Decitabine in Treating Patients With Previously Untreated Acute Myeloid Leukemia

Phase II Study of Decitabine in Acute Myeloid Leukemia

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

Study Overview

• Status: Completed
• Conditions: 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(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia; Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: pharmacological study; Genetic: microarray analysis; Drug: decitabine; Other: mass spectrometry; Genetic: DNA methylation analysis; Genetic: RNA analysis; Other: high performance liquid chromatography; Other: matrix-assisted laser desorption/ionization time of flight mass spectrometry

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (chemotherapy); 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.

Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Genetic: microarray analysis; Correlative studies; Other Names: gene expression profiling; Drug: decitabine; Given IV; Other Names: DAC; 5-aza-dCyd; 5AZA; Other: mass spectrometry; Correlative studies; Genetic: DNA methylation analysis; Correlative studies; Genetic: RNA analysis; Correlative studies; Other: high performance liquid chromatography; Correlative studies; Other Names: HPLC; Other: matrix-assisted laser desorption/ionization time of flight mass spectrometry; Correlative studies; Other Names: MALDI-TOF Mass Spectrometry

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S, Liu S, Havelange V, Becker H, Schaaf L, Mickle J, Devine H, Kefauver C, Devine SM, Chan KK, Heerema NA, Bloomfield CD, Grever MR, Byrd JC, Villalona-Calero M, Croce CM, Marcucci G. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7473-8. doi: 10.1073/pnas.1002650107. Epub 2010 Apr 5.

Study record dates

Study Major Dates

• Study Start: May 1, 2007
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: June 25, 2007
• First Submitted That Met QC Criteria: June 25, 2007
• First Posted (Estimate): June 27, 2007

Study Record Updates

• Last Update Posted (Estimate): June 27, 2016
• Last Update Submitted That Met QC Criteria: May 18, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Decitabine; Azacitidine
• Other Study ID Numbers: NCI-2009-00246; N01CM62207 (U.S. NIH Grant/Contract); OSU 07017