Decitabine in Treating Patients With Previously Untreated Acute Myeloid Leukemia

Phase 2

Completed

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

• Registration Number: NCT00492401
• Lead Sponsor: National Cancer Institute (NCI)

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.

Study Timeline

• Study Start: 2007-05
• Study First Submitted: 2007-06-25
• Study First Submitted QC: 2007-06-25
• Study First Posted: 2007-06-27
• Primary Completion: 2010-12
• Study Completion: 2014-10
• Results First Submitted: 2015-10-22
• Status Verified: 2016-05
• Results First Submitted QC: 2016-05-18
• Last Update Submitted: 2016-05-18
• Results First Posted: 2016-06-27
• Last Update Posted: 2016-06-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 55

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

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (chemotherapy)	laboratory biomarker analysis	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.
Treatment (chemotherapy)	pharmacological study	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.
Treatment (chemotherapy)	DNA methylation analysis	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.
Treatment (chemotherapy)	high performance liquid chromatography	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.
Treatment (chemotherapy)	microarray analysis	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.
Treatment (chemotherapy)	RNA analysis	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.
Treatment (chemotherapy)	mass spectrometry	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.
Treatment (chemotherapy)	matrix-assisted laser desorption/ionization time of flight mass spectrometry	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.
Treatment (chemotherapy)	decitabine	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.

Primary Outcome Measures

Name	Time	Method
Rate of Complete Remission	Up to 24 weeks	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

Name	Time	Method
Measurement of DNA Methylation in Peripheral Blood or Bone Marrow Cells	From baseline to up to day 28 of course 1	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	Pre treatment	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	From baseline to up to days 28 of course 2	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	From baseline to up to day 28 of course 1	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.

Trial Locations

Locations (1)

Ohio State University Medical Center; 🇺🇸 Columbus, Ohio, United States