Decitabine and FR901228 in Treating Patients With Relapsed or Refractory Leukemia, Myelodysplastic Syndromes, or Myeloproliferative Disorders

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 and FR901228 in treating patients with relapsed or refractory leukemia, myelodysplastic syndromes or myeloproliferative disorders. Drugs used in chemotherapy, such as decitabine and FR901228, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. FR901228 may also stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer. Giving decitabine together with FR901228 may kill more cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose and recommended phase II dose of decitabine and FR901228 (depsipeptide) in patients with relapsed or refractory leukemia, myelodysplastic syndromes, or myeloproliferative disease. II. Determine the safety and tolerability of this regimen in these patients. SECONDARY OBJECTIVES: I. Determine the clinical activity of this regimen in these patients. OUTLINE: This is a dose-escalation study. Patients receive decitabine IV over 1 hour on days 1-5 and 8-12 and FR901228 (depsipeptide) IV over 4 hours on days 5 and 12 OR days 5, 12, and 19. Treatment repeats every 4-6 weeks for at least 2 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing complete remission for 1 year are removed from the study. Cohorts of 6 patients receive escalating doses of decitabine and FR901228 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.

Official Title
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A Phase I Study of 5-AZA-2'-Deoxycytidine and Depsipeptide in Patients With Relapsed/Refractory Leukemia, Myelodysplastic Syndromes, or Myeloproliferative Disease

Conditions
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Chronic Myeloproliferative Disorders, Leukemia, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms

Intervention / Treatment
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* Drug: decitabine
* Drug: romidepsin


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed diagnosis of 1 of the following hematologic malignancies: Acute myeloid leukemia Previously untreated patients > 60 years of age who are not eligible for front-line therapy are eligible for this study Acute lymphoblastic leukemia Chronic myelogenous leukemia (CML) Documented hematologic resistance to imatinib mesylate OR no cytogenetic response after 12 months of prior treatment with imatinib mesylate Philadelphia chromosome-negative CML allowed provided disease is resistant to standard therapy (e.g., hydroxyurea) OR disease progressed (blasts > 5% and platelet count < 100,000/mm^3) during standard therapy Myelodysplastic syndromes International Prognostic Scoring System risk category ≥ intermediate-1 Patients who are not eligible for front-line therapy are eligible for this study Myeloproliferative disease Chronic lymphocytic leukemia Failed or progressed during ≥ 1 prior fludarabine-based therapy AND alemtuzmab Acute promyelocytic leukemia Progressed after prior treatment with standard chemotherapy, tretinoin, and arsenic trioxide Chronic myelomonocytic leukemia Resistant to standard therapy (e.g., hydroxyurea) OR disease progressed (blasts > 5% and platelet count < 100,000/mm^3) during standard therapy Relapsed or refractory disease No known brain or meningeal disease PATIENT CHARACTERISTICS: Age Over 18 Performance status ECOG 0-1 Life expectancy More than 8 weeks Hepatic Bilirubin < 2 mg/dL AST and ALT ≤ 2.5 times upper limit of normal Renal Creatinine < 2 mg/dL Cardiovascular QTc < 500 msec LVEF > 40% by MUGA No New York Heart Association class III or IV congestive heart failure No myocardial infarction within the past year No uncontrolled dysrhythmias No uncontrolled angina No left ventricular hypertrophy by EKG No history of serious ventricular arrhythmia (e.g., ventricular tachycardia or ventricular fibrillation ≥ 3 beats in a row) No other significant cardiac disease Immunologic No history of allergic reaction attributed to compounds of similar chemical or biologic composition to study drugs No ongoing or active infection No HIV positivity Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No psychiatric illness or social situation that would preclude study compliance No other uncontrolled illness PRIOR CONCURRENT THERAPY: Chemotherapy Recovered from prior chemotherapy At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) unless there is evidence of rapidly progressive disease Radiotherapy At least 4 weeks since prior radiotherapy and recovered Other No concurrent agents that cause QTc prolongation No other concurrent investigational or commercial agents or therapies for the malignancy No concurrent hydrochlorothiazide Concurrent potassium-conserving combinations (e.g., Maxide® or Dyazide®) or other antihypertensive agents allowed

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: Arm I<br>Patients receive decitabine IV over 1 hour on days 1-5 and 8-12 and FR901228 (depsipeptide) IV over 4 hours on days 5 and 12 OR days 5, 12, and 19. Treatment repeats every 4-6 weeks for at least 2 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing complete remission for 1 year are removed from the study. Cohorts of 6 patients receive escalating doses of decitabine and FR901228 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. | Drug: decitabine<br> <br> Drug: romidepsin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity at 6 weeks after each course |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete and partial response at 6 weeks after each course |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult erythroleukemia (M6a), adult acute myelomonocytic leukemia (M4), recurrent adult acute lymphoblastic leukemia, 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), recurrent adult acute myeloid leukemia, secondary acute myeloid leukemia, untreated adult acute myeloid leukemia, adult acute promyelocytic leukemia (M3), relapsing chronic myelogenous leukemia, refractory chronic lymphocytic leukemia, de novo myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasm, unclassifiable, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, atypical chronic myeloid leukemia, BCR-ABL1 negative, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, primary myelofibrosis, chronic neutrophilic leukemia, essential thrombocythemia, polycythemia vera, Philadelphia chromosome negative chronic myelogenous leukemia, chronic myelogenous leukemia, BCR-ABL1 positive, adult acute minimally differentiated myeloid leukemia (M0), adult acute myeloblastic leukemia without maturation (M1), adult acute myeloblastic leukemia with maturation (M2), adult acute monoblastic leukemia (M5a), adult acute monocytic leukemia (M5b), adult pure erythroid leukemia (M6b), adult acute megakaryoblastic leukemia (M7), adult acute basophilic leukemia, adult acute eosinophilic leukemia