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See Detailed Description. Different dose.

See Detailed Description. May reassigned to Arm C.

Daunorubicin Hydrochloride

Laboratory Biomarker Analysis

Mitoxantrone Hydrochloride

Pharmacological Study

Quality-of-Life Assessment

Questionnaire Administration

Sorafenib Tosylate

Richard Aplenc

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.

PRIMARY OBJECTIVES:

I. 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.

II. To determine the feasibility of combining bortezomib with standard chemotherapy in patients with de novo AML.

III. To compare the OS and EFS of high-risk patients treated with intensive Induction II with historical controls from AAML03P1 and AAML0531.

IV. 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:

I. To assess the anti-leukemic activity of sorafenib in patients with de novo high allelic ratio FLT3/ITD+ AML.

II. 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.

III. 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.

IV. 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.

V. To assess the health-related quality of life (HRQOL) of patients treated with chemotherapy and stem cell transplant (SCT) for AML.

VI. To evaluate bortezomib pharmacokinetics (PK) in patients receiving the combination regimen.

VII. To obtain sorafenib and metabolite steady state pharmacokinetics and pharmacokinetic-pharmacodynamic data in subjects with FLT3/ITD receiving sorafenib.

VIII. To compare the changes in shortening fraction/ejection fraction over time between patients treated with and without dexrazoxane.

IX. To refine the use of minimal-residual disease (MRD) detection with 4-color flow cytometry.

X. 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).

XI. To determine the leukemic involvement of the hematopoietic early progenitor cell and its role in defining response to therapy.

XII. 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.

XIV. 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.

XV. To evaluate the changes in protein expression and unfolded protein response (UPR) in patients with AML.

XVI. To determine the expression level of wild-type FLT3, and correlate with outcome and in vitro sensitivity to FLT3 inhibition.

XVII. 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.

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

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

Descriptive statistics will be used to summarize length of hospitalization time.

Cumulative incidence estimates that account for competing events will be used to estimate treatment-related mortality.

The proportion of patients achieving remission after 1 course of therapy will be estimated along with a corresponding 95% confidence interval.

The proportion of patients achieving remission after 2 courses of therapy will be estimated along with a corresponding 95% confidence interval.

Cumulative incidence estimates that account for competing events will be used to estimate time to count recovery.

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.

The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.

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.

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).

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.

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.

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.

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.

Median and range of bortezomib clearance during Induction II.

Median and range of sorafenib steady state concentration for Induction I.

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.

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.

The mean serum concentration of the day 28 GVHD biomarker will be estimated as well as the corresponding 95% confidence interval.

National Cancer Institute (NCI)

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.

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.

Arm A

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.

Arm B

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.

Arm C (Cohort 1)

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.

Arm C (Cohort 2)

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.

Arm C (Cohort 3)

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.

Arm D

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.

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Canada

Australia

New Zealand

Region of Enrollment

Results Reporting Coordinator

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.

Event-free Survival (EFS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations

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.

EFS for Patients on Arm C, Cohort 1

EFS for Patients on Arm C, Cohort 2

EFS for Patients on Arm C, Cohort 3

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.

Overall Survival (OS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations

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.

OS for Patients on Arm C, Cohort 1

OS for Patients on Arm C, Cohort 2

OS for Patients on Arm C, Cohort 3

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.

Relapse Rate for Patients Without High Allelic Ratio FLT3/ITD+ Mutations

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

Proportion of Patients Experiencing Grade 3 or Higher Non-hematologic Toxicities and Infections While on Protocol Therapy

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.

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

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.

Total Scale Score From Parent-reported Pediatric Quality of Life Inventory Module

Total Scale Score From Parent-reported Cancer Module

Total Scale Score From Parent-reported Multidimensional Fatigue Scale Module

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

Bortezomib Clearance

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

Arm C

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.

Sorafenib Steady State Concentration

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 .

Change in Shortening Fraction

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 .

Change in Ejection Fraction

Serum Concentrations of GVHD Biomarker

Course Duration

Incidence of Treatment-related Mortality

Length of Hospitalization

Remission Rate After 1 Course of Therapy

Remission Rate After 2 Courses of Therapy

Time to Blood Count Recovery

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 \& 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.

Spots Global Cancer Trial Database for leukemia cutis