Dasatinib, Cytarabine, and Idarubicin in Treating Patients With High-Risk Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. Of the dose levels studied, to determine the maximum tolerated dose of dasatinib when
given in combination with cytarabine and idarubicin for treatment of high risk acute myeloid
leukemia (AML). (Phase I)

II. To determine the anti-tumor activity of dasatinib when given in combination with
cytarabine and idarubicin, as assessed by complete remission rate (CR) and remission
duration. (Phase II)

SECONDARY OBJECTIVES:

I. To document CR and survival outcomes (overall, event-free). (Phase I)

II. To estimate the survival probabilities (overall and event-free) and cumulative incidence
of relapse/progression. (Phase II)

III. To describe and summarize all toxicities by organ and severity. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of dasatinib, followed by a phase II study.

Patients receive cytarabine intravenously (IV) continuously over 168 hours on days 1-7,
dasatinib orally (PO) once daily (QD) on days 1-7, and idarubicin hydrochloride IV on days
1-3. Patients with non-responsive disease on day 30 may receive a second course of therapy
(re-induction therapy) within 1 week in the absence of unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 2
months for up to 2 years.

Inclusion Criteria:

- Patients diagnosed with AML meeting one of the following criteria:

- Newly diagnosed, age 60 and older

- High risk cytogenetics and molecular abnormalities (National Comprehensive Cancer
Network [NCCN] criteria)

- Relapsed or refractory to prior chemotherapy

- Secondary AML

- Any prior chemotherapy must have been completed >= 2 weeks prior to day 1 of study
treatment and the participant must have recovered to eligibility levels from prior
toxicity

- Only one prior regimen is allowed for relapsed AML patients; note one prior
regimen is defined as follows:

- Induction chemotherapy followed by consolidation is considered one regimen

- Induction chemotherapy followed by re-induction in case of persistent
disease followed by consolidation is considered one regimen

- Hydroxyurea is allowed prior to day 1 of study treatment to keep white blood cell
(WBC) below 20 K

- Karnofsky performance status >= 60%

- Total bilirubin < 1.5 x institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal

- Creatinine < 1.5 x institutional upper limit or normal OR creatinine clearance >= 60
mL/min for patients with creatinine levels above 1.5 x institutional upper limit of
normal

- Ejection fraction (EF) >= 45%

- Ability to understand and sign a written informed consent document

- Patients should not be receiving any other investigational agents

Exclusion Criteria:

- Patients with clinically significant illness which would compromise participation in
the study, including, but not limited to: active or uncontrolled infection, immune
deficiencies or confirmed diagnosis of human immunodeficiency virus (HIV) infection,
active hepatitis B, active hepatitis C, or uncontrolled diabetes, uncontrolled
hypertension, symptomatic congestive heart failure, unstable angina pectoris,
myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmias; or
psychiatric illness/social situations that would limit compliance with study
requirements

- Patients with additional (other than AML) currently active primary malignancy other
than curatively treated carcinoma in situ (CIS) of the cervix, or basal or squamous
cell carcinoma of the skin; patients are not considered to have a "currently active"
malignancy if they have completed therapy for a prior malignancy and disease free from
prior malignancies for > 2 years

- Patients with active central nervous system (CNS) disease

- Patients with Chronic Myelogenous Leukemia (CML) in Myeloid blasts crisis

- Active infections, including opportunistic infections

- Women of childbearing potential (WOCBP) who have a positive serum pregnancy test
within 14 days of the first administration of oral dasatinib