Decitabine and Tretinoin in Treating Patients With Myelodysplastic Syndromes
|ClinicalTrials.gov Identifier: NCT00382200|
Recruitment Status : Active, not recruiting
First Posted : September 28, 2006
Last Update Posted : August 4, 2017
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|
- 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)
- 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 Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||50 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I/II Study of Decitabine and All-Trans Retinoic Acid (Tretinoin) for Patients With Myelodysplastic Syndromes|
|Study Start Date :||July 2006|
|Estimated Primary Completion Date :||July 2018|
|Estimated Study Completion Date :||July 2018|
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|
- 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 ]
- 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 ]
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00382200
|United States, New York|
|Memorial Sloan-Kettering Cancer Center|
|New York, New York, United States, 10065|
|Study Chair:||Virginia Klimek, MD||Memorial Sloan Kettering Cancer Center|