Overview

This trial is active, not recruiting.

Condition myelodysplastic syndromes
Treatments decitabine, tretinoin, dna methylation analysis, cytogenetic analysis, microarray analysis, flow cytometry, immunohistochemistry staining method
Phase phase 1/phase 2
Sponsor Memorial Sloan-Kettering Cancer Center
Collaborator National Cancer Institute (NCI)
Start date July 2006
End date July 2015
Trial size 50 participants
Trial identifier NCT00382200, 06-054, MSKCC-06054

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Decitabine and All-Trans Retonoic Acid (Tretinoin)
decitabine
tretinoin
dna methylation analysis
cytogenetic analysis
microarray analysis
flow cytometry
immunohistochemistry staining method

Primary Outcomes

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

Secondary Outcomes

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

Eligibility Criteria

Male or female participants at least 18 years old.

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

Additional Information

Official title Phase I/II Study of Decitabine and All-Trans Retinoic Acid (Tretinoin) for Patients With Myelodysplastic Syndromes
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.
Trial information was received from ClinicalTrials.gov and was last updated in October 2014.
Information provided to ClinicalTrials.gov by Memorial Sloan-Kettering Cancer Center.