Decitabine and Tretinoin in Treating Patients With Myelodysplastic Syndromes

Phase 1

Completed

Conditions: Myelodysplastic Syndromes

Interventions: Drug: decitabine
Drug: tretinoin
Genetic: DNA methylation analysis
Genetic: cytogenetic analysis
Genetic: microarray analysis
Other: flow cytometry
Other: immunohistochemistry staining method

Registration Number: NCT00382200

Lead Sponsor: Memorial Sloan Kettering Cancer Center

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 54

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Decitabine and All-Trans Retonoic Acid (Tretinoin)	tretinoin	Decitabine and All-Trans Retonoic Acid (Tretinoin)
Decitabine and All-Trans Retonoic Acid (Tretinoin)	DNA methylation analysis	Decitabine and All-Trans Retonoic Acid (Tretinoin)
Decitabine and All-Trans Retonoic Acid (Tretinoin)	decitabine	Decitabine and All-Trans Retonoic Acid (Tretinoin)
Decitabine and All-Trans Retonoic Acid (Tretinoin)	cytogenetic analysis	Decitabine and All-Trans Retonoic Acid (Tretinoin)
Decitabine and All-Trans Retonoic Acid (Tretinoin)	microarray analysis	Decitabine and All-Trans Retonoic Acid (Tretinoin)
Decitabine and All-Trans Retonoic Acid (Tretinoin)	flow cytometry	Decitabine and All-Trans Retonoic Acid (Tretinoin)
Decitabine and All-Trans Retonoic Acid (Tretinoin)	immunohistochemistry staining method	Decitabine and All-Trans Retonoic Acid (Tretinoin)

Primary Outcome Measures

Name	Time	Method
Number of Participants Evaluated for Hematologic and Nonhematologic Toxicities as Measured by NCI CTC v2.0	Up to 1 year
Maximum Tolerated Dose of Tretinoin When Administered With Decitabine as Determined by NCI CTC v2.0 (Phase II)	Up to 1 year
Overall Response Rate	Up to 1 year	Overall Response Rate is defined as Complete Response + Partial Response
Rate of Hematologic Improvement as Measured by Responding Cell Lines (Erythroid, Platelet, and Neutrophil Response) (Phase II)	After each cycle

Secondary Outcome Measures

Name	Time	Method
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