Decitabine in Treating Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This phase I trial is studying the side effects and best dose of decitabine in treating patients with myelodysplastic syndromes or acute myeloid leukemia. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die.

Detailed Description
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OBJECTIVES: I. Determine the maximum tolerated dose of decitabine in patients with high-risk myelodysplastic syndromes or acute myeloid leukemia. II. Determine the minimum effective dose of this drug that produces demethylation of DNA with tolerable toxicity in these patients. III. Determine the minimum effective dose of this drug that augments in vitro responses to retinoids. IV. Determine the pharmacokinetics of this drug in these patients. V. Determine the clinical response rate of patients treated with this drug. OUTLINE: This is a dose-escalation, multicenter study. Patients receive decitabine IV over 3 hours twice daily OR IV over 1 hour once daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of decitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. PROJECTED ACCRUAL: A maximum of 36 patients will be accrued for this study within 18 months.

Official Title
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Phase I Study of 5-Aza-2'-Deoxycytidine (Decitabine) as a Biologic Modifier of Retinoid Responsive Genes in Patients With High-Risk Myelodysplastic Syndromes and Acute Myelogenous Leukemia (De-novo, Relapsed or Secondary)

Conditions
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Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, 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), Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative, de Novo Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes, Untreated Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: decitabine
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: One of the following diagnoses: High-risk myelodysplastic syndromes (MDS) Acute myeloid leukemia (AML) De novo, secondary, or relapsed disease Any number of prior regimens for primary or relapsed disease Ineligible for or refuses aggressive management Measurable disease, defined as: More than 5% blasts in bone marrow of patients with MDS More than 30% blasts in bone marrow of patients with AML Involvement of cerebrospinal fluid allowed Performance status - ECOG 0-2 Performance status - Karnofsky 60-100% See Disease Characteristics Bilirubin no greater than 1.25 times upper limit of normal (ULN) AST and/or ALT no greater than 1.25 times ULN Creatinine less than 1.7 mg/dL Creatinine clearance at least 60 mL/min No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia No ongoing or active infection No other uncontrolled illness that would preclude study participation No psychiatric illness or social situation that would preclude study compliance No prior allergic reactions to compounds of similar chemical or biological composition to decitabine No other active malignancy Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception At least 4 weeks since prior biologic therapy (e.g., interferon, filgrastim [G-CSF], sargramostim [GM-CSF], thrombopoietin, or epoetin alfa) No concurrent hematopoietic growth factors (GM-CSF, thrombopoietin, or epoetin alfa) No concurrent prophylactic G-CSF Prior intrathecal cytarabine allowed for patients with cerebrospinal fluid involvement At least 4 weeks since prior chemotherapy (except low-dose chemotherapy administered to maintain WBC counts) (6 weeks for nitrosoureas or mitomycin) and recovered At least 24 hours since prior hydroxyurea Concurrent intrathecal cytarabine allowed for patients with cerebrospinal fluid involvement No prior radiotherapy greater than 3,000 cGy to marrow-producing areas At least 4 weeks since prior radiotherapy and recovered Prior investigational therapy allowed No other concurrent investigational agents No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent anticancer therapy

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: Treatment (decitabine)<br>Patients receive decitabine IV over 3 hours twice daily OR IV over 1 hour once daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of decitabine until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. | Drug: decitabine<br>* Given IV<br>* Other names: DAC;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of decitabine, graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0 |  | Up to day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimal effective dose of decitabine that will lead to demethylation of deoxyribonucleic acid (DNA) with tolerable toxicity as assessed by RXR gene |  | Up to day 28 | 
| Proportion of patients with in-vitro retinoid response |  | Up to 8 years | 
| Duration of clinical response |  | Up to 8 years | 
| Changes in gene expression, gene methylation and bone marrow aspirate sample measurements | The effect on gene expression due to pharmacological exposures (ie retinoic acid receptor [RAR] or retinoid X receptor [RXR]) will be assessed using chi-square tests. | Up to day 5 |