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

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and best dose of dasatinib when given together with cytarabine and idarubicin hydrochloride and to see how well they work in treating patients with acute myeloid leukemia that is likely to come back or spread. Dasatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine and idarubicin hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving dasatinib together with cytarabine and idarubicin hydrochloride may be a better treatment for acute myeloid leukemia.

Detailed Description
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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.

Official Title
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Phase I/II Study of the Combination of Dasatinib With Chemotherapy for High Risk Acute Myeloid Leukemia (AML) Patients

Conditions
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Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Recurrent Adult Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: cytarabine
* Drug: idarubicin
* Drug: dasatinib
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dasatinib 100mg/day + Cytarabine 200mg/m2/day + Idarubicin 12mg/m2/day<br>Patients receive cytarabine IV continuously over 168 hours on days 1-7, dasatinib PO 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. | Drug: cytarabine<br>* Given IV<br>* Other names: cytosine arabinoside;Drug: idarubicin<br>* Given IV<br>* Other names: IDA;Drug: dasatinib<br>* Given PO<br>* Other names: Sprycel;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Dasatinib 140mg/day + Cytarabine 200mg/m2/day + Idarubicin 12mg/m2/day<br>Patients receive cytarabine IV continuously over 168 hours on days 1-7, dasatinib PO 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. | Drug: cytarabine<br>* Given IV<br>* Other names: cytosine arabinoside;Drug: idarubicin<br>* Given IV<br>* Other names: IDA;Drug: dasatinib<br>* Given PO<br>* Other names: Sprycel;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of Dasatinib (Phase I) | Maximum tolerated dose of dasatinib, determined according to incidence of dose limiting toxicity (DLT), graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I) | From the first dose of Dasatinib through the DLT observation period (Day +28) | 
| Complete Remission Rate (Phase II) | Remission rates will be calculated as the percent of evaluable patients that have a confirmed CR, and exact 95% confidence intervals will be calculated for these estimates. | From the first cycle up to two years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (Phase II) | Overall survival was measured from the first dose of Dasatinib to death from any cause or last contact, whichever comes first. It was estimated using the product-limit method of Kaplan and Meier. | Time from start of study therapy until death, or last contact, whichever comes first, assessed up to 2 years | 
| Event-free Survival (Phase II) | Event-free survival was defined as time from the first dose of Dasatinib to relapse/progression, receipt of anti-leukemia therapy, death, or last contact, whichever comes first. It was estimated using the product-limit method of Kaplan and Meier. | Time from start of study therapy until death, relapse/progression, receipt of anti-leukemia therapy, or last contact, whichever comes first, assessed up to two years. |