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

This study is currently recruiting participants.
Verified July 2012 by Seoul St. Mary's Hospital
Sponsor:
Collaborator:
Janssen, LP
Information provided by (Responsible Party):
Yoo-Jin Kim, Seoul St. Mary's Hospital
ClinicalTrials.gov Identifier:
NCT01277484
First received: January 14, 2011
Last updated: July 11, 2012
Last verified: July 2012
History of Changes
  Purpose

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 Intervention Phase
Myelodysplastic Syndrome
Acute Myeloid Leukemia
 Drug: Decitabine
 Phase 1

Study Type: Interventional
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

Resource links provided by NLM:

Drug Information available for: Decitabine
U.S. FDA Resources

Further study details as provided by Seoul St. Mary's Hospital:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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



Estimated Enrollment: 20
Study Start Date: January 2011
Estimated Study Completion Date: March 2013
Estimated Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Dacogen

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.
  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Please refer to this study by its ClinicalTrials.gov identifier: NCT01277484

Contacts
Contact: Yoo-Jin Kim, MD, PhD 82-2-2258-6057 yoojink@catholic.ac.kr
Contact: ChungIn Lee 82-2-2258-7926 qodsucnd@gmail.com

Locations
Korea, Republic of
Seoul St. Mary's Hospital Recruiting
Seoul, Korea, Republic of, 137-701
Contact: Yoo-Jin Kim, MD, PhD         yoojink@catholic.ac.kr    
Principal Investigator: Yoo-Jin Kim, MD, PhD            
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
  More Information

Publications:

Responsible Party: Yoo-Jin Kim, Associate Professor, Seoul St. Mary's Hospital
ClinicalTrials.gov Identifier: NCT01277484     History of Changes
Other Study ID Numbers: DEC-KOR-9007
Study First Received: January 14, 2011
Last Updated: July 11, 2012
Health Authority: Korea: Food and Drug Administration

Keywords provided by Seoul St. Mary's Hospital:
decitabine
dose
schedule
safety
allogeneic stem cell transplantation

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Myelodysplastic Syndromes
Preleukemia
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
 Precancerous Conditions
Decitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on May 19, 2013