PODAC: Dose Finding Study of Post-BMT Decitabine Maintenance Treatment in Higher-risk MDS and MDS/AML

Sponsor

Seoul St. Mary's Hospital (Other)

Overall Status

Unknown status

CT.gov ID

NCT01277484

Collaborator

Janssen, LP (Industry)

Enrollment

Location

Arm

Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndrome Acute Myeloid Leukemia	Drug: Decitabine	Phase 1

Detailed Description

Transplant course

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

19 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (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

Study Start Date :

Jan 1, 2011

Actual Primary Completion Date :

Sep 1, 2014

Anticipated Study Completion Date :

Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: Decitabine 1. Dose finding study (cycle 1-cycle4) Indicated dose for 5 consecutive days every 28 days Cohort 1: 5mg/m2 of decitabine Cohort 2 and 3:Dose escalation up to 15mg/m2 using a mechanism-based pharmacokinetic / pharmacodynamic model Other Names: Dacogen

Arm

Intervention/Treatment

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.

Drug: Decitabine

1. Dose finding study (cycle 1-cycle4) Indicated dose for 5 consecutive days every 28 days Cohort 1: 5mg/m2 of decitabine Cohort 2 and 3:Dose escalation up to 15mg/m2 using a mechanism-based pharmacokinetic / pharmacodynamic model

Other Names:

Dacogen

Outcome Measures

Primary Outcome Measures

Dose and schedule finding of post-BMT Decitabine Treatment [For up to 2 years after the start of Decitabine]
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

Secondary Outcome Measures

Transplant outcomes of Decitabine maintenance treatment following transplantation [For up to 2 years after the start of Decitabine]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria for allogeneic transplantation::

Patients with a diagnosis of MDS (IPSS intermediate-2 or higher) before allogeneic transplantation
HLA-compatible unrelated (HLA-A, -B, -C and -DRB1 matched or with 2 allele mismatch)
Performance status < ECOG 2
Acceptable organ function defined as:Serum creatinine < 1.5 times the institutional ULN,Serum bilirubin < 1.5 times the institutional ULN,AST, ALT and alkaline phosphatase < 3 times the institutional ULN.

Inclusion Criteria for decitabine maintenance therapy:

6 to 10 weeks after alloHSCT
patients who are confirmed complete remission(CR) within 2 weeks for treatment start(CR:less than 5% blasts in an aspirate bone marrow sample or no leukemic blasts in the peripheral blood, no cytogenetic aberrations)
Performance status < ECOG 2
Acceptable organ function defined as:Serum creatinine < 1.5 times the institutional ULN,Serum bilirubin < 1.5 times the institutional ULN,AST, ALT and alkaline phosphatase < 3 times the institutional ULN.
Platelet count ≥ 30,000/μL without platelet transfusion for 7 days and ANC ≥ 1,000/μL without colony stimulating factor support at the time of enrollment
Written informed consent form

Exclusion Criteria:

HIV positive
Active uncontrolled infection
Pregnancy or breastfeeding
patients who have residual disease after allo SCT or primary graft failure
Uncontrolled grade 3- 4 acute GVHD
patients who are known or suspected hypersensitivity to decitabine
patient who are not suitable for the trial in accordance with principal investigator's decision

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Seoul St. Mary's Hospital	Seoul		Korea, Republic of	137-701

Sponsors and Collaborators

Seoul St. Mary's Hospital
Janssen, LP

Investigators

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