Decitabine and Tretinoin in Treating Patients With Myelodysplastic Syndromes

Memorial Sloan Kettering Cancer Center (MSK)

Status and phase

Completed

Phase 2

Phase 1

Conditions

Myelodysplastic Syndromes

Treatments

Genetic: cytogenetic analysis

Other: flow cytometry

Other: immunohistochemistry staining method

Drug: decitabine

Genetic: DNA methylation analysis

Drug: tretinoin

Genetic: microarray analysis

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00382200

06-054

MSKCC-06054

Details and patient eligibility

About

RATIONALE: Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of myelodysplastic cells, either by killing the cells or by stopping them from dividing. Tretinoin and decitabine may help myelodysplastic cells become more like normal cells, and to grow and spread more slowly. Giving decitabine together with tretinoin may be an effective treatment for myelodysplastic syndromes.

PURPOSE: This phase I/II trial is studying the side effects and best dose of tretinoin when given together with decitabine in treating patients with myelodysplastic syndromes.

Full description

OBJECTIVES:

Primary

Determine the hematologic and nonhematologic toxicities of decitabine in combination with tretinoin in patients with myelodysplastic syndromes. (Phase I)
Determine the maximum tolerated dose of tretinoin when administered with decitabine in these patients. (Phase I)
Determine the clinical remission rate (complete and partial remission) in patients treated with this regimen. (Phase II)
Determine the rate of hematologic improvement in these patients. (Phase II)

Secondary

Determine the efficacy of this regimen, in terms of improved bone marrow function, by monitoring frequency of transfusion, bleeding, and infection, as well as changes in bone marrow morphology and cytogenetics in these patients.
Assess differentiation by morphology and flow cytometry and apoptosis by flow cytometry in patients treated with this regimen.
Determine if gene expression changes in these patients are induced by this regimen.
Determine the efficacy of this regimen, in terms of inducing demethylation of specific genes, in these patients.
Correlate clinical response with gene expression, demethylation of specific genes, and flow cytometric indicators of differentiation and apoptosis.

OUTLINE: This is a phase I, dose-escalation study of tretinoin followed by a phase II, open-label study.

Phase I: Patients receive decitabine IV over 1 hour once daily on days 1-5 followed by oral tretinoin twice daily on days 10-19. Treatment repeats every 28 days for a minimum of 4 courses in the absence of disease progression or excessive toxicity. Patients who achieve a partial or complete response after completing 6 courses of treatment may receive 4 additional courses up to a total of 10 courses. Patients with stable disease or hematologic improvement are removed from study.

Cohorts of 3-6 patients receive escalating doses of tretinoin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity attributable to tretinoin at any dose level during course 1. A total of 6 patients are treated at the MTD.

Phase II: Patients receive decitabine as in phase I and tretinoin at the MTD. Patients undergo blood and bone marrow collection periodically during study for correlative demethylation and gene profiling studies and for evidence of differentiation and apoptosis. Samples are examined by flow cytometry, cytogenetics, histochemistry, and array-based whole genome methylation analysis.

After completion of study treatment, patients are followed at 30 days.

PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

Enrollment

54 patients

Sex

All

Ages

18 to 120 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

Histologically confirmed myelodysplastic syndromes (MDS)
International Prognostic scoring system (IPSS) score ≥ 0.5, including the following:
- Untreated or treated intermediate-1 risk disease
- Intermediate-2 risk disease
- High-risk disease
No treatment-related MDS
Ineligible for transplantation
No decitabine-refractory disease defined as disease progression after discontinuation of therapy
- If previously treated with decitabine, must have responded to therapy (hematologic improvement or better per International Working Group Response Criteria)

PATIENT CHARACTERISTICS:

Karnofsky performance status 60-100%
Bilirubin ≤ 2.5 mg/dL
AST and ALT ≤ 2 times upper limit of normal (ULN)
Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No other medical condition that, in the opinion of the treating physician, would preclude patient compliance or put patient at excessive risk of treatment-related toxicity
No other malignancy that would likely require systemic chemotherapy within 4 months after starting study treatment
No allergy to parabens, vitamin A, or retinoids

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
Prior azacytidine allowed
More than 4 weeks since prior cytotoxic chemotherapy or radiotherapy
More than 4 weeks since prior experimental therapy
Concurrent myeloid growth factors allowed only in the setting of febrile neutropenia according to established guidelines for use