Genomic Predictors of Decitabine Response in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndromes

Study Overview
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Brief Summary
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This clinical trial studies potential genetic markers which might be used to predict which patients with acute myeloid leukemia or myelodysplastic syndromes respond to decitabine. This study will contribute to the efforts to find effective and less toxic therapies to provide durable remissions in a significant proportion of elderly AML patients.

Official Title
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Genomic Predictors of Decitabine Response in AML/MDS

Conditions
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Leukemia, Myeloid, Acute, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: decitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All of the following: Patient must have non-M3 AML or MDS An adverse risk karyotype defined by: Complex karyotype by cytogenetics, or Deletion of all or part of chromosome 5, 7, 12, or 17 defined by FISH or cytogenetics, or Somatic TP53 mutation All of the following: Patient must have an ECOG performance status ≤ 2. Patient must have >10% disease burden measured by cytomorphology, flow cytometry, or cytogenetics. Patient must have peripheral white blood cell count < 50,000/mcl. Patient must have adequate organ function, defined as: Total bilirubin < 1.5 x ULN AST/ALT < 2.5 x ULN Serum creatinine < 2.0 x ULN Patient must have undergone ≤ 2 cycles of prior hypomethylating agent (decitabine or azacitidine). Patient must be enrolled in HRPO# 201011766 (Tissue Acquisition for Analysis of Genetic Progression Factors in Hematologic Diseases). Patient must be > 18 years of age. Patient must be able to understand and willing to sign an IRB-approved written informed consent document. Exclusion Criteria: Patient must not be pregnant or nursing Patient must not have acute promyelocytic leukemia or t(15;17) observed by FISH. Patient must not have known central nervous system (CNS) leukemia Patient must not have a history of positive human immunodeficiency virus (HIV) serology Patient must not have a history of positive hepatitis C serology Patient must not have undergone prior allogeneic stem cell transplant Patient must not have any uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, ongoing or active graft-versus-host disease (GVHD), congestive heart failure of New York Heart Association (NYHA) class 3 or 4, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements Patient must not have had radiation therapy within 14 days of enrollment Patient must not have received any chemotherapy within 21 days of enrollment and any acute treatment-related toxicities must have returned to baseline. Patients may be receiving hydrea at time of enrollment.

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: Decitabine<br>Patients receive decitabine IV over 1 hour on days 1-10 of a 28-day cycle. Treatment continues for 2 cycles. Patients then receive decitabine IV over 1 hour on days 1-10, 1-5, or 1-3 (depending on response). Treatment continues in the absence of disease progression or unacceptable toxicity. | Drug: decitabine<br> <br> * Other names: 5-aza-dCyd, 5AZA, DAC, Dacogen, deoxyazacytidine, dezocitidine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of Patient Specific Mutations With Overall Response Rate | -Best response after 4 treatment cycles as assessed according to International Working Group (IWG) criteria; bone marrow for gene sequencing will be collected at baseline; mutations will be correlated with overall response rate --Complete remission (CR), Complete remission with incomplete hematologic recovery (CRi), Marrow complete remission (mCR), Partial remission (PR), Stable disease (SD), Progressive disease (PD) | 4 months (4 treatment cycles) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare Outcomes of a 10-day Decitabine Per Cycle Regimen to a 5-day Regimen (Historical Controls) | The overall response rate (CR/CRi/mCR/PR) and complete response rate (CR/CRi/mCR) will be compared with historical controls. Response assessed according to IWG criteria. | 4 months (4 treatment cycles) | 
| Rate of Mutation Clearance During Treatment | Samples collected at baseline and after 10, 28 and 56 days of therapy; the rate of mutation clearance was measured as mean VAF change per day of treatment and was estimated using linear mixed model for repeated measurement data . | Up to Day 56 | 
| Peripheral Blood Decitabine Plasma Levels | To determine whether steady state serum concentrations of decitabine correlated with responses Complete remission (CR), Complete remission with incomplete hematologic recovery (CRi), Partial remission (PR), Stable disease (SD), Progressive disease (PD), Not applicable (NA) - assessed according to International Working Group (IWG) criteria | Day 4 | 
| Change in Bone Marrow Methylcytosine | -Change of total bone marrow deoxyribonucleic acid (DNA) methylcytosine from baseline to Day 10 | Baseline and Day 10 |