Decitabine in Treating Patients With Previously Untreated Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This phase II trial is studying how well decitabine works in treating patients with previously untreated acute myeloid leukemia. Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the rate of complete remission (CR) in patients with previously untreated acute myeloid leukemia treated with decitabine. SECONDARY OBJECTIVES: I. Determine the rate of overall survival at 1 year in patients treated with this drug. II. Determine the overall response rate (CR, incomplete CR, and partial remission) in patients treated with this drug. III. Correlate the biological activity of decitabine with clinical endpoints and maximum concentration of plasma decitabine. IV. Correlate intracellular concentration of decitabine with global DNA methylation, other biological endpoints, and clinical response. OUTLINE: Patients receive decitabine IV over 1 hour on days 1-10. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspiration and blood sample collection periodically for pharmacological and correlative studies. Samples are analyzed for gene expression, methylation of gene promoters, fetal hemoglobin (HgF), DNMT1 protein expression, maximum concentration of plasma decitabine, and global DNA methylation. Samples are analyzed by RT-PCR, Bio-COBRA, matrix-assisted laser desorption ionization time-of-flight mass spectrometry, SDS-PAGE (polyacrylamide gel electrophoresis), immunoblotting, and LC-MS/MS. After completion of study treatment, patients are followed for at least 30 days.

Official Title
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Phase II Study of Decitabine in Acute Myeloid Leukemia

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), Secondary Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: decitabine
* Other: laboratory biomarker analysis
* Other: pharmacological study
* Other: high performance liquid chromatography
* Genetic: microarray analysis
* Genetic: RNA analysis
* Other: mass spectrometry
* Genetic: DNA methylation analysis
* Other: matrix-assisted laser desorption/ionization time of flight mass spectrometry


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed acute myeloid leukemia (AML) meeting 1 of the following criteria: At least 60 years of age and not a candidate for or refused standard induction treatment Poor risk cytogenetics AML following antecedent hematologic disorder Therapy-related AML Secondary AML No granulocytic sarcoma as sole site of disease No active CNS disease or CNS relapse ECOG performance status 0-2 Life expectancy > 6 months Total bilirubin < 2.0 mg/dL Creatinine < 2.0 mg/dL AST and ALT < 2.5 times upper limit of normal Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No NYHA class III or IV congestive heart failure No uncontrolled infection No history of allergic reactions attributed to compounds of similar chemical or biologic composition to decitabine that are not easily managed No other uncontrolled illness including, but not limited to, any of the following: Symptomatic congestive heart failure Unstable angina pectoris Serious cardiac arrhythmia Psychiatric illness or social situations that would preclude compliance with study requirements No active second malignancy involving the blood or marrow or likely to progress and require therapy in the next 6 months No prior therapy for AML except emergency leukapheresis or hydroxyurea for leukocytosis No prior azacitidine or decitabine No prior cytarabine or other conventional chemotherapy agents for antecedent hematologic disorders Prior myeloid growth factors, recombinant erythropoietin, thalidomide, or lenalidomide allowed No concurrent palliative radiotherapy No other concurrent investigational agents No other concurrent direct anti-leukemia therapy No concurrent combination antiretroviral therapy for HIV-positive patients

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemotherapy)<br>Patients receive decitabine IV over 1 hour on days 1-10. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: decitabine<br>* Given IV<br>* Other names: DAC;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: high performance liquid chromatography<br>* Correlative studies<br>* Other names: HPLC;Genetic: microarray analysis<br>* Correlative studies<br>* Other names: gene expression profiling;Genetic: RNA analysis<br>* Correlative studies<br>Other: mass spectrometry<br>* Correlative studies<br>Genetic: DNA methylation analysis<br>* Correlative studies<br>Other: matrix-assisted laser desorption/ionization time of flight mass spectrometry<br>* Correlative studies<br>* Other names: MALDI-TOF Mass Spectrometry;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Complete Remission | Per International Working Group criteria: Morphologic complete remission (CRm): Defined as morphologic leukemia-free state, including <5% blasts in BM aspirate with marrow spicules and a count of > 200 nucleated cells and no blasts with Auer rods, no persistent extramedullary disease, ANC > 1000/uL, platelet count > 100,000/uL. Patient must be independent of transfusions for a minimum of 1 week before each marrow assessment. Morphologic complete remission with incomplete blood count recovery (CRi): Defined as CR with the exception of neutropenia <1000/uL or thrombocytopenia <100,000/ul. Complete Remission Rate (CRm + CRi) | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of DNA Methylation in Peripheral Blood or Bone Marrow Cells | Standard paired statistical tests, parametric and nonparametric, will be used to baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data. | From baseline to up to day 28 of course 1 | 
| Measurement of DNMT Protein in Peripheral Blood or Bone Marrow Cells | Expression studies were conducted using quantitative RT PCR. Expression of DNMT were normalized to the internal control to the ABL and levels of miR-29 to RNA U44. | Pre treatment | 
| Measurement of HbF in Peripheral Blood or Marrow Cells | Standard paired statistical tests, parametric and nonparametric, will be used to baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data. | From baseline to up to days 28 of course 2 | 
| Measurement of Gene Expression in Peripheral Blood or Bone Marrow | Standard paired statistical tests, parametric and nonparametric, will be used to baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data. | From baseline to up to day 28 of course 1 |