Decitabine and Tretinoin in Treating Patients With Myelodysplastic Syndromes

Sponsor

Memorial Sloan Kettering Cancer Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT00382200

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

204

Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes	Drug: decitabine Drug: tretinoin Genetic: DNA methylation analysis Genetic: cytogenetic analysis Genetic: microarray analysis Other: flow cytometry Other: immunohistochemistry staining method	Phase 1/Phase 2

Detailed 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

54 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I/II Study of Decitabine and All-Trans Retinoic Acid (Tretinoin) for Patients With Myelodysplastic Syndromes

Study Start Date :

Jul 1, 2006

Anticipated Primary Completion Date :

Jul 1, 2023

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Decitabine and All-Trans Retonoic Acid (Tretinoin) Decitabine and All-Trans Retonoic Acid (Tretinoin)	Drug: decitabine Drug: tretinoin Genetic: DNA methylation analysis Genetic: cytogenetic analysis Genetic: microarray analysis Other: flow cytometry Other: immunohistochemistry staining method

Arm

Intervention/Treatment

Experimental: Decitabine and All-Trans Retonoic Acid (Tretinoin)

Decitabine and All-Trans Retonoic Acid (Tretinoin)

Drug: decitabine

Drug: tretinoin

Genetic: DNA methylation analysis

Genetic: cytogenetic analysis

Genetic: microarray analysis

Other: flow cytometry

Other: immunohistochemistry staining method

Outcome Measures

Primary Outcome Measures

Hematologic and nonhematologic toxicities as measured by NCI CTC v2.0 (Phase I) [After each cycle]
Maximum tolerated dose of tretinoin when administered with decitabine as determined by NCI CTC v2.0 (Phase I) [After each cycle]
Clinical remission rate (complete and partial remission) (Phase II) [After each cycle]
Rate of hematologic improvement as measured by responding cell lines (erythroid, platelet, and neutrophil response) (Phase II) [After each cycle]

Secondary Outcome Measures

Change in bone marrow function as measured by frequency of transfusion, bleeding, and infection as well as changes in bone marrow morphology and cytogenetics [After each cycle]
Differentiation as measured by morphology and flow cytometry and apoptosis as measured by flow cytometry [After each cycle]
Gene expression changes as measured by Affymetrix gene profiling studies [After each cycle]
Demethylation of specific genes as measured by gene promoter methylation studies [After each cycle]
Correlation of clinical response, with gene expression, demethylation of specific genes, and flow cytometric indicators of differentiation and apoptosis [After each cycle]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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