Double Cord Versus Haploidentical (BMT CTN 1101)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01597778
Recruitment Status : Recruiting
First Posted : May 14, 2012
Last Update Posted : March 22, 2018
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
Blood and Marrow Transplant Clinical Trials Network
National Marrow Donor Program
Information provided by (Responsible Party):
Medical College of Wisconsin

Brief Summary:
Hematopoietic cell transplants (HCT)are one treatment option for people with leukemia or lymphoma. Family members,unrelated donors or banked umbilical cordblood units with similar tissue type can be used for HCT. This study will compare the effectiveness of two new types of bone marrow transplants in people with leukemia or lymphoma: one that uses bone marrow donated from family members with only partially matched bone marrow; and, one that uses two partially matched cord blood units.

Condition or disease Intervention/treatment Phase
Acute Lymphocytic Leukemia Acute Myelogenous Leukemia Burkitt's Lymphoma Follicular Lymphoma Hodgkin Lymphoma Mantle Cell Lymphoma Non-Hodgkin Lymphoma Biological: Haploidentical Bone Marrow Transplant Biological: Double Umbilical Cord Blood Transplant Phase 3

Detailed Description:

Reduced intensity conditioning (RIC) blood or marrow transplantation (BMT) has allowed older and less clinically fit patients to receive potentially curative treatment with allogeneic HCT for high risk or advanced hematological malignancies. Patients lacking an HLA-matched sibling may receive a graft from a suitably HLA-matched unrelated donor. However, up to a third of patients will not have an HLA-matched sibling or a suitably matched adult unrelated donor (i.e., no more than a mismatch at a single locus). Even when a suitably matched unrelated donor is identified, data from the National Marrow Donor Program (NMDP) indicate that a median of four months is required to complete searches that result in transplantation; thus, some number of patients succumb to their disease while awaiting identification and evaluation of a suitably matched adult unrelated donor.

Single or dual center studies have shown that partially HLA-mismatched related bone marrow (haplo-BM) and unrelated double umbilical cord blood (dUCB) are valuable sources of donor cells for RIC HCT, thus extending this treatment modality to patients who lack other donors. In order to study the reproducibility, and thus, the wider applicability of these two alternative donor strategies, The Blood and Marrow Transplantation Clinical Trials Network (BMT CTN) conducted two parallel multicenter prospective Phase II clinical trials. These two studies evaluated the safety and efficacy of related haplo-BM (BMT CTN 0603) and dUCB (BMT CTN 0604) transplantation after RIC. Both of these alternative donor approaches produced early results similar to that reported with unrelated donor, and even HLA-matched sibling, HCT. These data demonstrate not only the efficacy of both of these approaches, but also that both can be safely exported from the single center setting. Both haplo-BM and dUCB grafts can be obtained rapidly for greater than 90% of patients lacking an HLA-matched donor. This study will test the hypothesis that progression free survival at two years after RIC haplo-BM transplantation is similar to the progression free survival after RIC dUCB transplantation.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 410 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multi-Center, Phase III, Randomized Trial of Reduced Intensity Conditioning (RIC) and Transplantation of Double Unrelated Umbilical Cord Blood (dUCB) Versus HLA-Haploidentical Related Bone Marrow (Haplo) for Patients With Hematologic Malignancies (BMT CTN #1101)
Actual Study Start Date : June 2012
Estimated Primary Completion Date : June 2018
Estimated Study Completion Date : June 2019

Arm Intervention/treatment
Experimental: Haploidentical Bone Marrow Transplant
Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen.
Biological: Haploidentical Bone Marrow Transplant

The conditioning regimen consists of:

Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1

The GVHD prophylaxis regimen consists of:

Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35

Experimental: Double Umbilical Cord Blood Transplant
Participants will receive a double umbilical cord blood transplant using a reduced intensity conditioning regimen.
Biological: Double Umbilical Cord Blood Transplant

The preparative regimen consists of:

Fludarabine 40 mg/m2 IV Days -6, -5, -4,-3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI) 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the 3 months of enrollment or an autologous transplant within 24 months of enrollment or 300 cGy Day -1 for patients who have not received cytotoxic chemotherapy within the 3 months of enrollment and who have not received an autologous transplant within 24 months of enrollment.

The GVHD prophylaxis regimen consists of:

Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL.

Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day -3 until Day 35

Primary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: Year 2 ]
    The primary endpoint is PFS at 2-years from the date of randomization. PFS is defined as the time interval from date of randomization and time to relapse/progression, to death or to last follow-up.

Secondary Outcome Measures :
  1. Neutrophil Recovery [ Time Frame: Day 56 ]
    Neutrophil recovery is defined as achieving an absolute neutrophil count greater than or equal to 500/mm^3 for three consecutive measurements on three different days. The first of the three days will be designated the day of neutrophil recovery.

  2. Primary Graft Failure [ Time Frame: Day 56 ]
    Primary graft failure is defined as less than 5% donor chimerism on all measurements up to and including Day 56.

  3. Secondary Graft Failure [ Time Frame: Day 100 ]
    Secondary graft failure is defined as initial neutrophil recovery followed by neutropenia with less than 5% donor chimerism in the absence of recurrent disease. If chimerism assays were not performed and absolute neutrophil count less than 500/mm^3 is sustained , then it will be counted as a secondary graft failure.

  4. Platelet Recovery [ Time Frame: Days 100 and 180 ]
    Platelet recovery is defined by two different metrics as the first day of a sustained platelet count greater than 20,000/mm^3 or greater than 50,000/mm^3 with no platelet transfusions in the preceding seven days. The first day of the sustained platelet count will be designated the day of platelet engraftment.

  5. Donor Cell Engraftment [ Time Frame: Day 56 ]
    Donor cell engraftment is defined as donor chimerism greater than or equal to 5% on greater than or equal to Day 56 after transplantation. Chimerism may be evaluated in whole blood or blood cell fractions, including CD3 and CD33 or CD15 fractions).

  6. Acute Graft-versus-Host Disease (aGVHD) [ Time Frame: Year 3 ]
    The cumulative incidences of grade II - IV and III - IV acute aGVHD will be determined. The time to onset of acute grades II-IV aGVHD and grades III-IV aGVHD will be recorded, as well as the maximum grade achieved.

  7. Chronic Graft-versus-Host Disease (cGHVD) [ Time Frame: Year 3 ]
    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 chronic GVHD will be assessed.

  8. Overall Survival [ Time Frame: Year 3 ]
    Overall survival is defined as the time interval between date of randomization and death from any cause or for surviving patients, to last follow-up.

  9. Treatment-related Mortality (TRM) [ Time Frame: Year 1 and 2 ]
    The cumulative incidence of TRM will be estimated, event for this endpoint is death without evidence of disease progression or recurrence.

  10. Infections [ Time Frame: Year 3 ]
    All Grade 2 and 3 infections will be reported.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients 18 to 70 years old
  • Patients must have available both: a)One or more potential related mismatched donors (biologic parent(s) or siblings (full or half) or children). At least low resolution DNA based human leukocyte antigen (HLA) typing at HLA-A, -B, and -DRB1 for potential haploidentical sibling donors is required. b)At least two potential umbilical cord blood units identified. Each unit must have a minimum of 1.5 x 10^7/kg pre-cryopreserved total nucleated cell dose. For non-red blood cell depleted units, the minimum pre-cryopreserved total nucleated cell dose of each unit must be at least 2.0 x 10^7/kg. Units must be HLA matched at a minimum of 4/6 to the recipient at HLA-A, HLA-B (at low resolution using DNA based typing) and HLA-DRB1 (at high resolution using DNA based typing). Confirmatory typing is not required for randomization.
  • Acute Lymphoblastic Leukemia (ALL) in first complete remission (CR1) that is NOT considered favorable-risk as defined by the presence of at least one of the following: Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), other Mixed Lineage Leukemia (MLL) rearrangements; White blood cell counts of greater than 30,000/mcL (B-ALL) or greater than 100,000/mcL (T-ALL)at diagnosis; Recipient age older than 30 years at diagnosis; Time to CR greater than 4 weeks
  • Acute Myelogeneous Leukemia (AML) in CR1 that is NOT considered as favorable-risk. Favorable risk is defined as having one of the following: t(8.21) without CKIT mutation, inv(16) without CKIT mutation or t(16;16), normal karyotype with mutated NPM1 and not FLT-ITD, normal karyotype with double mutated CEBPA, Acute promyelocytic leukemia (APL) in first molecular remission at end of consolidation
  • Acute Leukemias in 2nd or subsequent CR
  • Biphenotypic/Undifferentiated/Prolymphocytic Leukemias in first or subsequent CR, adult T-cell leukemia/lymphoma in first or subsequent CR
  • Burkitt's lymphoma: second or subsequent CR
  • Lymphoma fulfilling the following criteria: Chemotherapy-sensitive (at least stable disease lymphomas that have failed at least 1 prior regimen of multi-agent chemotherapy and are INELIGIBLE for an autologous transplant. Patients with chronic lymphocytic leukemia (CLL) are not eligible regardless of disease status.
  • Performance status: Karnofsky score greater than or equal to 70%.

Additional Patient Inclusion Criteria for Conditioning:

  • Patients with Adequate Physical Function as Measured by: a. Cardiac: Left ventricular ejection fraction at rest must be greater than or equal to 40%, or shortening fraction less than 25%; b. Hepatic: Bilirubin less than or equal to 2.5 mg/dL, except for patients with Gilbert's syndrome or hemolysis. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and Alkaline Phosphatase less than 5 x upper limit of normal; c. Renal: Serum creatinine within normal range, or if serum creatinine outside normal range, then renal function (measured or estimated creatinine clearance or GFR)greater than 40 mL/min/1.73m^; d. Pulmonary: Diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin), forced expiratory volume in one second (FEV1), and forced vital capacity (FVC) greater than 50% predicted;
  • Additional Patient Inclusion Criteria for Patients Assigned to Haploidentical BM Arm: Patients must be HLA typed at high resolution using DNA based typing at the following HLA-loci: HLA-A, -B, -C and DRB1 and have available a related haploidentical BM donor with 2, 3, or 4 HLA-mismatches. A unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch. The donor and recipient must be HLA identical for at least one antigen (using high resolution DNA based typing) at the following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1. Fulfillment of this criterion shall be considered sufficient evidence that the donor and recipient share one HLA haplotype, and typing of additional family members is not required.
  • Additional Patient Inclusion Criteria for Patients Assigned to Double Umbilical Cord Blood Arm:

    1. Patients must have available two UCB units fulfilling the following criteria:

      1. Each unit must have a minimum of 1.5 x 10^7/kg pre-cryopreserved total nucleated cell dose. For non-red blood cell depleted units, the minimum pre-cryopreserved total nucleated cell dose of each unit must be at least 2.0 x10^7/kg.
      2. Units must be HLA matched at a minimum of 4/6 to the recipient at HLA -A, HLA-B (at low resolution using DNA based typing), and HLA -DRB1 (at high resolution using DNA based typing).
      3. Additional graft selection criteria specified in section 2.5
    2. Patients must have received at least one cycle of the cytotoxic chemotherapy regimens (or regimen of similar intensity) listed in Appendix D within 3 months of enrollment (measured from the start date of chemotherapy) OR have had an autologous transplant within 24 months of enrollment OR receive 300 cGy as part of the preparative regimen

Exclusion Criteria:

  • Patients with suitably matched related or unrelated donor, as defined per institutional practice.
  • Recipients of prior autologous hematopoietic stem cell transplantation are ineligible if disease recurrence occurred less than 6 months from their autologous stem cell transplant.
  • Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings).
  • Prior allogeneic HCT.
  • Patients with history of primary idiopathic myelofibrosis or any severe marrow fibrosis.
  • Planned use of prophylactic donor lymphocyte infusion (DLI) therapy.
  • Anti-donor HLA antibodies.

Additional exclusion criteria:

  • Pregnancy or breast-feeding.
  • Evidence of HIV infection or known HIV positive serology.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01597778

Contact: Jamie Garrison
Contact: Adam Mendizabal

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United States, Alabama
University of Alabama at Birmingham Recruiting
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Cincinnati, Ohio, United States, 45236
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Medical College of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53211
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Sponsors and Collaborators
Medical College of Wisconsin
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
Blood and Marrow Transplant Clinical Trials Network
National Marrow Donor Program
Study Director: Mary Horowitz, MD, MS Center for International Blood and Marrow Transplant Research (CIBMTR), Medical College of Wisconsin

Additional Information:
Responsible Party: Medical College of Wisconsin Identifier: NCT01597778     History of Changes
Other Study ID Numbers: BMTCTN1101
2U10HL069294-11 ( U.S. NIH Grant/Contract )
5U24CA076518 ( U.S. NIH Grant/Contract )
First Posted: May 14, 2012    Key Record Dates
Last Update Posted: March 22, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc where indicated).
Supporting Materials: Study Protocol
Informed Consent Form (ICF)
Time Frame: Within 6 months of official study closure at participating sites.
Access Criteria: Available to the public

Keywords provided by Medical College of Wisconsin:
Haplo identical transplant
Cord blood transplant
Reduced intensity conditioning regimen

Additional relevant MeSH terms:
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia, Myeloid
Hodgkin Disease
Lymphoma, Mantle-Cell
Burkitt Lymphoma
Leukemia, Myeloid, Acute
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Epstein-Barr Virus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections
Lymphoma, B-Cell
Mycophenolic Acid
Antibiotics, Antineoplastic
Antineoplastic Agents
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents