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

Phase 1/Phase 2
18 Years
Open (Enrolling)
Myelodysplastic Syndromes

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Trial Information

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,
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.

Inclusion Criteria


- Histologically confirmed myelodysplastic syndromes (MDS)

- International Prognostic scoring system (IPSS) score ≥ 0.5, including the following:

- Untreated or treated intermediate-1 risk disease

- Intermediate-2 risk disease

- High-risk disease

- No treatment-related MDS

- Ineligible for transplantation

- No decitabine-refractory disease defined as disease progression after discontinuation
of therapy

- If previously treated with decitabine, must have responded to therapy
(hematologic improvement or better per International Working Group Response


- 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

- No other malignancy that would likely require systemic chemotherapy within 4 months
after starting study treatment

- No allergy to parabens, vitamin A, or retinoids


- See Disease Characteristics

- Prior azacytidine allowed

- More than 4 weeks since prior cytotoxic chemotherapy or radiotherapy

- More than 4 weeks since prior experimental therapy

- Concurrent myeloid growth factors allowed only in the setting of febrile neutropenia
according to established guidelines for use

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Hematologic and nonhematologic toxicities as measured by NCI CTC v2.0 (Phase I)

Outcome Time Frame:

After each cycle

Safety Issue:


Principal Investigator

Virginia Klimek, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

July 2006

Completion Date:

July 2013

Related Keywords:

  • Myelodysplastic Syndromes
  • de novo myelodysplastic syndromes
  • previously treated myelodysplastic syndromes
  • Myelodysplastic Syndromes
  • Preleukemia



Memorial Sloan-Kettering Cancer Center New York, New York  10021