Decitabine and Tretinoin in Treating Patients With Myelodysplastic Syndromes

Condition(s) targeted: Myelodysplastic Syndromes

Intervention: decitabine (Drug); tretinoin (Drug); DNA methylation analysis (Procedure); cytogenetic analysis (Procedure); flow cytometry (Procedure); gene expression profiling (Procedure); immunohistochemistry staining method (Procedure); polymerase chain reaction (Procedure)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Memorial Sloan-Kettering Cancer Center

Official(s) and/or principal investigator(s):
Virginia Klimek, MD, Study Chair, Affiliation: Memorial Sloan-Kettering Cancer Center

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.

Official title: Phase I/II Study of Decitabine and All-Trans Retinoic Acid (Tretinoin) for Patients With Myelodysplastic Syndromes

Study design: Treatment, Open Label

Primary outcome:

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)

Secondary outcome:

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

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 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.

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

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

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

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- More than 4 weeks since prior cytotoxic chemotherapy or radiotherapy

- More than 4 weeks since prior experimental therapy

Memorial Sloan-Kettering Cancer Center, New York, New York 10021, United States; Recruiting
Virginia Klimek, MD, Phone: 212-639-6519

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: July 2006
Last updated: October 21, 2008