Trial Information

A Phase III Randomized Trial for Patients With de Novo AML Using Bortezomib and Sorafenib (IND#114480, NSC# 681239, NSC# 724772) for Patients With High Allelic Ratio FLT3/ITD

PRIMARY OBJECTIVES:

I. To compare event-free survival (EFS) and overall survival (OS) of patients with de novo
acute myeloid leukemia (AML) with or without high allelic ratio FLT3/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 COG-AAML0531.

IV. To determine the feasibility of combining sorafenib with standard chemotherapy in
patients with de novo high allelic ratio FLT3/ITD+ AML.

SECONDRY 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 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 COG-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 AAML103P1 and
AAML0531.

V. To assess the health-related quality of life (HRQOL) of patients treated with
chemotherapy and 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 RT-PCR (e.g., t(8;21), inv(16), t(9;11), 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, RUNX1,
MLL-PTD, TET2, c-CBL, KIT, and other novel AML-associated genes in pediatric AML.

XIV. To correlate the expression of CD74 antigen as well as 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.

OUTLINE: This is a multicenter, dose-escalation study of sorafenib tosylate and an
open-label randomized study. Patients are stratified according to disease risk (low vs
high). Patients are randomized to 1 of 2 treatment arms or offered treatment on a third arm.

INDUCTION I:

ARM A: Patients receive cytarabine intrathecally (IT) on day 1 and ADE chemotherapy
comprising cytarabine IV over 15-30 minutes on days 1-10; daunorubicin IV over 1-15 minutes
on days 1, 3, and 5; and etoposide IV over 1-2 hours on days 1-5.

ARM B: Patients receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A.
Patients also receive bortezomib IV on days 1, 4, and 8.

ARM C (high-risk [HR] FLT3/ITD+ disease): Patients receive cytarabine IT and ADE
chemotherapy as in Induction I, Arm A and sorafenib tosylate orally (PO) on days 11-28.

INDUCTION II: Patients without HR FLT3/ITD+ disease begin Induction II administration on day
29.

ARM A (low-risk [LR] patients): Patients receive cytarabine IT and ADE chemotherapy as in
Induction I Arm A.

ARM A (HR patients): Patients 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.

ARM B (LR patients): Patients receive cytarabine IT, ADE chemotherapy, and bortezomib as in
Induction I Arm B.

ARM B (HR patients): Patients receive cytarabine IT and MA chemotherapy as in Induction II,
Arm A (HR patients) and bortezomib IV on days 1, 4, and 8.

ARM C (patients with HR FLT3/ITD+ disease, cohorts 1 and 2): Patients receive cytarabine IT
on day 1, cytarabine IV over 15-30 minutes on days 1-8, daunorubicin IV over 1-15 minutes on
days 1, 3, and 5, and etoposide IV over 1-2 hours on days 1-5, and sorafenib tosylate PO on
days 1-28.

Patients who achieve complete remission (CR) proceed to Intensification I (beginning on day
29). Patients with refractory disease are off protocol therapy.

INTENSIFICATION I:

ARM A: 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.

ARM B: Patients receive cytarabine IT and AE chemotherapy in Intensification II, Arm A, and
bortezomib IV on days 1, 4, and 8.

ARM C (cohorts 1 and 2): Patients receive cytarabine IT and AE chemotherapy in
Intensification II, Arm A, and sorafenib tosylate PO on daily on days 1-28.

Patients who achieve CR proceed to Intensification II or stem cell transplantation (SCT)
beginning on day 29. Patients with refractory disease are off protocol therapy.

INTENSIFICATION II:

ARM A (LR): Patients receive cytarabine IT on day 1 and MA chemotherapy as in Induction II,
Arm A (HR patients).

ARM B (LR): Patients receive cytarabine IT on day 1, MA chemotherapy as in Induction II, Arm
A (HR patients), and bortezomib IV on days 1, 4, and 8.

ARMS A AND B (HR and no donor for SCT): Patients receive high-dose cytarabine IV over 3
hours on days 1, 2, 8, and 9 and asparaginase intramuscularly (IM) on days 2 and 9.

ARM C (HR cohorts 1 and 2): Patients receive cytarabine IT on day 1, MA chemotherapy as in
Induction II, Arm A (HR patients), and sorafenib tosylate PO on days 1-28.

STEM CELL TRANPLANTATION (SCT) (HR patients with matched family [MFD] or unrelated donor):

CONDITIONING REGIMEN: Patients receive fludarabine 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.

GRAFT-VS-HOST DISEASE (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.

Blood, bone marrow, and tissue samples are collected at baseline and periodically during
study for mutation and translocation analysis, cytogenetic/FISH analysis, gene and protein
expression, and other studies. Some patients (aged 2 to 18 years) and/or parents may
complete questionnaires about health-related quality of life (Pediatric Quality of Life
(PedsQL) 4.0 Generic Core Scale, the PedsQL 3.0 Acute Cancer Module, and the PedsQL
Multidimensional Fatigue Scale) and parental stress (Pediatric Inventory for Parents (PIP)
scale) at baseline and periodically during the study and follow-up.

After completion of study therapy, patients are followed up monthly for 6 months, every 2
months for 6 months, every 3 months for 1 year, every 6 months for 1 year, and then yearly
for up to 8 years.