A Proof of Concept Study of Non-DNA Damaging DNMT1 Depletion Therapy for Myelodysplastic Syndrome
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.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Number of Patients With Response as Defined by IWG (International Working Group) Criteria for Myelodysplasia
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.
Formal assessment at week 12 for study primary end-point (hematologic improvement).
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
United States: Food and Drug Administration
|Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center||Cleveland, Ohio 44106-5065|
|Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center||Cleveland, Ohio 44195|