Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Decitabine and Tretinoin in Treating Patients With Myelodysplastic Syndromes

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II, Phase I	Biomarker/Laboratory analysis, Treatment	Active	18 and over	NCI	MSKCC-06054 NCT00382200

Objectives

Primary

1. Determine the hematologic and nonhematologic toxicities of decitabine in combination with tretinoin in patients with myelodysplastic syndromes. (Phase I)
2. Determine the maximum tolerated dose of tretinoin when administered with decitabine in these patients. (Phase I)
3. Determine the clinical remission rate (complete and partial remission) in patients treated with this regimen. (Phase II)
4. Determine the rate of hematologic improvement in these patients. (Phase II)

Secondary

1. 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.
2. Assess differentiation by morphology and flow cytometry and apoptosis by flow cytometry in patients treated with this regimen.
3. Determine if gene expression changes in these patients are induced by this regimen.
4. Determine the efficacy of this regimen, in terms of inducing demethylation of specific genes, in these patients.
5. Correlate clinical response with gene expression, demethylation of specific genes, and flow cytometric indicators of differentiation and apoptosis.

Entry Criteria

Disease Characteristics:

• Histologically confirmed myelodysplastic syndromes (MDS)



• International Prognostic scoring system (IPSS) score ≥ 0.5



• No treatment-related MDS



• Ineligible for transplantation



• No azacytidine-refractory disease
  • If previously treated with azacytidine, must have responded to therapy (hematologic improvement or better per International Working Group Response Criteria)
  • Disease progression after discontinuation of therapy



• Azacytidine-naive patients must have IPSS intermediate-2 or high-risk disease*

   [Note: *All azacytidine-naive patients are eligible in the second stage of phase II]

Prior/Concurrent Therapy:

• See Disease Characteristics
• More than 4 weeks since prior cytotoxic chemotherapy or radiotherapy
• More than 4 weeks since prior experimental therapy

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

Expected Enrollment

A total of 50 patients will be accrued for this study.

Outcomes

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

Change in bone marrow function as measured by frequency of transfusion, bleeding, and infection as well as changes in bone marrow morphology and cytogenetics
Differentiation as measured by morphology and flow cytometry and apoptosis as measured by flow cytometry
Gene expression changes as measured by Affymetrix gene profiling studies
Demethylation of specific genes as measured by gene promoter methylation studies
Correlation of 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 2 to 3 hours 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 polymerase chain reaction-based assays.

After completion of study treatment, patients are followed at 30 days.

Trial Contact Information

Trial Lead Organizations

Memorial Sloan-Kettering Cancer Center

Virginia Klimek, MD, Protocol chair		Ph: 212-639-6519; 800-525-2225

U.S.A.
New York
	New York
	Memorial Sloan-Kettering Cancer Center
		Virginia Klimek, MD	Ph:  212-639-6519 800-525-2225

Registry Information
Official Title		Phase I/II Study of Decitabine and All-Trans Retinoic Acid (Tretinoin) for Patients With Myelodysplastic Syndromes
Trial Start Date		2006-07-12
Trial Completion Date		2010-07-12 (estimated)
Registered in ClinicalTrials.gov		NCT00382200
Date Submitted to PDQ		2006-07-25
Information Last Verified		2008-12-14
NCI Grant/Contract Number		CA08748

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