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Family-mismatched/Haploidentical Donors Versus Matched Unrelated Donors

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ClinicalTrials.gov Identifier: NCT01751997
Recruitment Status : Active, not recruiting
First Posted : December 18, 2012
Last Update Posted : September 18, 2019
Sponsor:
Information provided by (Responsible Party):
Byung-Sik Cho, Seoul St. Mary's Hospital

Tracking Information
First Submitted Date  ICMJE December 14, 2012
First Posted Date  ICMJE December 18, 2012
Last Update Posted Date September 18, 2019
Actual Study Start Date  ICMJE January 2013
Actual Primary Completion Date May 21, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 14, 2012)
Overall survival [ Time Frame: annually through 3 years ]
Overall survival is defined as the time interval between date of enrollment and death from any cause or for surviving patients, to last follow-up
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01751997 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 28, 2019)
  • Neutrophil recovery [ Time Frame: 56 days ]
    defined as achieving an absolute neutrophil count greater than or equal to 500/mm^3 for three consecutive measurements on three difference days. The first of the 3 days will be designated the day of neutrophil recovery.
  • Primary Graft failure [ Time Frame: 56 days ]
    defined as failure to achieve a neutrophil count greater than 500/mm^3 for 3 consecutive days at any time after transplantation.
  • Secondary Graft failure [ Time Frame: 100 days ]
    defined as the development of an absolute neutrophil count less than 500/mm^3 after achievement of initial engraftment in the absence of recurrent disease.
  • Platelet recovery [ Time Frame: 100 days and 180 days ]
    defined as the first day of a sustained platelet count greater than 20,000/mm^3 without platelet transfusions in preceding 7 days. The first day of the sustained platelet count will be designated the day of platelet engraftment.
  • Donor cell engraftment [ Time Frame: 56 days ]
    Donor cell engraftment is defined as donor chimerism greater than or equal 5% on Day 56 after transplantation. Chimerism may be evaluated in whole blood or blood cell fractions, including cluster of differentiation (CD) 3 and CD33 or CD15 fractions. The actual measurement dates may be within +/- 7 days of the above recommended time points.
  • Acute graft-versus-host disease (aGVHD) [ Time Frame: every 3 months through 3 years ]
    The cumulative incidence of aGVHD (grade II-IV and III-IV) will be determined. The time to onset of aGVHD will be recorded, as well as the maximum grade achieved.
  • Chronic graft-versus-host disease (cGVHD) [ Time Frame: every 3 months through 3 years ]
    The cumulative incidence of cGVHD will be determined. Data will be collected directly from providers and chart review according to the recommendations of the NIH Consensus Conference. The NIH global severity scores of mild, moderate, and severe cGVHD will be assessed.
  • Disease free survival [ Time Frame: annually through year 3 ]
    defined as the time interval from date of enrollment and time to relapse/progression, to death or to last follow-up
  • Non-relapse mortality [ Time Frame: annually through year 3 ]
    The cumulative incidence of non-relapse mortality will be estimated at Days 100, 180, and at 1 and 2 years after transplantation. An event for this endpoint is death without evidence of disease progression or recurrence
  • Infection [ Time Frame: annually through year 3 ]
    All grade 2 and 3 infections will be reported. Grade 1 cytomegalovirus infections through Day 56 will also be reported.
  • WT1 MRD assessment [ Time Frame: before and 1 month after transplantation, then every 3 months through 3 years ]
    WT1 MRD assessment
  • BAALC MRD assessment [ Time Frame: before and 1 month after transplantation, then every 3 months through 3 years ]
    BAALC MRD assessment
  • NGS-based MRD assessment [ Time Frame: before and 1 month after transplantation, then every 3 months through 3 year ]
    NGS-based MRD assessment
  • T cells reconstitution [ Time Frame: before and 2 weeks and 1 month after transplantation, then every 3 months through 1 year ]
    T cell subsets
  • NK cells reconstitution [ Time Frame: before and 2 weeks and 1 month after transplantation, then every 3 months through 1 year ]
    NK cell subsets
  • B cells reconstitution [ Time Frame: before and 2 weeks and 1 month after transplantation, then every 3 months through 1 year ]
    B cells
Original Secondary Outcome Measures  ICMJE
 (submitted: December 14, 2012)
  • Neutrophil recovery [ Time Frame: 56 days ]
    defined as achieving an absolute neutrophil count greater than or equal to 500/mm^3 for three consecutive measurements on three difference days. The first of the 3 days will be designated the day of neutrophil recovery.
  • Primary Graft failure [ Time Frame: 56 days ]
    defined as failure to achieve a neutrophil count greater than 500/mm^3 for 3 consecutive days at any time after transplantation.
  • Secondary Graft failure [ Time Frame: 100 days ]
    defined as the development of an absolute neutrophil count less than 500/mm^3 after achievement of initial engraftment in the absence of recurrent disease.
  • Platelet recovery [ Time Frame: 100 days and 180 days ]
    defined as the first day of a sustained platelet count greater than 20,000/mm^3 without platelet transfusions in preceding 7 days. The first day of the sustained platelet count will be designated the day of platelet engraftment.
  • Donor cell engraftment [ Time Frame: 56 days ]
    Donor cell engraftment is defined as donor chimerism greater than or equal 5% on Day 56 after transplantation. Chimerism may be evaluated in whole blood or blood cell fractions, including cluster of differentiation (CD) 3 and CD33 or CD15 fractions. The actual measurement dates may be within +/- 7 days of the above recommended time points.
  • Acute graft-versus-host disease (aGVHD) [ Time Frame: every 3 months through 3 years ]
    The cumulative incidence of aGVHD (grade II-IV and III-IV) will be determined. The time to onset of aGVHD will be recorded, as well as the maximum grade achieved.
  • Chronic graft-versus-host disease (cGVHD) [ Time Frame: every 3 months through 3 years ]
    The cumulative incidence of cGVHD will be determined. Data will be collected directly from providers and chart review according to the recommendations of the NIH Consensus Conference. The NIH global severity scores of mild, moderate, and severe cGVHD will be assessed.
  • Disease free survival [ Time Frame: annually through year 3 ]
    defined as the time interval from date of enrollment and time to relapse/progression, to death or to last follow-up
  • Non-relapse mortality [ Time Frame: annually through year 3 ]
    The cumulative incidence of non-relapse mortality will be estimated at Days 100, 180, and at 1 and 2 years after transplantation. An event for this endpoint is death without evidence of disease progression or recurrence
  • Infection [ Time Frame: annually through year 3 ]
    All grade 2 and 3 infections will be reported. Grade 1 cytomegalovirus infections through Day 56 will also be reported.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Family-mismatched/Haploidentical Donors Versus Matched Unrelated Donors
Official Title  ICMJE The Comparison of Transplantation From Family-mismatched/Haploidentical Donors With Matched Unrelated Donors in Adult Patients With Acute Myeloid Leukemia
Brief Summary

This study will compare the clinical outcomes of transplants from family-mismatched/haploidentical donors (FMT) with transplants from 8/8-matched unrelated donor (MUT), which is a current gold standard donors when lacking of HLA-matched-siblings

  1. Primary objectives: Overall survival of FMT may be similar to that of MUT
  2. Secondary objectives:

    i. Comparison of disease-free survival, relapse, non-relapse mortality, immune reconstitution cytomegalovirus infection, and acute or chronic graft-versus-host disease between FMT and MUT.

    ii. Investigation of possible biomarkers related with above events after transplantation

Detailed Description For patients lacking an HLA-identical sibling, 8/8-matched unrelated donors are currently the "gold standard" for a donor, since outcomes after HLA-identical sibling have been compared to 8/8-matched unrelated donors. Currently, there are three alternative graft sources, including mismatched unrelated donors, familial mismatch/haploidentical donors, and umbilical cord bloods. Compared with other sources, transplants from familial mismatch/haploidentical donors (FMT) have the benefit of an immediate availability of a donor, particularly for those patients who urgently need transplantation. Initial reports had characterized FMT to a poor engraftment and a high incidence of graft-versus-host disease. However, outcomes of FMT have significantly improved over the past decade in the optimization of conditioning regimen and graft selection to allow a stable engraftment across major HLA barriers, with promising leukemia-free survival in adults with acute leukemia. Despite the encouraging results and potential benefit of FMT, there have been few studies comparing clinical outcomes of FMT with other donor types, particularly in acute myeloid leukemia (AML) as a single disease. Since August 2008, we have been continuously performing FMT using unmanipulated donor cells and a less aggressive conditioning regimen in high-risk AML lacking an HLA-identical sibling, 8/8 or 7/8-matched unrelated donors. We reported the feasibility of FMT using our novel reduced-intensity regimen without ex vivo T-cell depletion, showing early results similar to outcomes of transplant from 8/8-matched unrelated donors (MUT). This study will test the hypothesis that overall survival at 3 years after FMT is similar to overall survival after MUT.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Acute Myeloid Leukemia
Intervention  ICMJE
  • Drug: Transplants from 8/8-matched Unrelated donors
    • Myeloablative conditioning

      1. Total body irradiation; 165 cGy, every 12 hours, 8 doses, days -7 to -4 (total 1320 cGy)
      2. Cyclophosphamide; 60 mg/kg/day, IV for 30 minutes, days -3 to -2 (total 120 mg/kg)
      3. Antithymocyte globulin (ATG); 1.25 mg/kg/day, IV for 6 hours, days -3 to -2, (total 2.5 mg/kg)
    • Reduced-intensity conditioning; older patients (age > 55 years) and/or patients with comorbidities

      1. Fludarabine; 30 mg/m^2/day, IV for 1 hour, days -8 to -4 (total 150 mg/m^2)
      2. Busulfex; 3.2 mg/kg/day, IV for 3 hours, days -3 to -2 (total 6.4 mg/kg)
      3. Total body irradiation; 200 cGy, every 12 hours 2 doses, days -1 (total 400 cGy)
      4. ATG; 1.25 mg/kg/day, IV for 6 hours, days -3 to -2, (total 2.5 mg/kg)
    • GVHD prophylaxis

      1. Tacrolimus; 0.03 mg/kg/day, IV for 24 hours from day -1 (0.12 mg/kg/day, PO, if tolerable)
      2. Methotrexate; 5 mg/m^2/day, IV push, days +1, +3, +6, +11
  • Drug: Transplants from family-mismatched/haploidentical donors
    • Reduced-intensity conditioning

      1. Total body irradiation; 200 cGy, every 12 hours, 4 doses, days -9 to -8 (total 800 cGy)
      2. Fludarabine; 30 mg/m^2/day, IV for 1 hour, days -7 to -3 (total 150 mg/m^2)
      3. Busulfex; 3.2 mg/kg/day, IV for 3 hours, days -6 to -5 (total 6.4 mg/kg)
      4. ATG; 1.25 mg/kg/day, IV for 6 hours, days -4 to -1 (total 5.0 mg/kg)
    • GVHD prophylaxis

      1. Tacrolimus; 0.03 mg/kg/day, IV for 24 hours from day -1 (0.12 mg/kg/day, PO, if tolerable)
      2. Methotrexate; 5 mg/m^2/day, IV push, days +1, +3, +6, +11
Study Arms  ICMJE
  • Active Comparator: Transplants from 8/8-matched unrelated
    Participants will receive transplants from 8/8-matched unrelated donors using myeloablative or reduced-intensity conditioning according to age or comorbidity.
    Intervention: Drug: Transplants from 8/8-matched Unrelated donors
  • Experimental: Transplants from family-mismatched/haploidentical donors
    Participants will receive FMT using a reduced intensity conditioning regimens.
    Intervention: Drug: Transplants from family-mismatched/haploidentical donors
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: December 14, 2012)
116
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2019
Actual Primary Completion Date May 21, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria

  • Patients with AML aged from 18 to 65 years
  • Eastern Cooperative Oncology Group (ECOG) performance < 2
  • High risk group for relapse

    1. Complete remission (CR) 1 with unfavorable prognostic factor; presenting white blood cell > 100,000/microliter or prior myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) or MDS/MPN or cytogenetics & molecular features (intermediate and adverse)
    2. CR2 or CR3 at transplantation
  • No HLA-matched sibling and unrelated donor (HLA-A, -B, -C, and -DRB1)
  • Acceptable organ function defined as serum creatinine < 2 mg/dl, unless considered due to leukemia and serum bilirubin < 3 mg/dl, unless considered due to leukemia
  • Written informed consent form

Exclusion Criteria

  • Active uncontrolled infections
  • Corrected pulmonary diffusion capacity of <40%
  • Cardiac ejection fraction of <35%
  • ECOG performance status :2, 3, 4
  • Active central nervous system involvement of disease
  • Serological evidence of infection with HIV
  • Pregnancy or breastfeeding
  • Patient who are not suitable for the trial in accordance with principal investigator's decision
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 17 Years to 65 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Korea, Republic of
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01751997
Other Study ID Numbers  ICMJE CBMTC-AML-1
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Byung-Sik Cho, Seoul St. Mary's Hospital
Study Sponsor  ICMJE Byung-Sik Cho
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Hee-Je Kim, MD, PhD Seoul St. Mary's Hematology Hospital
PRS Account Seoul St. Mary's Hospital
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP