Combination Chemotherapy and Dasatinib in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of dasatinib 100 mg/day given after intensive
induction (daunorubicin hydrochloride [daunorubicin]/cytarabine), and consolidation
chemotherapy (high-dose cytarabine) and as single agent in maintenance therapy to newly
diagnosed patients with core binding factor acute myeloid leukemia (AML).

II. 30-day survival rate during induction (the lack of early/hypoplastic death).

III. The absence of pleural or pericardial effusion, and absence of liver toxicity that
exceeds grade 2.

SECONDARY OBJECTIVES:

I. To assess clinical outcomes such as event-free survival (EFS), complete response (CR)
rate, cumulative incidence of relapse (CIR), cumulative incidence of death (CID),
disease-free survival (DFS), and overall survival (OS).

II. To describe the frequency and severity of adverse events of patients treated on this
study during induction, consolidation, and continuation therapy.

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

OUTLINE:

INDUCTION THERAPY (course 1): Patients receive daunorubicin hydrochloride intravenously (IV)
on days 1-3, cytarabine IV continuously over 168 hours on days 1-7, and dasatinib orally (PO)
once daily (QD) on days 8-21. Patients with responsive disease on day 21 undergo
consolidation therapy, and patients with non-responsive disease on day 21 (bone marrow
cellularity >= 20 % and leukemia blasts >= 5%) receive a second course of induction therapy.

INDUCTION THERAPY (course 2): Patients receive daunorubicin hydrochloride IV on days 1-3,
cytarabine IV continuously over 120 hours on days 1-5, and dasatinib PO once a day on days
6-19. Patients achieving complete response receive consolidation therapy.

CONSOLIDATION THERAPY: Patients receive high-dose cytarabine IV over 3 hours on days 1, 3,
and 5, and dasatinib PO QD on days 6-26 or 7-27. Treatment repeats every 28 days for up to 4
courses in the absence of disease progression or unacceptable toxicity. Patients in complete
remission receive continuation therapy.

CONTINUATION THERAPY: Patients receive dasatinib PO on days 1-28. Treatment repeats every 28
days for 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up every 2 months for 2 years, every
3 months for 2 years, and then every year for up to 10 years from study entry.

Inclusion Criteria:

- Documentation of disease as assessed by the Alliance reference laboratory at the Ohio
State University per Cancer and Leukemia Group B (CALGB) 20202, molecular diagnosis of
core-binding factor (CBF) acute myeloid leukemia (AML) by reverse transcriptase
polymerase chain reaction (RT-PCR) positive for RUNX1-RUNX1T1 fusion transcript
resulting from t(8;21)(q22;q22) (or a variant form) or CBFB-MYH11 fusion transcript
resulting from inv(16)(p13.1q22) or t(16;16)(p13.1;q22) (any % bone marrow or blood
blasts render the diagnosis of CBF AML based on the World Health Organization [WHO]
classification)

- No prior chemotherapy for leukemia or myelodysplasia with the following exceptions:

- Emergency leukapheresis

- Emergency treatment for hyperleukocytosis with hydroxyurea,

- Cranial radiotherapy (RT) for central nervous system (CNS) leukostasis (one dose
only),

- Growth factor/cytokine support/non-cytotoxic molecular-targeted agents

- AML patients with a history of antecedent myelodysplasia (MDS) remain eligible for
treatment on this trial

- Patients who have developed therapy related myeloid neoplasm (t-MN) after prior
radiation therapy or chemotherapy for another cancer or disorder are eligible

- Left ventricular ejection fraction >= lower limit of institutional normal by
multigated acquisition (MUGA) or echocardiogram (ECHO) scan

- Patients must not have had myocardial infarction within 6 months of registration

- Patients must not have had ventricular tachyarrhythmia within 6 months of registration

- Patients must have no major conduction abnormality (unless a cardiac pacemaker is
present)

- Bilirubin must not be < 2.5 times upper limit of normal

- Patients must be non-pregnant and non-nursing; pregnant or nursing patients may not be
enrolled; women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test within a sensitivity of at least 25 mIU/mL within 72 hours prior to
registration; women of child-bearing potential must either commit to continued
abstinence from heterosexual intercourse or begin TWO acceptable methods of birth
control - one highly effective method (e.g., intrauterine device [IUD], hormonal,
tubal ligation, or partner's vasectomy), and one additional effective method (e.g.,
latex condom, diaphragm, or cervical cap) - AT THE SAME TIME, before she begins
dasatinib therapy, during treatment and at least 12 weeks after treatment is complete;
"Women of childbearing potential" is defined as a sexually active mature woman who has
not undergone a hysterectomy or who has had menses at any time in the preceding 24
consecutive months

- Patients with congenital long QT syndrome or non-congenital corrected QT (QTc)
prolongation (defined as a QTc interval consistently equal to or greater than 480
msecs) that cannot be corrected by infusion of electrolytes and/or discontinuation of
other medications prior to start of treatment are excluded