Decitabine and Tretinoin in Treating Patients With Myelodysplastic Syndromes
Condition: Myelodysplastic Syndromes
MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome
Study type: Interventional
Phase: Phase 1/Phase 2

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.
    

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.
    

Intervention name(s): decitabine; tretinoin; DNA methylation analysis; cytogenetic analysis; microarray analysis; flow cytometry; immunohistochemistry staining method
Intervention type(s): Drug; Drug; Genetic; Genetic; Genetic; Other; Other
Intervention MeSH terms: Decitabine; Tretinoin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: de novo myelodysplastic syndromes; previously treated myelodysplastic syndromes