Phase I/II Study of Decitabine and All-Trans Retinoic Acid (Tretinoin) for Patients With Myelodysplastic Syndromes
- 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,
- 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.
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Hematologic and nonhematologic toxicities as measured by NCI CTC v2.0 (Phase I)
After each cycle
Virginia Klimek, MD
Memorial Sloan-Kettering Cancer Center
United States: Food and Drug Administration
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