Clinical trial NCT00382200: Decitabine and Tretinoin 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Myelodysplastic Syndromes
Keywords: de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
Lead sponsor: Memorial Sloan Kettering Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2006-09-28
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: DISEASE CHARACTERISTICS:

* 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 Criteria)

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
* 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

Primary outcomes:
measure: Number of Participants Evaluated for Hematologic and Nonhematologic Toxicities as Measured by NCI CTC v2.0
timeFrame: Up to 1 year
measure: Maximum Tolerated Dose of Tretinoin When Administered With Decitabine as Determined by NCI CTC v2.0 (Phase II)
timeFrame: Up to 1 year
measure: Overall Response Rate
timeFrame: Up to 1 year
measure: Rate of Hematologic Improvement as Measured by Responding Cell Lines (Erythroid, Platelet, and Neutrophil Response) (Phase II)
timeFrame: After each cycle
Secondary outcomes:
measure: Change in Bone Marrow Function as Measured by Frequency of Transfusion, Bleeding, and Infection as Well as Changes in Bone Marrow Morphology and Cytogenetics
timeFrame: After each cycle
measure: Differentiation as Measured by Morphology and Flow Cytometry and Apoptosis as Measured by Flow Cytometry
timeFrame: After each cycle
measure: Gene Expression Changes as Measured by Affymetrix Gene Profiling Studies
timeFrame: After each cycle
measure: Demethylation of Specific Genes as Measured by Gene Promoter Methylation Studies
timeFrame: After each cycle
measure: Correlation of Clinical Response, With Gene Expression, Demethylation of Specific Genes, and Flow Cytometric Indicators of Differentiation and Apoptosis
timeFrame: After each cycle
Other outcomes:
Locations:
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
Study officials:
affiliation: Memorial SloanKettering Cancer Center
name: Raajit Rampal, MD, PhD
role: STUDY_CHAIR
References: