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Decitabine in Treating Patients With Previously Untreated Acute Myeloid Leukemia

Primary Purpose

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
decitabine
laboratory biomarker analysis
pharmacological study
high performance liquid chromatography
microarray analysis
RNA analysis
mass spectrometry
DNA methylation analysis
matrix-assisted laser desorption/ionization time of flight mass spectrometry
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Ohio State University Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (chemotherapy)

Arm Description

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.

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

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.
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.
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.
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.

Full Information

First Posted
June 25, 2007
Last Updated
May 18, 2016
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00492401
Brief Title
Decitabine in Treating Patients With Previously Untreated Acute Myeloid Leukemia
Official Title
Phase II Study of Decitabine in Acute Myeloid Leukemia
Study Type
Interventional

2. Study Status

Record Verification Date
May 2016
Overall Recruitment Status
Completed
Study Start Date
May 2007 (undefined)
Primary Completion Date
December 2010 (Actual)
Study Completion Date
October 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
55 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (chemotherapy)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
decitabine
Other Intervention Name(s)
5-aza-dCyd, 5AZA, DAC
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
pharmacological study
Other Intervention Name(s)
pharmacological studies
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
high performance liquid chromatography
Other Intervention Name(s)
HPLC
Intervention Description
Correlative studies
Intervention Type
Genetic
Intervention Name(s)
microarray analysis
Other Intervention Name(s)
gene expression profiling
Intervention Description
Correlative studies
Intervention Type
Genetic
Intervention Name(s)
RNA analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
mass spectrometry
Intervention Description
Correlative studies
Intervention Type
Genetic
Intervention Name(s)
DNA methylation analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
matrix-assisted laser desorption/ionization time of flight mass spectrometry
Other Intervention Name(s)
MALDI-TOF Mass Spectrometry
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Rate of Complete Remission
Description
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)
Time Frame
Up to 24 weeks
Secondary Outcome Measure Information:
Title
Measurement of DNA Methylation in Peripheral Blood or Bone Marrow Cells
Description
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.
Time Frame
From baseline to up to day 28 of course 1
Title
Measurement of DNMT Protein in Peripheral Blood or Bone Marrow Cells
Description
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.
Time Frame
Pre treatment
Title
Measurement of HbF in Peripheral Blood or Marrow Cells
Description
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.
Time Frame
From baseline to up to days 28 of course 2
Title
Measurement of Gene Expression in Peripheral Blood or Bone Marrow
Description
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.
Time Frame
From baseline to up to day 28 of course 1

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
William Blum
Organizational Affiliation
Ohio State University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ohio State University Medical Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
20368434
Citation
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.
Results Reference
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Decitabine in Treating Patients With Previously Untreated Acute Myeloid Leukemia

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