Bortezomib and Sorafenib Tosylate in Treating Patients With Newly Diagnosed 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 1
of 2 treatment arms or offered treatment on 1 of 2 arms. (Arms A and B are closed to new
patient enrollment as of 02/04/2016)

INDUCTION I:

ARM A: 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.

ARM B: 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.

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.

ARM D (unknown FLT3/ITD status prior to study enrollment): Patients receive cytarabine IT and
ADE chemotherapy as in Induction I, Arm A. 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.

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, cohort 3): 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.

Patients who achieve complete remission (CR) proceed to Intensification I (beginning on day
37). 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 (cohort 3): Patients receive cytarabine IT and AE chemotherapy in Intensification II,
Arm A, and sorafenib tosylate PO on daily on days 6-28.

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:

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 cohort 3): Patients receive cytarabine IT on day 1, MA chemotherapy as in Induction
II, Arm A (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 in Arm C receive sorafenib tosylate PO starting on day 40-100 after
completion of intensification II or SCT for one year.

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.

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