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

November 18, 2015 updated by: Yoo-Jin Kim, Seoul St. Mary's Hospital

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

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

  1. 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

      1. Myeloablative-intensity conditioning regimen: FB4+ATG
      2. Reduced-intensity conditioning regimen; FB2+ATG
      3. 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.

  2. 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 Type

Interventional

Enrollment (Actual)

19

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Dose and schedule finding of post-BMT Decitabine Treatment
Time Frame: 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
For up to 2 years after the start of Decitabine

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Transplant outcomes of Decitabine maintenance treatment following transplantation
Time Frame: 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
For up to 2 years after the start of Decitabine

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Seoul St. Mary's Hospital

Collaborators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2011

Primary Completion (Actual)

September 1, 2014

Study Completion (Anticipated)

December 1, 2015

Study Registration Dates

First Submitted

January 14, 2011

First Submitted That Met QC Criteria

January 14, 2011

First Posted (Estimate)

January 17, 2011

Study Record Updates

Last Update Posted (Estimate)

November 20, 2015

Last Update Submitted That Met QC Criteria

November 18, 2015

Last Verified

November 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DEC-KOR-9007

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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