Sorafenib Tosylate and Chemotherapy in Treating Older Patients With Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine if the 1-year overall survival rate of patients age >= 60 with FLT3-ITD AML
treated with a sorafenib (sorafenib tosylate) containing induction and post-remission therapy
is significantly higher than the historical 1-year overall survival rate of similar patients
who were not treated with sorafenib.

SECONDARY OBJECTIVES:

I. To determine the rates of complete remission (CR), CR with incomplete count recovery
(CRi), and cytogenetic complete remission (CCyR) to induction chemotherapy.

II. To determine the overall survival, event-free survival, and remission duration in
patients treated on this study.

III. To describe the frequency and severity of adverse events for patients treated on this
study.

IV. To describe the interaction of pre-treatment disease and patient characteristics
including morphology, cytogenetics, immunophenotype, molecular genetic features, white blood
cell (WBC) count and hemogram, and performance status on clinical outcomes.

V. To assess FLT3 ligand concentrations and FLT3 plasma inhibitory activity during treatment
and determine the relationship to clinical outcomes. (Cancer and Leukemia Group B [CALGB]
21003) VI. To describe the interaction of FLT3 mutation type (tyrosine kinase domain [TKD]
vs. ITD) and allelic ratio on clinical outcomes. (CALGB 21003) VII. To characterize geriatric
assessment measures in the context of a treatment trial for AML defined by: the observed
distribution and number of missing values for each measurement. (CALGB 361006) VIII. To
identify specific geriatric assessment measures which are independently associated with
overall survival (OS), 30-day treatment-related mortality and key quality of life outcomes
(number of days hospitalized, number of oncology clinic visits, admission to a nursing
facility) in patients receiving induction chemotherapy for AML. (CALGB 361006) IX. To explore
the impact of induction chemotherapy on physical, cognitive, psychosocial factors. (CALGB
361006)

OUTLINE:

INDUCTION THERAPY: Patients receive daunorubicin hydrochloride intravenously (IV) on days
1-3, cytarabine IV continuously on days 1-7, and sorafenib tosylate orally (PO) twice daily
(BID) on days 1-7. Patients then undergo a bone marrow aspirate or biopsy on day 14.

Patients with persistent disease undergo a second remission induction therapy comprising
daunorubicin hydrochloride IV on days 1-2, cytarabine IV continuously on days 1-5, and
sorafenib tosylate PO BID on days 1-7. Patients who achieve complete response (CR)* proceed
to consolidation therapy.

CONSOLIDATION THERAPY: Patients** receive cytarabine IV over 3 hours on days 1-5 and
sorafenib tosylate PO BID on days 1-28. Treatment repeats every 28 days for 2 cycles in the
absence of disease progression or unacceptable toxicity. Patients with continued CR proceed
to maintenance therapy.

MAINTENANCE THERAPY: Patients receive sorafenib tosylate PO BID on days 1-28. Treatment
repeats every 28 days for up to 12 cycles in the absence of disease progression or
unacceptable toxicity.

NOTE: *Patients who achieve CR and who are eligible for hematopoietic stem cell transplant
(HSCT) are encouraged to enroll in Cancer and Leukemia Group B (CALGB) 100103. Patients in CR
who are unable or unwilling to undergo HSCT receive two cycles of remission consolidation
therapy.

NOTE: ** Patients in CR/complete remission with incomplete count recovery (CRi) who are
unable or unwilling to complete remission consolidation therapy may proceed directly to
maintenance therapy after consulting with the CALGB study chair.

After completion of study therapy, patients are followed up every 2 months for 2 years, every
3 months for 2 years, and then yearly for a maximum of 10 years.

Inclusion Criteria:

- Unequivocal histologic diagnosis of AML according to World Health Organization (WHO)
criteria, EXCLUDING:

- Acute promyelocytic leukemia t(15;17)(q22;q12); promyelocytic leukemia
(PML)-retinoic acid receptor, alpha (RARA)

- Acute myeloid leukemia with t(8;21)(q22;q22); runt-related transcription factor 1
(RUNX1-RUNXT1) as determined by the Ohio State University (OSU) Molecular
Reference Laboratory, per CALGB 20202

- Acute myeloid leukemia with inv(16)(p13.1;q22) or t(16;16(p13.1;q22);
core-binding factor, beta subunit (CBFB)-myosin, heavy chain 11, smooth muscle
(MYH11) as determined by the OSU Molecular Reference Laboratory, per CALGB 20202

- AML patients with an antecedent hematologic disorder are eligible for treatment on
this trial provided that they have not received chemotherapy, including lenalidomide,
azacitidine or decitabine for their hematologic disorder; patients with
therapy-related AML are eligible if there had been no further exposure to chemotherapy
or radiation therapy for > 3 years and their primary malignancy is in remission

- FLT3 mutation (ITD or point mutation) determined by the OSU Molecular Reference
Laboratory, per CALGB 20202

- No prior chemotherapy for AML with the following exceptions:

- Emergency leukapheresis

- Emergency treatment for hyperleukocytosis with hydroxyurea

- Cranial radiation therapy (RT) for central nervous system (CNS) leukostasis (one
dose only)

- Growth factor/cytokine support

- All-trans retinoic acid (ATRA)