidimensional Fatigue Scale Module |
|---|---|
| Description | Results represent the total scale scores from the parent report of the PedsQL™ Multidimensional Fatigue Scale for timepoint 1 (up to 14 days from start of therapy). Items are reverse-scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. Therefore, a higher number is a better outcome. The total score is the sum of all the items divided by the number of items answered on all the scales. "Scores on a scale" is used for a unit of measure. |
| Time Frame | Up to 14 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients ineligible or who did not start treatment are excluded from results. Patients on Arms C (cohort 3) or Arm D are excluded due to enrolling post quality of life study accrual completion. Results are limited to only patients with an evaluable total scale score. |
| Arm/Group Title | Arm A | Arm B | Arm C (Cohort 1) | Arm C (Cohort 2) |
|---|---|---|---|---|
| Arm/Group Description | INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. | IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. | IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year. | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year. |
| Measure Participants | 226 | 194 | 8 | 16 |
| Mean (Inter-Quartile Range) [Scores on a scale] |
60.5
|
58.1
|
71.2
|
48.2
|
| Title | Bortezomib Clearance |
|---|---|
| Description | Median and range of bortezomib clearance during Induction II. |
| Time Frame | Day 8 of Induction II |
Outcome Measure Data
| Analysis Population Description |
|---|
| Only eligible patients on Arm B with evaluable Bortezomib PK clearance data during Induction II are reported. |
| Arm/Group Title | Arm B |
|---|---|
| Arm/Group Description | IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. |
| Measure Participants | 53 |
| Median (Full Range) [Liters/hour/m^2] |
8.42
|
| Title | Sorafenib Steady State Concentration |
|---|---|
| Description | Median and range of sorafenib steady state concentration for Induction I. |
| Time Frame | Up to 30 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data reported from Arm C were collected and analyzed regardless of the cohort as pre-specified in the study protocol. Only eligible patients on Arm C with evaluable Sorafenib steady state concentration data during Induction I are reported. |
| Arm/Group Title | Arm C |
|---|---|
| Arm/Group Description | Arm C (Cohort 1) IND II:cytarabine IT; cytarabine IV; daunorubicin hydrochloride IV; etoposide IV; sorafenib tosylate PO INT I:cytarabine IT; AE chemotherapy as Arm A, Intensification II; sorafenib tosylate PO INT II:cytarabine IT; MA chemotherapy as Arm A, Induction II (HR patients); sorafenib tosylate PO. SCT (HR pts w/ matched family [MFD] or unrelated donor): fludarabine phosphate IV; busulfan IV; allogeneic SCT; GVHD prophylaxis. MAINTENANCE:sorafenib tosylate PO Arm C (Cohort 2 and 3) IND I:cytarabine IT; ADE as Arm A, IND I; sorafenib tosylate PO IND II:cytarabine IT; cytarabine IV; daunorubicin hydrochloride IV; etoposide IV; sorafenib tosylate PO INT I:cytarabine IT; AE as Arm A, INT II, & sorafenib tosylate PO INT II:cytarabine IT; MA as Arm A, IND II (HR patients); sorafenib tosylate PO. SCT (HR pts w/ matched family [MFD] or unrelated donor): fludarabine phosphate IV; busulfan IV; allogeneic SCT; GVHD prophylaxis. MAINTENANCE:sorafenib tosylate PO |
| Measure Participants | 23 |
| Median (Full Range) [Nanogram/Milliliter] |
1090.0
|
| Title | Change in Shortening Fraction |
|---|---|
| Description | Mean percentage change in shortening fraction from baseline to the end of Induction I will be determined for eligible patients enrolled on Arms A, B and C. |
| Time Frame | Up to 4 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients ineligible, did not start treatment, or on Arm D are excluded from results. Shortening fraction data were not collected at end of Induction I for patients enrolled to Arm D. Results are limited to patients with evaluable shortening fraction data from study entry and at end of Induction I . |
| Arm/Group Title | Arm A | Arm B | Arm C (Cohort 1) | Arm C (Cohort 2) | Arm C (Cohort 3) |
|---|---|---|---|---|---|
| Arm/Group Description | INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. | IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. | IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year. | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year. | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO days 11-28. IND II: Pts receive cytarabine IT day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours days 1-5, sorafenib tosylate PO days 9-36. INT I: Pts receive cytarabine IT & AE as in Arm A, INT II, & sorafenib tosylate PO daily days 6-28. INT II: Pts receive cytarabine IT day 1, MA as in Arm A, IND II (HR patients), & sorafenib tosylate PO days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily days -5 to -2. Pts undergo allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for 1 year. |
| Measure Participants | 499 | 503 | 9 | 32 | 41 |
| Mean (Standard Error) [Percentage change] |
-1.8445
(5.2070)
|
-2.6298
(6.7797)
|
-2.2333
(4.7689)
|
-3.6700
(5.3115)
|
-3.4246
(4.8583)
|
| Title | Change in Ejection Fraction |
|---|---|
| Description | The mean percentage change in ejection fraction from baseline to the end of Induction I will be determined for eligible patients enrolled on Arms A, B and C. |
| Time Frame | Up to 4 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients ineligible, did not start treatment, or on Arm D are excluded from results. Ejection fraction data were not collected at end of Induction I for patients enrolled to Arm D. Results are limited to patients with evaluable ejection fraction data from study entry and at end of Induction I . |
| Arm/Group Title | Arm A | Arm B | Arm C (Cohort 1) | Arm C (Cohort 2) | Arm C (Cohort 3) |
|---|---|---|---|---|---|
| Arm/Group Description | INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. | IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. | IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year. | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year. | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO days 11-28. IND II: Pts receive cytarabine IT day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours days 1-5, sorafenib tosylate PO days 9-36. INT I: Pts receive cytarabine IT & AE as in Arm A, INT II, & sorafenib tosylate PO daily days 6-28. INT II: Pts receive cytarabine IT day 1, MA as in Arm A, IND II (HR patients), & sorafenib tosylate PO days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily days -5 to -2. Pts undergo allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for 1 year. |
| Measure Participants | 426 | 425 | 6 | 30 | 38 |
| Mean (Standard Deviation) [Percentage change] |
-2.0272
(7.1843)
|
-2.3453
(7.6974)
|
-7.5000
(12.5340)
|
-5.1997
(7.0532)
|
-3.4624
(6.7516)
|
| Title | Serum Concentrations of GVHD Biomarker |
|---|---|
| Description | The mean serum concentration of the day 28 GVHD biomarker will be estimated as well as the corresponding 95% confidence interval. |
| Time Frame | Up to day 28 after SCT |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data were never collected |
| Arm/Group Title | Arm A | Arm B | Arm C (Cohort 1) | Arm C (Cohort 2) | Arm C (Cohort 3) |
|---|---|---|---|---|---|
| Arm/Group Description | INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. | IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. | IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year. | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year. | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO days 11-28. IND II: Pts receive cytarabine IT day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours days 1-5, sorafenib tosylate PO days 9-36. INT I: Pts receive cytarabine IT & AE as in Arm A, INT II, & sorafenib tosylate PO daily days 6-28. INT II: Pts receive cytarabine IT day 1, MA as in Arm A, IND II (HR patients), & sorafenib tosylate PO days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily days -5 to -2. Pts undergo allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for 1 year. |
| Measure Participants | 0 | 0 | 0 | 0 | 0 |
| Title | Course Duration |
|---|---|
| Description | Descriptive statistics will be used to summarize length of hospitalization time. |
| Time Frame | Up to 6 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Incidence of Treatment-related Mortality |
|---|---|
| Description | Cumulative incidence estimates that account for competing events will be used to estimate treatment-related mortality. |
| Time Frame | Up to 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Length of Hospitalization |
|---|---|
| Description | Descriptive statistics will be used to summarize length of hospitalization time. |
| Time Frame | Up to 6 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Remission Rate After 1 Course of Therapy |
|---|---|
| Description | The proportion of patients achieving remission after 1 course of therapy will be estimated along with a corresponding 95% confidence interval. |
| Time Frame | 4 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Remission Rate After 2 Courses of Therapy |
|---|---|
| Description | The proportion of patients achieving remission after 2 courses of therapy will be estimated along with a corresponding 95% confidence interval. |
| Time Frame | 8 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Time to Blood Count Recovery |
|---|---|
| Description | Cumulative incidence estimates that account for competing events will be used to estimate time to count recovery. |
| Time Frame | Up to 6 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
Adverse Events
| Time Frame | While patients were on protocol therapy (including up to 4 courses, stem cell transplant course, and 3 courses of maintenance therapy)) or up to 7 years in follow-up. | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study. | |||||||||||
| Arm/Group Title | Arm A | Arm B | Arm C (Cohort 1) | Arm C (Cohort 2) | Arm C (Cohort 3) | Arm D | ||||||
| Arm/Group Description | INDUCTION (IND) 1Pts receive intrathecal (IT) cytarabine on day 1 and ADE with IV cytarabine over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes days1, 3, 5; etoposide IV 1-2 hours days1-5. IND IILow risk (LR) pts receive cytarabine IT and ADE chemotherapy as in INDI. High risk (HR) cytarabine IT day 1, MA chemo comprising high-dose cytarabine IV over 1-3 hours days1-4, mitoxantrone IV over 15-30 minutes days 3-6. INTENSIFICATION (INT) I: cytarabine IT day 1, AE chemo with high-dose cytarabine IV over 1-3 hours, etoposide IV over 1-2 hours days 1-5. INT II: LR-cytarabine IT day 1; Induction II MA chemo. HR and no SCT donor - high-dose cytarabine IV over 3 hours days1, 2, 8, 9; asparaginase intramuscularly (IM) days2,9. SCT: : pts receive fludarabine phosphate IV over 30 minutes once daily days -5 to -2, busulfan IV over 2 hours 4 times daily days -5 to -2. Allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. | IND I: Pts receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8. IND II: LR pts receive cytarabine IT, ADE chemotherapy, bortezomib as in IND I. HR pts receive cytarabine IT, MA as in IND II, Arm A (HR patients) and bortezomib IV on days 1, 4, 8. INT I: Pts receive cytarabine IT and AE in Arm A, Intensification II, and bortezomib IV on days 1, 4, 8. INT II: LR pts receive cytarabine IT on day 1, MA as in Arm A, IND II (HR patients), and bortezomib IV on days 1, 4, 8. HR pts with no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, 9 and asparaginase intramuscularly (IM) on days 2 and 9. SCT - Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2.Pts undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. | IND II: Pts receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, sorafenib tosylate PO on days 9-36. INT I: Pts receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INT II: Pts receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), sorafenib tosylate PO on days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2, busulfan IV over 2 hours 4 times daily on days -5 to -2. Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for one year. | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including IND I & concurrently with chemo). IND II: Pts receive cytarabine IT day (d) 1, cytarabine IV over 1-30 minutes on d 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours d 1-5, sorafenib tosylate PO d 9-36. INTE I: Pts receive cytarabine IT and AE in Arm A, INT II, and sorafenib tosylate PO on daily d 6-28. INT II: Pts receive cytarabine IT on d 1, MA as in Arm A, IND II (HR pts), sorafenib tosylate PO d 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on d -5 to -2, busulfan IV over 2 hours 4 times daily d -5 to -2. Pts undergo allogeneic SCT within 36-48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting d 40-100 after INT II or SCT for 1 year. | IND I: Pts receive cytarabine IT & ADE as in Arm A, IND I & sorafenib tosylate PO days 11-28. IND II: Pts receive cytarabine IT day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes days 1, 3, 5, etoposide IV over 1-2 hours days 1-5, sorafenib tosylate PO days 9-36. INT I: Pts receive cytarabine IT & AE cin Arm A, INT II, & sorafenib tosylate PO daily days 6-28. INT II: Pts receive cytarabine IT day 1, MA as in Arm A, IND II (HR patients), & sorafenib tosylate PO days 7-34. SCT (HR patients with matched family [MFD] or unrelated donor): Pts receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily days -5 to -2. Pts undergo allogeneic SCT within 36 to 48 hours after last busulfan dose. Pts receive GVHD prophylaxis. MAINTENANCE: Pts receive sorafenib tosylate PO starting day 40-100 after INT II or SCT for 1 year. | INDUCTION I: Patients with unknown FLT3/ITD status prior to study enrollment receive cytarabine IT and ADE chemotherapy as in Arm A, Induction I. If patients are determined to be HR FLT3/ITD+ no later than the end of Induction I they will be eligible to participate in Arm C. | ||||||
All Cause Mortality |
||||||||||||
| Arm A | Arm B | Arm C (Cohort 1) | Arm C (Cohort 2) | Arm C (Cohort 3) | Arm D | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 198/559 (35.4%) | 189/575 (32.9%) | 7/12 (58.3%) | 11/33 (33.3%) | 16/47 (34%) | 2/376 (0.5%) | ||||||
Serious Adverse Events |
||||||||||||
| Arm A | Arm B | Arm C (Cohort 1) | Arm C (Cohort 2) | Arm C (Cohort 3) | Arm D | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 82/559 (14.7%) | 305/575 (53%) | 6/12 (50%) | 16/33 (48.5%) | 30/47 (63.8%) | 2/376 (0.5%) | ||||||
| Blood and lymphatic system disorders | ||||||||||||
| Anemia | 0/559 (0%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Blood and lymphatic system disorders - Other, specify | 1/559 (0.2%) | 4/575 (0.7%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Bone marrow hypocellular | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Disseminated intravascular coagulation | 3/559 (0.5%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Febrile neutropenia | 0/559 (0%) | 21/575 (3.7%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hemolysis | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hemolytic uremic syndrome | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Leukocytosis | 0/559 (0%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Cardiac disorders | ||||||||||||
| Asystole | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Atrial fibrillation | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Atrial flutter | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Cardiac arrest | 3/559 (0.5%) | 4/575 (0.7%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Cardiac disorders - Other, specify | 0/559 (0%) | 7/575 (1.2%) | 0/12 (0%) | 1/33 (3%) | 2/47 (4.3%) | 0/376 (0%) | ||||||
| Chest pain - cardiac | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Heart failure | 4/559 (0.7%) | 15/575 (2.6%) | 0/12 (0%) | 1/33 (3%) | 2/47 (4.3%) | 0/376 (0%) | ||||||
| Left ventricular systolic dysfunction | 3/559 (0.5%) | 23/575 (4%) | 0/12 (0%) | 2/33 (6.1%) | 4/47 (8.5%) | 0/376 (0%) | ||||||
| Myocardial infarction | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pericardial effusion | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pericarditis | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Restrictive cardiomyopathy | 0/559 (0%) | 4/575 (0.7%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Right ventricular dysfunction | 2/559 (0.4%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Sinus bradycardia | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Sinus tachycardia | 0/559 (0%) | 10/575 (1.7%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Supraventricular tachycardia | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Ventricular arrhythmia | 0/559 (0%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Ventricular fibrillation | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Ventricular tachycardia | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Endocrine disorders | ||||||||||||
| Adrenal insufficiency | 0/559 (0%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Endocrine disorders - Other, specify | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hypothyroidism | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Eye disorders | ||||||||||||
| Eye disorders - Other, specify | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Optic nerve disorder | 0/559 (0%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Papilledema | 0/559 (0%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Gastrointestinal disorders | ||||||||||||
| Abdominal distension | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Abdominal pain | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Anal pain | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Ascites | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Colitis | 0/559 (0%) | 9/575 (1.6%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Colonic perforation | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Diarrhea | 0/559 (0%) | 9/575 (1.6%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Enterocolitis | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Esophagitis | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Gastric hemorrhage | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Gastritis | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Gastrointestinal disorders - Other, specify | 0/559 (0%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Ileus | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 1/33 (3%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Lower gastrointestinal hemorrhage | 0/559 (0%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Mucositis oral | 0/559 (0%) | 3/575 (0.5%) | 1/12 (8.3%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Nausea | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Oral pain | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pancreatitis | 0/559 (0%) | 8/575 (1.4%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Small intestinal obstruction | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Typhlitis | 2/559 (0.4%) | 24/575 (4.2%) | 0/12 (0%) | 1/33 (3%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Upper gastrointestinal hemorrhage | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Vomiting | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| General disorders | ||||||||||||
| Chills | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Death NOS | 38/559 (6.8%) | 35/575 (6.1%) | 1/12 (8.3%) | 5/33 (15.2%) | 6/47 (12.8%) | 0/376 (0%) | ||||||
| Edema face | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Fever | 0/559 (0%) | 13/575 (2.3%) | 0/12 (0%) | 0/33 (0%) | 3/47 (6.4%) | 0/376 (0%) | ||||||
| Gait disturbance | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hypothermia | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Multi-organ failure | 1/559 (0.2%) | 8/575 (1.4%) | 0/12 (0%) | 0/33 (0%) | 2/47 (4.3%) | 0/376 (0%) | ||||||
| Non-cardiac chest pain | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pain | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hepatobiliary disorders | ||||||||||||
| Bile duct stenosis | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Cholecystitis | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Hepatic failure | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hepatobiliary disorders - Other, specify | 0/559 (0%) | 4/575 (0.7%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Immune system disorders | ||||||||||||
| Allergic reaction | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Anaphylaxis | 0/559 (0%) | 5/575 (0.9%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Immune system disorders - Other, specify | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Infections and infestations | ||||||||||||
| Anorectal infection | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Appendicitis | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Bladder infection | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Bronchial infection | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Catheter related infection | 0/559 (0%) | 5/575 (0.9%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Cecal infection | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Duodenal infection | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Encephalitis infection | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Enterocolitis infectious | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Esophageal infection | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Infections and infestations - Other, specify | 2/559 (0.4%) | 13/575 (2.3%) | 0/12 (0%) | 2/33 (6.1%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Lung infection | 1/559 (0.2%) | 13/575 (2.3%) | 1/12 (8.3%) | 2/33 (6.1%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Lymph gland infection | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Meningitis | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Mucosal infection | 0/559 (0%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Periorbital infection | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Sepsis | 17/559 (3%) | 50/575 (8.7%) | 0/12 (0%) | 1/33 (3%) | 4/47 (8.5%) | 0/376 (0%) | ||||||
| Skin infection | 0/559 (0%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Soft tissue infection | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Tracheitis | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Upper respiratory infection | 1/559 (0.2%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Urinary tract infection | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Injury, poisoning and procedural complications | ||||||||||||
| Infusion related reaction | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Postoperative hemorrhage | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Vascular access complication | 0/559 (0%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Investigations | ||||||||||||
| Activated partial thromboplastin time prolonged | 0/559 (0%) | 4/575 (0.7%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Alanine aminotransferase increased | 0/559 (0%) | 16/575 (2.8%) | 0/12 (0%) | 0/33 (0%) | 2/47 (4.3%) | 0/376 (0%) | ||||||
| Aspartate aminotransferase increased | 1/559 (0.2%) | 10/575 (1.7%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Blood bilirubin increased | 2/559 (0.4%) | 16/575 (2.8%) | 0/12 (0%) | 1/33 (3%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Carbon monoxide diffusing capacity decreased | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Creatinine increased | 0/559 (0%) | 8/575 (1.4%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Ejection fraction decreased | 2/559 (0.4%) | 18/575 (3.1%) | 0/12 (0%) | 2/33 (6.1%) | 4/47 (8.5%) | 0/376 (0%) | ||||||
| Electrocardiogram QT corrected interval prolonged | 1/559 (0.2%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Fibrinogen decreased | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| GGT increased | 0/559 (0%) | 4/575 (0.7%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Investigations - Other, specify | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Lipase increased | 0/559 (0%) | 4/575 (0.7%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Lymphocyte count decreased | 0/559 (0%) | 5/575 (0.9%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Neutrophil count decreased | 0/559 (0%) | 8/575 (1.4%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Platelet count decreased | 0/559 (0%) | 7/575 (1.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Serum amylase increased | 0/559 (0%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Urine output decreased | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Weight loss | 0/559 (0%) | 0/575 (0%) | 0/12 (0%) | 1/33 (3%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| White blood cell decreased | 0/559 (0%) | 5/575 (0.9%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Metabolism and nutrition disorders | ||||||||||||
| Acidosis | 0/559 (0%) | 4/575 (0.7%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Alkalosis | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Anorexia | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Dehydration | 0/559 (0%) | 3/575 (0.5%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hypercalcemia | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hyperglycemia | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hyperkalemia | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Hypernatremia | 2/559 (0.4%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Hypertriglyceridemia | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hypoalbuminemia | 0/559 (0%) | 6/575 (1%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hypocalcemia | 0/559 (0%) | 8/575 (1.4%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hypokalemia | 1/559 (0.2%) | 27/575 (4.7%) | 0/12 (0%) | 2/33 (6.1%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Hypomagnesemia | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hyponatremia | 0/559 (0%) | 10/575 (1.7%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hypophosphatemia | 1/559 (0.2%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Metabolism and nutrition disorders - Other, specify | 2/559 (0.4%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Tumor lysis syndrome | 1/559 (0.2%) | 3/575 (0.5%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||
| Arthralgia | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Back pain | 0/559 (0%) | 4/575 (0.7%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Neck pain | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pain in extremity | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 1/376 (0.3%) | ||||||
| Nervous system disorders | ||||||||||||
| Ataxia | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Central nervous system necrosis | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Cerebrospinal fluid leakage | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Cognitive disturbance | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Depressed level of consciousness | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Dizziness | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Dysesthesia | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Edema cerebral | 1/559 (0.2%) | 4/575 (0.7%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Encephalopathy | 1/559 (0.2%) | 5/575 (0.9%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Headache | 0/559 (0%) | 4/575 (0.7%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hydrocephalus | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hypersomnia | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Intracranial hemorrhage | 2/559 (0.4%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 1/376 (0.3%) | ||||||
| Leukoencephalopathy | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Nervous system disorders - Other, specify | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Neuralgia | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Paresthesia | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Peripheral sensory neuropathy | 0/559 (0%) | 14/575 (2.4%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Reversible posterior leukoencephalopathy syndrome | 0/559 (0%) | 4/575 (0.7%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Seizure | 1/559 (0.2%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Somnolence | 0/559 (0%) | 4/575 (0.7%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Syncope | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Psychiatric disorders | ||||||||||||
| Agitation | 0/559 (0%) | 2/575 (0.3%) | 1/12 (8.3%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Anxiety | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Delirium | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Renal and urinary disorders | ||||||||||||
| Acute kidney injury | 5/559 (0.9%) | 15/575 (2.6%) | 0/12 (0%) | 3/33 (9.1%) | 3/47 (6.4%) | 0/376 (0%) | ||||||
| Cystitis noninfective | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hematuria | 0/559 (0%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Proteinuria | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Renal and urinary disorders - Other, specify | 1/559 (0.2%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||
| Adult respiratory distress syndrome | 3/559 (0.5%) | 15/575 (2.6%) | 0/12 (0%) | 2/33 (6.1%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Apnea | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Aspiration | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Atelectasis | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Bronchopulmonary hemorrhage | 3/559 (0.5%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Bronchospasm | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Cough | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Dyspnea | 1/559 (0.2%) | 12/575 (2.1%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Epistaxis | 0/559 (0%) | 7/575 (1.2%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hypoxia | 3/559 (0.5%) | 55/575 (9.6%) | 1/12 (8.3%) | 3/33 (9.1%) | 3/47 (6.4%) | 0/376 (0%) | ||||||
| Laryngeal edema | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Laryngeal mucositis | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Mediastinal hemorrhage | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pharyngeal mucositis | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pleural effusion | 0/559 (0%) | 8/575 (1.4%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pneumonitis | 0/559 (0%) | 9/575 (1.6%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Productive cough | 0/559 (0%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Pulmonary edema | 3/559 (0.5%) | 12/575 (2.1%) | 0/12 (0%) | 0/33 (0%) | 2/47 (4.3%) | 0/376 (0%) | ||||||
| Pulmonary hypertension | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Respiratory failure | 10/559 (1.8%) | 22/575 (3.8%) | 0/12 (0%) | 2/33 (6.1%) | 2/47 (4.3%) | 0/376 (0%) | ||||||
| Respiratory, thoracic and mediastinal disorders - Other, specify | 1/559 (0.2%) | 6/575 (1%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Sore throat | 0/559 (0%) | 1/575 (0.2%) | 1/12 (8.3%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Stridor | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Tracheal mucositis | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Wheezing | 0/559 (0%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Skin and subcutaneous tissue disorders | ||||||||||||
| Erythroderma | 0/559 (0%) | 0/575 (0%) | 1/12 (8.3%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pain of skin | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Palmar-plantar erythrodysesthesia syndrome | 0/559 (0%) | 1/575 (0.2%) | 1/12 (8.3%) | 1/33 (3%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Pruritus | 0/559 (0%) | 1/575 (0.2%) | 1/12 (8.3%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Rash maculo-papular | 0/559 (0%) | 10/575 (1.7%) | 1/12 (8.3%) | 2/33 (6.1%) | 3/47 (6.4%) | 0/376 (0%) | ||||||
| Skin and subcutaneous tissue disorders - Other, specify | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Toxic epidermal necrolysis | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Urticaria | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Vascular disorders | ||||||||||||
| Capillary leak syndrome | 0/559 (0%) | 5/575 (0.9%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Flushing | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hypertension | 0/559 (0%) | 10/575 (1.7%) | 0/12 (0%) | 1/33 (3%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Hypotension | 7/559 (1.3%) | 47/575 (8.2%) | 1/12 (8.3%) | 3/33 (9.1%) | 3/47 (6.4%) | 0/376 (0%) | ||||||
| Peripheral ischemia | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Thromboembolic event | 3/559 (0.5%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
Other (Not Including Serious) Adverse Events |
||||||||||||
| Arm A | Arm B | Arm C (Cohort 1) | Arm C (Cohort 2) | Arm C (Cohort 3) | Arm D | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 506/559 (90.5%) | 529/575 (92%) | 12/12 (100%) | 32/33 (97%) | 41/47 (87.2%) | 7/376 (1.9%) | ||||||
| Blood and lymphatic system disorders | ||||||||||||
| Anemia | 4/559 (0.7%) | 5/575 (0.9%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Blood and lymphatic system disorders - Other, specify | 3/559 (0.5%) | 1/575 (0.2%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Bone marrow hypocellular | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Disseminated intravascular coagulation | 3/559 (0.5%) | 3/575 (0.5%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Febrile neutropenia | 212/559 (37.9%) | 175/575 (30.4%) | 6/12 (50%) | 8/33 (24.2%) | 12/47 (25.5%) | 2/376 (0.5%) | ||||||
| Leukocytosis | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Lymph node pain | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Thrombotic thrombocytopenic purpura | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Cardiac disorders | ||||||||||||
| Asystole | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Cardiac arrest | 4/559 (0.7%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Cardiac disorders - Other, specify | 8/559 (1.4%) | 16/575 (2.8%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Chest pain - cardiac | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Heart failure | 21/559 (3.8%) | 22/575 (3.8%) | 1/12 (8.3%) | 2/33 (6.1%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Left ventricular systolic dysfunction | 30/559 (5.4%) | 28/575 (4.9%) | 1/12 (8.3%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pericardial effusion | 4/559 (0.7%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pulmonary valve disease | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Restrictive cardiomyopathy | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Right ventricular dysfunction | 3/559 (0.5%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Sinus bradycardia | 1/559 (0.2%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Sinus tachycardia | 13/559 (2.3%) | 7/575 (1.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Supraventricular tachycardia | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Tricuspid valve disease | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Ventricular arrhythmia | 2/559 (0.4%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Ventricular fibrillation | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Ventricular tachycardia | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Congenital, familial and genetic disorders | ||||||||||||
| Congenital, familial and genetic disorders - Other, specify | 0/559 (0%) | 0/575 (0%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Ear and labyrinth disorders | ||||||||||||
| Hearing impaired | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Endocrine disorders | ||||||||||||
| Adrenal insufficiency | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Endocrine disorders - Other, specify | 0/559 (0%) | 0/575 (0%) | 1/12 (8.3%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Eye disorders | ||||||||||||
| Blurred vision | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Eye disorders - Other, specify | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Eye pain | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Periorbital edema | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Vitreous hemorrhage | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Gastrointestinal disorders | ||||||||||||
| Abdominal distension | 3/559 (0.5%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Abdominal pain | 28/559 (5%) | 26/575 (4.5%) | 1/12 (8.3%) | 4/33 (12.1%) | 5/47 (10.6%) | 0/376 (0%) | ||||||
| Anal mucositis | 3/559 (0.5%) | 1/575 (0.2%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Anal pain | 7/559 (1.3%) | 4/575 (0.7%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Anal ulcer | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Ascites | 3/559 (0.5%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Colitis | 20/559 (3.6%) | 15/575 (2.6%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Constipation | 2/559 (0.4%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Dental caries | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Diarrhea | 37/559 (6.6%) | 48/575 (8.3%) | 1/12 (8.3%) | 5/33 (15.2%) | 4/47 (8.5%) | 1/376 (0.3%) | ||||||
| Duodenal ulcer | 0/559 (0%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Dysphagia | 0/559 (0%) | 0/575 (0%) | 1/12 (8.3%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Enterocolitis | 2/559 (0.4%) | 8/575 (1.4%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Esophageal hemorrhage | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Esophageal pain | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Esophageal ulcer | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Esophagitis | 4/559 (0.7%) | 2/575 (0.3%) | 1/12 (8.3%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Gastric hemorrhage | 0/559 (0%) | 0/575 (0%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Gastric ulcer | 0/559 (0%) | 0/575 (0%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Gastritis | 1/559 (0.2%) | 4/575 (0.7%) | 0/12 (0%) | 0/33 (0%) | 2/47 (4.3%) | 0/376 (0%) | ||||||
| Gastrointestinal disorders - Other, specify | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Gastrointestinal fistula | 0/559 (0%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Gastrointestinal pain | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Gingival pain | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Ileal perforation | 0/559 (0%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Ileus | 5/559 (0.9%) | 10/575 (1.7%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Lower gastrointestinal hemorrhage | 2/559 (0.4%) | 0/575 (0%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Malabsorption | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Mucositis oral | 115/559 (20.6%) | 92/575 (16%) | 4/12 (33.3%) | 10/33 (30.3%) | 11/47 (23.4%) | 0/376 (0%) | ||||||
| Nausea | 40/559 (7.2%) | 40/575 (7%) | 1/12 (8.3%) | 4/33 (12.1%) | 3/47 (6.4%) | 0/376 (0%) | ||||||
| Oral hemorrhage | 2/559 (0.4%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Oral pain | 11/559 (2%) | 5/575 (0.9%) | 0/12 (0%) | 1/33 (3%) | 3/47 (6.4%) | 0/376 (0%) | ||||||
| Pancreatitis | 2/559 (0.4%) | 5/575 (0.9%) | 0/12 (0%) | 2/33 (6.1%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Proctitis | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Rectal mucositis | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Rectal pain | 7/559 (1.3%) | 4/575 (0.7%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Retroperitoneal hemorrhage | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Small intestinal mucositis | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Small intestinal obstruction | 2/559 (0.4%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Toothache | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Typhlitis | 36/559 (6.4%) | 22/575 (3.8%) | 0/12 (0%) | 1/33 (3%) | 2/47 (4.3%) | 0/376 (0%) | ||||||
| Upper gastrointestinal hemorrhage | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Vomiting | 21/559 (3.8%) | 23/575 (4%) | 0/12 (0%) | 4/33 (12.1%) | 2/47 (4.3%) | 1/376 (0.3%) | ||||||
| General disorders | ||||||||||||
| Edema face | 2/559 (0.4%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Edema limbs | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Edema trunk | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Fatigue | 4/559 (0.7%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Fever | 53/559 (9.5%) | 94/575 (16.3%) | 2/12 (16.7%) | 5/33 (15.2%) | 7/47 (14.9%) | 0/376 (0%) | ||||||
| General disorders and administration site conditions - Other, specify | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Localized edema | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Multi-organ failure | 7/559 (1.3%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Non-cardiac chest pain | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pain | 13/559 (2.3%) | 13/575 (2.3%) | 1/12 (8.3%) | 1/33 (3%) | 4/47 (8.5%) | 0/376 (0%) | ||||||
| Hepatobiliary disorders | ||||||||||||
| Cholecystitis | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Gallbladder necrosis | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hepatic failure | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hepatobiliary disorders - Other, specify | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 1/33 (3%) | 2/47 (4.3%) | 0/376 (0%) | ||||||
| Portal hypertension | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Immune system disorders | ||||||||||||
| Allergic reaction | 7/559 (1.3%) | 8/575 (1.4%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Anaphylaxis | 10/559 (1.8%) | 4/575 (0.7%) | 0/12 (0%) | 2/33 (6.1%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Autoimmune disorder | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Immune system disorders - Other, specify | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Serum sickness | 0/559 (0%) | 0/575 (0%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Infections and infestations | ||||||||||||
| Abdominal infection | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Anorectal infection | 6/559 (1.1%) | 4/575 (0.7%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Appendicitis | 6/559 (1.1%) | 9/575 (1.6%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Bladder infection | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Bone infection | 5/559 (0.9%) | 1/575 (0.2%) | 1/12 (8.3%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Bronchial infection | 1/559 (0.2%) | 5/575 (0.9%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Catheter related infection | 14/559 (2.5%) | 16/575 (2.8%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Cecal infection | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Conjunctivitis | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Device related infection | 0/559 (0%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Encephalitis infection | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Endocarditis infective | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Endophthalmitis | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Enterocolitis infectious | 31/559 (5.5%) | 29/575 (5%) | 0/12 (0%) | 2/33 (6.1%) | 1/47 (2.1%) | 1/376 (0.3%) | ||||||
| Esophageal infection | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Eye infection | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Gallbladder infection | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Gum infection | 0/559 (0%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Hepatic infection | 4/559 (0.7%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hepatitis viral | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Infections and infestations - Other, specify | 275/559 (49.2%) | 293/575 (51%) | 6/12 (50%) | 19/33 (57.6%) | 16/47 (34%) | 0/376 (0%) | ||||||
| Infective myositis | 4/559 (0.7%) | 1/575 (0.2%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Joint infection | 0/559 (0%) | 0/575 (0%) | 2/12 (16.7%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Kidney infection | 1/559 (0.2%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Lip infection | 0/559 (0%) | 4/575 (0.7%) | 1/12 (8.3%) | 0/33 (0%) | 2/47 (4.3%) | 0/376 (0%) | ||||||
| Lung infection | 60/559 (10.7%) | 72/575 (12.5%) | 3/12 (25%) | 8/33 (24.2%) | 6/47 (12.8%) | 1/376 (0.3%) | ||||||
| Lymph gland infection | 2/559 (0.4%) | 7/575 (1.2%) | 0/12 (0%) | 1/33 (3%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Meningitis | 2/559 (0.4%) | 1/575 (0.2%) | 1/12 (8.3%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Mucosal infection | 6/559 (1.1%) | 3/575 (0.5%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Nail infection | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Otitis externa | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Otitis media | 1/559 (0.2%) | 3/575 (0.5%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Papulopustular rash | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Paronychia | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pelvic infection | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Penile infection | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Periorbital infection | 2/559 (0.4%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Peritoneal infection | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pharyngitis | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pleural infection | 2/559 (0.4%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Salivary gland infection | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Scrotal infection | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Sepsis | 88/559 (15.7%) | 72/575 (12.5%) | 0/12 (0%) | 3/33 (9.1%) | 3/47 (6.4%) | 1/376 (0.3%) | ||||||
| Sinusitis | 11/559 (2%) | 17/575 (3%) | 1/12 (8.3%) | 1/33 (3%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Skin infection | 36/559 (6.4%) | 26/575 (4.5%) | 1/12 (8.3%) | 0/33 (0%) | 3/47 (6.4%) | 0/376 (0%) | ||||||
| Small intestine infection | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Soft tissue infection | 8/559 (1.4%) | 10/575 (1.7%) | 1/12 (8.3%) | 2/33 (6.1%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Splenic infection | 2/559 (0.4%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Tooth infection | 2/559 (0.4%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Tracheitis | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Upper respiratory infection | 13/559 (2.3%) | 24/575 (4.2%) | 1/12 (8.3%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Urinary tract infection | 18/559 (3.2%) | 20/575 (3.5%) | 0/12 (0%) | 1/33 (3%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Vaginal infection | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Vulval infection | 4/559 (0.7%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Wound infection | 1/559 (0.2%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Injury, poisoning and procedural complications | ||||||||||||
| Infusion related reaction | 4/559 (0.7%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Injury, poisoning and procedural complications - Other, specify | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Tracheal obstruction | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Vascular access complication | 3/559 (0.5%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Venous injury | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Wound dehiscence | 0/559 (0%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Investigations | ||||||||||||
| Activated partial thromboplastin time prolonged | 6/559 (1.1%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Alanine aminotransferase increased | 84/559 (15%) | 79/575 (13.7%) | 0/12 (0%) | 7/33 (21.2%) | 14/47 (29.8%) | 2/376 (0.5%) | ||||||
| Alkaline phosphatase increased | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Aspartate aminotransferase increased | 56/559 (10%) | 63/575 (11%) | 0/12 (0%) | 5/33 (15.2%) | 7/47 (14.9%) | 1/376 (0.3%) | ||||||
| Blood bilirubin increased | 25/559 (4.5%) | 20/575 (3.5%) | 1/12 (8.3%) | 3/33 (9.1%) | 5/47 (10.6%) | 0/376 (0%) | ||||||
| CPK increased | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Cardiac troponin I increased | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Cholesterol high | 0/559 (0%) | 0/575 (0%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Creatinine increased | 1/559 (0.2%) | 10/575 (1.7%) | 1/12 (8.3%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Ejection fraction decreased | 22/559 (3.9%) | 29/575 (5%) | 1/12 (8.3%) | 4/33 (12.1%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Electrocardiogram QT corrected interval prolonged | 153/559 (27.4%) | 175/575 (30.4%) | 3/12 (25%) | 10/33 (30.3%) | 14/47 (29.8%) | 0/376 (0%) | ||||||
| Fibrinogen decreased | 1/559 (0.2%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| GGT increased | 16/559 (2.9%) | 19/575 (3.3%) | 0/12 (0%) | 3/33 (9.1%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| INR increased | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Investigations - Other, specify | 3/559 (0.5%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Lipase increased | 10/559 (1.8%) | 9/575 (1.6%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Neutrophil count decreased | 188/559 (33.6%) | 193/575 (33.6%) | 3/12 (25%) | 7/33 (21.2%) | 5/47 (10.6%) | 0/376 (0%) | ||||||
| Platelet count decreased | 4/559 (0.7%) | 7/575 (1.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Serum amylase increased | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Urine output decreased | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Weight gain | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Weight loss | 12/559 (2.1%) | 7/575 (1.2%) | 0/12 (0%) | 2/33 (6.1%) | 0/47 (0%) | 0/376 (0%) | ||||||
| White blood cell decreased | 2/559 (0.4%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Metabolism and nutrition disorders | ||||||||||||
| Acidosis | 5/559 (0.9%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Alkalosis | 5/559 (0.9%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Anorexia | 123/559 (22%) | 130/575 (22.6%) | 5/12 (41.7%) | 7/33 (21.2%) | 11/47 (23.4%) | 0/376 (0%) | ||||||
| Dehydration | 12/559 (2.1%) | 6/575 (1%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Glucose intolerance | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hypercalcemia | 2/559 (0.4%) | 5/575 (0.9%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Hyperglycemia | 59/559 (10.6%) | 59/575 (10.3%) | 3/12 (25%) | 6/33 (18.2%) | 6/47 (12.8%) | 1/376 (0.3%) | ||||||
| Hyperkalemia | 17/559 (3%) | 10/575 (1.7%) | 1/12 (8.3%) | 3/33 (9.1%) | 2/47 (4.3%) | 0/376 (0%) | ||||||
| Hypermagnesemia | 3/559 (0.5%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hypernatremia | 2/559 (0.4%) | 9/575 (1.6%) | 1/12 (8.3%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hypertriglyceridemia | 5/559 (0.9%) | 4/575 (0.7%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hyperuricemia | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hypoalbuminemia | 14/559 (2.5%) | 19/575 (3.3%) | 0/12 (0%) | 1/33 (3%) | 2/47 (4.3%) | 1/376 (0.3%) | ||||||
| Hypocalcemia | 31/559 (5.5%) | 29/575 (5%) | 3/12 (25%) | 3/33 (9.1%) | 1/47 (2.1%) | 1/376 (0.3%) | ||||||
| Hypoglycemia | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hypokalemia | 149/559 (26.7%) | 152/575 (26.4%) | 5/12 (41.7%) | 9/33 (27.3%) | 9/47 (19.1%) | 0/376 (0%) | ||||||
| Hypomagnesemia | 5/559 (0.9%) | 4/575 (0.7%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hyponatremia | 34/559 (6.1%) | 28/575 (4.9%) | 2/12 (16.7%) | 5/33 (15.2%) | 2/47 (4.3%) | 0/376 (0%) | ||||||
| Hypophosphatemia | 39/559 (7%) | 42/575 (7.3%) | 1/12 (8.3%) | 3/33 (9.1%) | 7/47 (14.9%) | 0/376 (0%) | ||||||
| Iron overload | 2/559 (0.4%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Metabolism and nutrition disorders - Other, specify | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Tumor lysis syndrome | 9/559 (1.6%) | 12/575 (2.1%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 1/376 (0.3%) | ||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||
| Arthralgia | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 2/33 (6.1%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Avascular necrosis | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Back pain | 8/559 (1.4%) | 7/575 (1.2%) | 1/12 (8.3%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Bone pain | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Buttock pain | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 2/47 (4.3%) | 0/376 (0%) | ||||||
| Chest wall pain | 3/559 (0.5%) | 0/575 (0%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Flank pain | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Generalized muscle weakness | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Musculoskeletal and connective tissue disorder - Other, specify | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Myalgia | 0/559 (0%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Myositis | 4/559 (0.7%) | 3/575 (0.5%) | 1/12 (8.3%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Neck pain | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pain in extremity | 6/559 (1.1%) | 5/575 (0.9%) | 2/12 (16.7%) | 1/33 (3%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify | 24/559 (4.3%) | 13/575 (2.3%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Nervous system disorders | ||||||||||||
| Aphonia | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Cognitive disturbance | 1/559 (0.2%) | 1/575 (0.2%) | 1/12 (8.3%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Depressed level of consciousness | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Dizziness | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Encephalopathy | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Headache | 22/559 (3.9%) | 16/575 (2.8%) | 1/12 (8.3%) | 2/33 (6.1%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hydrocephalus | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Nervous system disorders - Other, specify | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Neuralgia | 0/559 (0%) | 3/575 (0.5%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Paresthesia | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Peripheral motor neuropathy | 4/559 (0.7%) | 11/575 (1.9%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Peripheral sensory neuropathy | 15/559 (2.7%) | 29/575 (5%) | 1/12 (8.3%) | 2/33 (6.1%) | 2/47 (4.3%) | 0/376 (0%) | ||||||
| Reversible posterior leukoencephalopathy syndrome | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Seizure | 2/559 (0.4%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Stroke | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Syncope | 6/559 (1.1%) | 5/575 (0.9%) | 0/12 (0%) | 2/33 (6.1%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Vasovagal reaction | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Psychiatric disorders | ||||||||||||
| Agitation | 2/559 (0.4%) | 2/575 (0.3%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Anxiety | 6/559 (1.1%) | 2/575 (0.3%) | 0/12 (0%) | 1/33 (3%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Confusion | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Delirium | 5/559 (0.9%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Depression | 4/559 (0.7%) | 0/575 (0%) | 0/12 (0%) | 1/33 (3%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Hallucinations | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Insomnia | 4/559 (0.7%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Irritability | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Psychiatric disorders - Other, specify | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Suicidal ideation | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Renal and urinary disorders | ||||||||||||
| Acute kidney injury | 7/559 (1.3%) | 9/575 (1.6%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Cystitis noninfective | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Hematuria | 9/559 (1.6%) | 3/575 (0.5%) | 1/12 (8.3%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Renal and urinary disorders - Other, specify | 3/559 (0.5%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Renal calculi | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Renal colic | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Urinary retention | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Urinary tract obstruction | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Urinary tract pain | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Reproductive system and breast disorders | ||||||||||||
| Genital edema | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Menorrhagia | 2/559 (0.4%) | 2/575 (0.3%) | 0/12 (0%) | 1/33 (3%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Pelvic pain | 0/559 (0%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Perineal pain | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Uterine hemorrhage | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Vaginal hemorrhage | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Vaginal inflammation | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Vaginal pain | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||
| Adult respiratory distress syndrome | 9/559 (1.6%) | 6/575 (1%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Apnea | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Aspiration | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Atelectasis | 6/559 (1.1%) | 5/575 (0.9%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Bronchial obstruction | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Bronchopleural fistula | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Bronchopulmonary hemorrhage | 2/559 (0.4%) | 3/575 (0.5%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Dyspnea | 9/559 (1.6%) | 12/575 (2.1%) | 1/12 (8.3%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Epistaxis | 16/559 (2.9%) | 4/575 (0.7%) | 0/12 (0%) | 3/33 (9.1%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Hoarseness | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hypoxia | 42/559 (7.5%) | 30/575 (5.2%) | 2/12 (16.7%) | 4/33 (12.1%) | 4/47 (8.5%) | 0/376 (0%) | ||||||
| Laryngeal edema | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Laryngeal mucositis | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Laryngeal stenosis | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Nasal congestion | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pharyngeal hemorrhage | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pharyngeal mucositis | 6/559 (1.1%) | 2/575 (0.3%) | 1/12 (8.3%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pharyngolaryngeal pain | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Pleural effusion | 7/559 (1.3%) | 13/575 (2.3%) | 1/12 (8.3%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Pleural hemorrhage | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pleuritic pain | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pneumonitis | 8/559 (1.4%) | 10/575 (1.7%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pneumothorax | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pulmonary edema | 19/559 (3.4%) | 11/575 (1.9%) | 1/12 (8.3%) | 0/33 (0%) | 2/47 (4.3%) | 0/376 (0%) | ||||||
| Pulmonary hypertension | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Respiratory failure | 21/559 (3.8%) | 14/575 (2.4%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 1/376 (0.3%) | ||||||
| Respiratory, thoracic and mediastinal disorders - Other, specify | 9/559 (1.6%) | 4/575 (0.7%) | 0/12 (0%) | 0/33 (0%) | 2/47 (4.3%) | 0/376 (0%) | ||||||
| Sleep apnea | 1/559 (0.2%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Sore throat | 6/559 (1.1%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Stridor | 6/559 (1.1%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Wheezing | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Skin and subcutaneous tissue disorders | ||||||||||||
| Bullous dermatitis | 0/559 (0%) | 0/575 (0%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Erythema multiforme | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Erythroderma | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Pain of skin | 4/559 (0.7%) | 6/575 (1%) | 0/12 (0%) | 1/33 (3%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Palmar-plantar erythrodysesthesia syndrome | 1/559 (0.2%) | 2/575 (0.3%) | 0/12 (0%) | 1/33 (3%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Pruritus | 2/559 (0.4%) | 2/575 (0.3%) | 0/12 (0%) | 1/33 (3%) | 2/47 (4.3%) | 0/376 (0%) | ||||||
| Rash acneiform | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Rash maculo-papular | 47/559 (8.4%) | 62/575 (10.8%) | 2/12 (16.7%) | 9/33 (27.3%) | 12/47 (25.5%) | 0/376 (0%) | ||||||
| Skin and subcutaneous tissue disorders - Other, specify | 6/559 (1.1%) | 2/575 (0.3%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Skin ulceration | 4/559 (0.7%) | 0/575 (0%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
| Urticaria | 3/559 (0.5%) | 4/575 (0.7%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Surgical and medical procedures | ||||||||||||
| Surgical and medical procedures - Other, specify | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Vascular disorders | ||||||||||||
| Capillary leak syndrome | 3/559 (0.5%) | 3/575 (0.5%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hematoma | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Hypertension | 29/559 (5.2%) | 23/575 (4%) | 1/12 (8.3%) | 7/33 (21.2%) | 7/47 (14.9%) | 0/376 (0%) | ||||||
| Hypotension | 79/559 (14.1%) | 49/575 (8.5%) | 1/12 (8.3%) | 5/33 (15.2%) | 2/47 (4.3%) | 0/376 (0%) | ||||||
| Superficial thrombophlebitis | 0/559 (0%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Thromboembolic event | 2/559 (0.4%) | 1/575 (0.2%) | 0/12 (0%) | 1/33 (3%) | 0/47 (0%) | 0/376 (0%) | ||||||
| Vascular disorders - Other, specify | 1/559 (0.2%) | 1/575 (0.2%) | 0/12 (0%) | 0/33 (0%) | 1/47 (2.1%) | 0/376 (0%) | ||||||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Results Reporting Coordinator |
|---|---|
| Organization | Children's Oncology Group |
| Phone | 626-447-0064 |
| resultsreportingcoordinator@childrensoncologygroup.org |
Responsible Party:
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01371981
Other Study ID Numbers:
- NCI-2011-02670
- NCI-2011-02670
- CDR0000701850
- AAML1031
- COG-AAML1031
- S12-02301
- AAML1031
- AAML1031
- U10CA180886
- U10CA098543
First Posted:
Jun 13, 2011
Last Update Posted:
Jul 28, 2022
Last Verified:
Jul 1, 2022