Decitabine and Tretinoin in Treating Patients With Myelodysplastic Syndromes

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT00382200
First received: September 26, 2006
Last updated: October 11, 2013
Last verified: October 2013
  Purpose

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.


Condition Intervention Phase
Myelodysplastic Syndromes
Drug: decitabine
Drug: tretinoin
Genetic: DNA methylation analysis
Genetic: cytogenetic analysis
Genetic: microarray analysis
Other: flow cytometry
Other: immunohistochemistry staining method
Phase 1
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Study of Decitabine and All-Trans Retinoic Acid (Tretinoin) for Patients With Myelodysplastic Syndromes

Resource links provided by NLM:


Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:
  • Hematologic and nonhematologic toxicities as measured by NCI CTC v2.0 (Phase I) [ Time Frame: After each cycle ] [ Designated as safety issue: Yes ]
  • Maximum tolerated dose of tretinoin when administered with decitabine as determined by NCI CTC v2.0 (Phase I) [ Time Frame: After each cycle ] [ Designated as safety issue: Yes ]
  • Clinical remission rate (complete and partial remission) (Phase II) [ Time Frame: After each cycle ] [ Designated as safety issue: No ]
  • Rate of hematologic improvement as measured by responding cell lines (erythroid, platelet, and neutrophil response) (Phase II) [ Time Frame: After each cycle ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change in bone marrow function as measured by frequency of transfusion, bleeding, and infection as well as changes in bone marrow morphology and cytogenetics [ Time Frame: After each cycle ] [ Designated as safety issue: No ]
  • Differentiation as measured by morphology and flow cytometry and apoptosis as measured by flow cytometry [ Time Frame: After each cycle ] [ Designated as safety issue: No ]
  • Gene expression changes as measured by Affymetrix gene profiling studies [ Time Frame: After each cycle ] [ Designated as safety issue: No ]
  • Demethylation of specific genes as measured by gene promoter methylation studies [ Time Frame: After each cycle ] [ Designated as safety issue: No ]
  • Correlation of clinical response, with gene expression, demethylation of specific genes, and flow cytometric indicators of differentiation and apoptosis [ Time Frame: After each cycle ] [ Designated as safety issue: No ]

Estimated Enrollment: 50
Study Start Date: July 2006
Estimated Study Completion Date: July 2014
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Decitabine and All-Trans Retonoic Acid (Tretinoin)
Decitabine and All-Trans Retonoic Acid (Tretinoin)
Drug: decitabine Drug: tretinoin Genetic: DNA methylation analysis Genetic: cytogenetic analysis Genetic: microarray analysis Other: flow cytometry Other: immunohistochemistry staining method

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00382200

Locations
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Investigators
Study Chair: Virginia Klimek, MD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT00382200     History of Changes
Other Study ID Numbers: 06-054, MSKCC-06054
Study First Received: September 26, 2006
Last Updated: October 11, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Memorial Sloan-Kettering Cancer Center:
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Decitabine
Tretinoin
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Keratolytic Agents
Dermatologic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 19, 2014