Decitabine in Treating Patients With Previously Untreated Acute Myeloid Leukemia

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00492401
• Collaborator: (none)
• Enrollment: 55
• Location: 1
• Arm: 1
• Duration (Months): 89
• Patients Per Site Per Month: 0.6

Study Details

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

Condition or Disease	Intervention/Treatment	Phase
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	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	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Determine the rate of complete remission (CR) in patients with previously untreated acute myeloid leukemia treated with decitabine.

SECONDARY OBJECTIVES:

1. Determine the rate of overall survival at 1 year in patients treated with this drug.

2. Determine the overall response rate (CR, incomplete CR, and partial remission) in patients treated with this drug.

3. Correlate the biological activity of decitabine with clinical endpoints and maximum concentration of plasma decitabine.

4. 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 Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Decitabine in Acute Myeloid Leukemia
• Study Start Date: May 1, 2007
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Oct 1, 2014

Arms and Interventions

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.

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

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ohio State University Medical Center	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: William Blum, Ohio State University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00492401
• Other Study ID Numbers: NCI-2009-00246; OSU 07017; N01CM62207
• First Posted: Jun 27, 2007
• Last Update Posted: Jun 27, 2016
• Last Verified: May 1, 2016

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Decitabine; Azacitidine

Study Results

Participant Flow

Arm/Group Title	Decitabine
Arm/Group Description	Decitabine 20mg/m2/day IV over 1 hour, days 1-10, repeat cycle every 28 days
Period Title: Overall Study
STARTED	55
COMPLETED	55
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Decitabine
Arm/Group Description	Decitabine 20mg/m2/day IV over 1 hour, days 1-10, repeat cycle every 28 days
Overall Participants	55
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	6 10.9%
>=65 years	49 89.1%
Sex: Female, Male (Count of Participants)
Female	19 34.5%
Male	36 65.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	55 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	55 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (patients) [Number]
United States	54
Canada	1

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Decitabine
Arm/Group Description	Decitabine 20mg/m2/day IV over 1 hour, days 1-10, repeat cycle every 28 days
Measure Participants	55
Number [patients]	25

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Data was not collected and analyzed

Arm/Group Title	Decitabine
Arm/Group Description	Decitabine 20mg/m2/day IV over 1 hour, days 1-10, repeat cycle every 28 days
Measure Participants	0

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Only pre treatment samples available for testing for 23 patients

Arm/Group Title	Responders	Non Responder
Arm/Group Description	Any patient that achieved a CR (Complete Response), or Incomplete CR was categorized as a responder.	Any patient that did not achieve a CR (Complete Response), or Incomplete CR was categorized as a non responder.
Measure Participants	14	9
Expression levels of MiR-29b	0.0056394	0.0024305
Expression levels of DNMT3a	0.000196066	0.000341819

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Decitabine, Non Responder
	Comments	Expression levels of miR-29b in pre treatment marrow samples from responding or non responding patients were compared using Wilcoxon rank sum tests
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.02
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Decitabine, Non Responder
	Comments	Expression levels of DNMT3a in pre treatment marrow samples from responding or non responding patients were compared using Wilcoxon rank sum tests
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.06
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Data was not collected and analyzed for this trial

Arm/Group Title	Decitabine
Arm/Group Description	Decitabine 20mg/m2/day IV over 1 hour, days 1-10, repeat cycle every 28 days
Measure Participants	0

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Data was not collected and analyzed for this trial

Arm/Group Title	Decitabine
Arm/Group Description	Decitabine 20mg/m2/day IV over 1 hour, days 1-10, repeat cycle every 28 days
Measure Participants	0

Adverse Events

Adverse Event Reporting Description	Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3.0
Arm/Group Title	Treatment (Chemotherapy)
Arm/Group 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. decitabine: Given IV laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies high performance liquid chromatography: Correlative studies microarray analysis: Correlative studies RNA analysis: Correlative studies mass spectrometry: Correlative studies DNA methylation analysis: Correlative studies matrix-assisted laser desorption/ionization time of flight mass spectrometry: Correlative studies
All Cause Mortality
	Treatment (Chemotherapy)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Chemotherapy)
	Affected / at Risk (%)	# Events
Total	0/53 (0%)
Other (Not Including Serious) Adverse Events
	Treatment (Chemotherapy)
	Affected / at Risk (%)	# Events
Total	53/53 (100%)
Cardiac disorders
Decreased left ventricular ejection fraction	1/53 (1.9%)	1
Gastrointestinal disorders
Mucositis/gingivitis	3/53 (5.7%)	3
Arrhythmia	3/53 (5.7%)	3
General disorders
Fatigue	3/53 (5.7%)	3
Fever	2/53 (3.8%)	2
Abnormal gait	2/53 (3.8%)	2
Pain	7/53 (13.2%)	7
Infections and infestations
Documented infection	31/53 (58.5%)	31
Febrile neutropenia	5/53 (9.4%)	5
Investigations
Prolonged QTc	2/53 (3.8%)	2
Metabolism and nutrition disorders
Anorexia	1/53 (1.9%)	1
Nervous system disorders
Dysgeusia	1/53 (1.9%)	1
Syncope	3/53 (5.7%)	3
Psychiatric disorders
Confusion	1/53 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/53 (5.7%)	3
Hypoxia	8/53 (15.1%)	8
Skin and subcutaneous tissue disorders
Decubitus ulcer	1/53 (1.9%)	1
Rash	2/53 (3.8%)	2
Vascular disorders
Hypertension	2/53 (3.8%)	2
Thrombosis	3/53 (5.7%)	3
Hemorrhage/hematoma	5/53 (9.4%)	5

Limitations/Caveats

After completing the target accrual of 33 subjects, the study was expanded to include 22 additional patients. All patients who received decitabine are included in the analyses, except for two who had not completed therapy at the time of the analysis.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.