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

NCT01277484 | Unknown Phase 1

• 1 other identifier: DEC-KOR-9007
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

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.

Conditions

Myelodysplastic Syndrome; Acute Myeloid Leukemia

Keywords

decitabine; dose; schedule; safety; allogeneic stem cell transplantation

Outcome Measures

Primary Outcomes (1)

• Dose and schedule finding of post-BMT Decitabine Treatment

  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 Outcomes (1)

• Transplant outcomes of Decitabine maintenance treatment following transplantation

  For up to 2 years after the start of Decitabine

Study Arms (1)

Decitabine, MDS treatment, IV injection

EXPERIMENTAL

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

Interventions

Decitabine DRUG

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

Also known as: Dacogen

Decitabine, MDS treatment, IV injection

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Seoul St. Mary's Hospital: lead
• Janssen, LP: collaborator

Study Sites (1)

Seoul St. Mary's Hospital

Seoul, 137-701, South Korea

Location

Related Publications (9)

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  PMID: 6952920 BACKGROUND

• Heaney ML, Golde DW. Myelodysplasia. N Engl J Med. 1999 May 27;340(21):1649-60. doi: 10.1056/NEJM199905273402107. No abstract available.

  PMID: 10341278 BACKGROUND

• Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997 Mar 15;89(6):2079-88.

  PMID: 9058730 BACKGROUND

• Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, Arcese W, Ljungman P, Ferrant A, Verdonck L, Niederwieser D, van Rhee F, Mittermueller J, de Witte T, Holler E, Ansari H; European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood. 1995 Sep 1;86(5):2041-50.

  PMID: 7655033 BACKGROUND

• Cho BS, Kim YJ, Cho SG, Kim SY, Eom KS, Kim HJ, Lee S, Min CK, Kim DW, Lee JW, Min WS, Kim CC. The beneficial effect of chronic graft-versus-host disease on the clinical outcome of transplantation with fludarabine/busulfan-based reduced-intensity conditioning for patients with de novo myelodysplastic syndrome. Int J Hematol. 2007 Jun;85(5):446-55. doi: 10.1532/IJH97.A30616.

  PMID: 17562624 BACKGROUND

• Kim YJ, Kim DW, Lee S, Min CK, Lee DG, Choi SM, Eom KS, Kim HJ, Lee JW, Min WS, Kim CC. Comparison of 2 preparative regimens for stem cell transplantation from HLA-matched sibling donors in patients with advanced myelodysplastic syndrome. Int J Hematol. 2005 Jul;82(1):66-71. doi: 10.1532/IJH97.A30501.

  PMID: 16105763 BACKGROUND

• Kim SY, Cho SG, Cho BS, Kim MS, Eom KS, Kim YJ, Kim HJ, Lee S, Min CK, Kim DW, Lee JW, Min WS. Azacytidine treatment after discontinuation of immunosuppressants in patients with myelodysplastic syndrome and relapse after allo-SCT at a single center. Bone Marrow Transplant. 2010 Aug;45(8):1375-6. doi: 10.1038/bmt.2009.355. Epub 2009 Dec 21. No abstract available.

  PMID: 20023706 BACKGROUND

• de Lima M, Giralt S, Thall PF, de Padua Silva L, Jones RB, Komanduri K, Braun TM, Nguyen HQ, Champlin R, Garcia-Manero G. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study. Cancer. 2010 Dec 1;116(23):5420-31. doi: 10.1002/cncr.25500. Epub 2010 Jul 29.

  PMID: 20672358 BACKGROUND

• Han S, Kim YJ, Lee J, Jeon S, Hong T, Park GJ, Yoon JH, Yahng SA, Shin SH, Lee SE, Eom KS, Kim HJ, Min CK, Lee S, Yim DS. Model-based adaptive phase I trial design of post-transplant decitabine maintenance in myelodysplastic syndrome. J Hematol Oncol. 2015 Oct 23;8:118. doi: 10.1186/s13045-015-0208-3.

  PMID: 26497198 DERIVED

MeSH Terms

Conditions

Myelodysplastic Syndromes; Leukemia, Myeloid, Acute

Interventions

Decitabine

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Yoo-Jin Kim, MD, PhD

  Division of Hematology,Department of Internal Medicine,Catholic Blood and Marrow Transplantation Center,Seoul St. Mary's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: January 14, 2011
• First Posted: January 17, 2011
• Study Start: January 1, 2011
• Primary Completion: September 1, 2014
• Study Completion: December 1, 2015
• Last Updated: November 20, 2015

Record last verified: 2015-11

Locations

KR (1)