Details

Details

Title A Multi-Center, Phase III, Randomized Trial of Reduced Intensity (RIC) Conditioning and Transplantation of Double Unrelated Umbilical Cord Blood (dUCB) versus HLA-Haploidentical Related Bone Marrow (Haplo) for Patients with Hematologic Malignancies

IRB CTN1101

CC 12-1407

Hospital Main Campus

Stage N/A

Phase Phase 3

Disease Blood & Marrow Transplant (BMT), Hematologic Malignancy

Description

Description

Primary Objective:

The primary objective is to compare progression-free-survival at 2 years post-randomization between patients who receive unrelated double cord blood unit transplantation versus HLA-haploidentical related bone marrow transplantation.

Secondary Objectives:

Patients enrolled in this study will also be followed for the following endpoints: neutrophil recovery, graft failure, platelet recovery, donor cell engraftment, acute graft-versus-host-disease (GVHD) and chronic GVHD, overall survival, treatment-related mortality, infections, hospital admission and length of stay, health related quality of life, relapse/progression and cost effectiveness (see companion 1101 study document for ancillary cost effectiveness protocol).

Inclusion Criteria

Inclusion Criteria

  1. Age: Subjects ≥ 18 and ≤ 70 years old
  2. Patients must have available both:
    1. One or more potential related mismatched donors (biologic parent (s) or siblings (full or half) or children). At least low resolution DNA based typing at HLA-A, -B and -DRB1 for potential haplo-identical sibling donors is required pre-randomization. HLA typing of biological parents and children as potential haplo-identical donors is not required pre-randomization.
    2. At least two potential umbilical cord blood units identified.
      1. Each unit must have a minimum of 1.5 x 107/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 107/kg.
      2. Units must be HLA matched at a minimum of 4/6 to the recipient at HLAA, 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.
  3. Patients must have received either
    1. At least one cycle of at least one of the following cytotoxic chemotherapy regimens (or regimen of similar intensity) within 3 months of enrollment (measured from the start date of chemotherapy)
      1. Multi-agent chemotherapy (e.g. CVP+/-R, CHOP+/-R, ICE+/-R, DHAP+/-R, ESHAP+/-R, �)
      2. Chemotherapy regimens like those that are given as induction or consolidation of acute leukemia (7+3, HiDAc, mitoxantrone+etoposide, FLAG, FLIG, and others)
      3. Single drug alkylator agent (cyclophosphamide ≥1.5 g/m2 or equivalent)
      4. Bendamustine
      5. Single agent alemtuzumab or brentuximab vedotin

      Antineoplastic agents that are not considered adequate cytotoxic chemotherapy include:

      1. Single agent steroids
      2. Single agent monoclonal antibody +/- steroids with the exception of alemtuzumab
      3. Single agent hypomethylating agent (e.g. azacytidine)
      4. Single agent antimetabolite +/- steroids (e.g. low dose methotrexate, low dose cytarabine)
      5. Single agent proteasome inhibitor +/- monoclonal antibody (except for alemtuzumab or brentuximab vedotin) +/- steroids
      6. Hydroxyurea
      7. Localized radiation therapy
      8. Interferon
    2. Autologous hematopoietic stem cell transplantation < 2 years prior to enrollment.

    Please consult with the protocol chairs for any drugs or regimens not listed above.

  4. Acute Leukemias (includes T lymphoblastic lymphoma):
    1. Acute Lymphoblastic Leukemia (ALL) in first complete remission (CR1) (see remission definition in Chapter 3) that is NOT considered favorable-risk as defined by the presence of at least one of the following:
      1. Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), other MLL rearrangements,
      2. White blood cell counts of greater than 30,000/mcL (B-ALL) or greater than 100,000/mcL (T-ALL) at diagnosis,
      3. Recipient age older than 30 years at diagnosis,
      4. Time to CR greater than 4 weeks
    2. Acute Myelogeneous Leukemia (AML) in first complete remission (CR1) (see remission definition in Chapter 3) that is NOT considered as favorable-risk.

      3. Favorable risk is defined as having one of the following:

      1. t(8,21) without CKIT mutation
      2. inv(16) without CKIT mutation or t(16;16)
      3. Normal karyotype with mutated NPM1 and not FLT3-ITD
      4. Normal karyotype with double mutated CEBPA
      5. APL in first molecular remission at end of consolidation
    3. Acute Leukemias in 2nd or subsequent CR (see remission definition in Chapter 3).
    4. Biphenotypic/Undifferentiated/Prolymphocytic Leukemias in first or subsequent CR, adult T-cell leukemia/lymphoma in first or subsequent CR
  5. Burkitt's lymphoma: second or subsequent CR.
  6. Lymphoma fulfilling the following criteria:
    1. Chemotherapy-sensitive (complete or partial response; see response criteria in Chapter 3) lymphomas that have failed at least 1 prior regimen of multi-agent chemotherapy and are INELIGIBLE for an autologous transplant.
    2. Marginal zone B-cell lymphoma or follicular lymphoma that has progressed after at least two prior therapies (excluding single agent Rituxan).
  7. Performance status: Karnofsky score ≥ 70%.
Exclusion Criteria

Exclusion Criteria

  1. Patients with suitably matched related or unrelated donor, as defined per institutional practice.

    2. An unrelated donor search is not required for a patient to be eligible for this protocol, or a search and donor mobilization may be abandoned, if the clinical situation dictates an urgent transplant. Clinical urgency is defined as 6-8 weeks from referral to transplant or a low-likelihood of finding a matched, unrelated donor.

  2. Recipients of prior autologous hematopoietic stem cell transplantation are ineligible if disease recurrence occurred < 6 months from their autologous hematopoietic stem cell transplant.
  3. Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings).
  4. Prior allogeneic hematopoietic stem cell transplant.
  5. Patients with history of primary idiopathic myelofibrosis or any severe marrow fibrosis.
  6. Planned use of prophylactic donor lymphocyte infusion (DLI) therapy.
  7. Anti-donor HLA antibodies. Positive anti-donor HLA antibody is defined as a positive crossmatch test of any titer (by complement-dependent cytotoxicity or flow cytometric testing) or the presence of anti-donor HLA antibody to the high expression loci HLA-A, -B, -C, or -DRB1 with mean fluorescence intensity >1000 by solid phase immunoassay.
  8. Fertile men or women unwilling to use 2 effective forms of birth control or abstinence.
  9. German centers only: Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer, or participation in any other interventional clinical study.