Differentiation Therapy With Decitabine in Treating Patients With Myelodysplastic Syndrome
RATIONALE: Decitabine may help myelodysplastic cells become more like normal stem cells. PURPOSE: This clinical trial studies differentiation therapy with decitabine in treating patients with myelodysplastic syndrome.
Chronic Myelomonocytic Leukemia
de Novo Myelodysplastic Syndromes
Refractory Anemia With Excess Blasts
Refractory Anemia With Ringed Sideroblasts
Refractory Cytopenia With Multilineage Dysplasia
Other: flow cytometry
Other: DNA methylation analysis
Other: cytogenetic analysis
Genetic: microarray analysis
Genetic: gene expression analysis
Other: pharmacological study
Genetic: polymorphism analysis
|Study Design:||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Proof of Concept Study of Non-DNA Damaging DNMT1 Depletion Therapy for Myelodysplastic Syndrome|
- Number of Patients With Response as Defined by IWG (International Working Group) Criteria for Myelodysplasia [ Time Frame: Formal assessment at week 12 for study primary end-point (hematologic improvement). ] [ Designated as safety issue: No ]The criteria for complete remission (CR) and partial remission (PR) involve specific improvements in marrow and peripheral blood measurements obtained on 2 or more successive assessments. The response parameters in peripheral blood must be maintained for at least 8 weeks. Responses designated as CR include less than 5% marrow blasts without evidence of dysplasia and normalization of peripheral blood counts, including a hemoglobin level of 110 g/L (11 g/dL) or more, a neutrophil count of 1.5 × 109/L or more, and a platelet count of 100 × 109/L or more. For PR, patients must demonstrate all CR criteria if abnormal before treatment except that marrow blasts should decrease by 50% or more compared with pretreatment levels, or patients may demonstrate a less-advanced MDS disease classification category than prior to treatment.
- Number of Patients That Experience > Grade 2 Non-hematologic Toxicity by National Cancer Institute (NCI)/Cancer Therapy Evaluation Program (CTEP) v4 Criteria [ Time Frame: up to 12 months of treatment ] [ Designated as safety issue: Yes ]Incidence of treatment-emergent adverse events (AEs) will be presented in tables that include causality, seriousness, severity/grade, and whether the AE resulted in death or discontinuation of treatment, Laboratory data will be summarized in tables that show changes from pre-treatment values and frequencies of abnormal values. Descriptive statistics will also be provided.
- Cytogenetic Response as Per IWG Criteria [ Time Frame: at 12 months ] [ Designated as safety issue: No ]Described as the number of patients with a major cytogenetic response (refers to disappearance of a cytogenetic abnormality) or a minor cytogenetic response (50% or more reduction of abnormal metaphases).
- Proportion of Patients With Pharmacodynamic Evidence of Drug Effect. [ Time Frame: Day 0, 42, 84 ] [ Designated as safety issue: No ]Evidence of pharmacodynamic effect will be correlated with clinical response criteria.
- Proportion of Patients With Bone Marrow Evidence of Cytotoxicity. [ Time Frame: Day 0, 42, 84 ] [ Designated as safety issue: No ]Cytotoxicity will be correlated with clinical response criteria
- Proportion of Patients With Bone Marrow Evidence of Terminal Differentiation Response to Therapy. [ Time Frame: Day 0,42,84 ] [ Designated as safety issue: No ]Bone marrow evidence of terminal differentiation will be correlated with response criteria
- Proportion of Patients With Particular Genetic Abnormalities Detected by Whole Exome Sequencing Correlation With Clinical Response [ Time Frame: Baseline ] [ Designated as safety issue: No ]Proportion of patients with particular genetic abnormalities detected by whole exome sequencing correlation with clinical response
|Study Start Date:||July 2010|
|Study Completion Date:||August 2012|
|Primary Completion Date:||December 2011 (Final data collection date for primary outcome measure)|
Experimental: Arm I: decitabine
INDUCTION PHASE: Patients receive decitabine subcutaneously (SQ) twice weekly for 4 weeks or thrice weekly until achieving bone marrow blasts < 5%. MAINTENANCE PHASE: Patients then receive decitabine SQ twice weekly for up to 52 weeks in the absence of disease progression or unacceptable toxicity.
Other: flow cytometry
Correlative studiesOther: DNA methylation analysis
Correlative studiesOther: cytogenetic analysis
Correlative studiesDrug: decitabine
Other Names:Genetic: microarray analysis
Other Name: gene expression profilingGenetic: gene expression analysis
Correlative studiesOther: pharmacological study
Other Name: pharmacological studiesGenetic: polymorphism analysis
I. Demonstrate that differentiation therapy with DNMT1 depleting but non-DNA damaging doses of decitabine is efficacious and can be administered weekly for > = 12 months. SECONDARY OBJECTIVES: I. Assess safety of the regimen.
II. Retrospectively compare study and standard regimen clinical responses. III. Assess the ability of a pharmacodynamic assay that measures DNMT1 depletion in peripheral blood white blood cells to predict clinical responses to decitabine.
IV. Assess PCR for aberrant methylation signature as an early marker of relapse. V. Identify biologic features of MDS that correlate with response to decitabine, thereby facilitating future patient selection.
VI. In cases of relapse or resistance, assess the role of the enzyme CDA in altering decitabine metabolism and preventing DNMT1 depletion.
INDUCTION PHASE: Patients receive decitabine subcutaneously (SC) twice weekly for 4 weeks or thrice weekly until achieving bone marrow blasts < 5%.
MAINTENANCE PHASE: Patients then receive decitabine SC twice weekly for up to 52 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01165996
|United States, Ohio|
|Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center|
|Cleveland, Ohio, United States, 44195|
|Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center|
|Cleveland, Ohio, United States, 44106|
|Principal Investigator:||Yogen Saunthararajah||Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center|
|Principal Investigator:||Brenda Cooper, MD||Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center|