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

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00114257

Collaborator

(none)

Enrollment

Location

Arm

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Myeloproliferative Disorders Leukemia Myelodysplastic Syndromes Myelodysplastic/Myeloproliferative Neoplasms	Drug: decitabine Drug: romidepsin	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

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.
Determine the safety and tolerability of this regimen in these patients.

SECONDARY OBJECTIVES:

Determine the clinical activity of this regimen in these patients.

OUTLINE: This is a dose-escalation 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

36 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

May 1, 2005

Actual Primary Completion Date :

Sep 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I 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 Drug: romidepsin

Arm

Intervention/Treatment

Experimental: Arm I

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

Drug: romidepsin

Outcome Measures

Primary Outcome Measures

Toxicity at 6 weeks after each course []

Secondary Outcome Measures

Complete and partial response at 6 weeks after each course []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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