Dose Finding Study of Post-BMT Decitabine Maintenance Treatment in Higher-risk MDS and MDS/AML (PODAC)
Brief Scientific Rationale:
Decitabine has been shown to be effective for treatment of MDS and associated with very limited extramedullary toxicity at the lower doses. Furthermore, the hypomethylating effects of decitabine require an extended period of therapy and are likely to be more beneficial in the setting of a minimal residual disease after transplantation. The drug might exert a cytoreductive effect on the MDS clone, but ex vivo expansion strategy using decitabine and HDAC inhibitor provides a potential to expand the number of hematopoietic stem cells. There are lots of evidence which showed the the drug have immunostimulatory effects and can be used to enhance graft-versus leukemia effects. And also, some investigator suggested that decitabine could induce FOXP3 expression, promoting the conversion of naïve T cells to Tregs which are known to suppress GVHD while maintaining GVL effect in allo-SCT setting. As such, decitabine is an ideal agent to be investigated in the post-transplant setting.
The investigators hypothesized that post-transplant maintenance therapy with decitabine may reduce relapse rate, which may maximize the beneficial effects from reduced TRM of ATG-containing FB4 or FB2 conditioning regimen in higher-risk MDS or AML evolving from MDS patients.
Acute Myeloid Leukemia
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Single Arm, Open Label, Phase I Study for Dose and Schedule Finding of Decitabine in Patients With Higher-risk MDS and MDS/AML Receiving Allogeneic Stem Cell Transplantation|
- Dose and schedule finding of post-BMT Decitabine Treatment [ Time Frame: For up to 2 years after the start of Decitabine ] [ Designated as safety issue: Yes ]To find the safe dose and schedule of administration of the drug decitabine that can be given to patients with higher risk MDS or secondary AML evolving from MDS who received allogeneic stem cell transplantation
- Transplant outcomes of Decitabine maintenance treatment following transplantation [ Time Frame: For up to 2 years after the start of Decitabine ] [ Designated as safety issue: Yes ]
To evaluate the benefit of maintenance therapy with decitabine in prolonging the duration of survival and relapse-free survival after allo-SCT.
To evaluate the effect of maintenance therapy with decitabine on donor chimerism,GVHD, and other transplant toxicities.
To evaluate the effect of maintenance therapy with decitabine on immune recovery including NK cells, Treg and Th17 T cells
|Study Start Date:||January 2011|
|Estimated Study Completion Date:||December 2015|
|Primary Completion Date:||September 2014 (Final data collection date for primary outcome measure)|
Experimental: Decitabine, MDS treatment, IV injection
For the patients who achieve remission after allogeneic BMT and meet the enrollment criteria, decitabine will be given at a dose of 5mg/kg/day ~ 15mg/kg/day iv over 1 hour for 5 consecutive days starting 42-90 days after transplantation. The drug will be repeated every 4 weeks for up to 12 cycles.
1. Dose finding study (cycle 1-cycle4)
Other Name: Dacogen
- BMT from an HLA-matched sibling or a suitably matched (up to 2-allele mismatched) family or unrelated donor will be performed according to the policies of the institute.
A preparative regimen will be started 6 days before the day of stem cell infusion
- Myeloablative-intensity conditioning regimen: FB4+ATG
- Reduced-intensity conditioning regimen; FB2+ATG
- Graft-versus-host disease prophylaxis
- Sibling transplant: Cyclosporine and short-course Methotrexate
- Unrelated transplant: Tacrolimus and short-course Methotrexate
- The dose of calcineurin inhibitors (cyclosporine and tacrolimus) will be gradually tapered from day 60 (for all sibling transplants) or day 90 (for all unrelated transplants) and discontinued within 2 or 3 months after SCT in the absence of graft-versus-host disease.
Decitabine maintenance course
- For the patients who finish the above transplant procedure and meet the enrollment criteria, decitabine will be given at a dose of 5mg/m2/day ~ 15mg/m2/day iv over 1 hour for 5 consecutive days. The drug will be repeated every 4 weeks for up to 12 cycles.
- Dose escalation strategy between cohorts and between cycles in the same cohort patients will be based upon the quantitatively measured hematological toxicity (e.g., ANC or platelet count at nadir). In other words, a mechanism-based pharmacokinetic / pharmacodynamic model developed using sparsely sampled patients' PK data and toxicity response will be used to titrate next cycle doses for the patients and initial doses for new cohort patients. In other words, a mechanism-based pharmacokinetic / pharmacodynamic model developed using sparsely sampled patients' PK data and toxicity response will be used to titrate next cycle doses for the patients and initial doses for new cohort patients.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01277484
|Korea, Republic of|
|Seoul St. Mary's Hospital|
|Seoul, Korea, Republic of, 137-701|
|Principal Investigator:||Yoo-Jin Kim, MD, PhD||Division of Hematology,Department of Internal Medicine,Catholic Blood and Marrow Transplantation Center,Seoul St. Mary's Hospital|