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 CTN 1101
Hospital Main Campus
Phase Phase 3
Disease Blood & Marrow Transplant (BMT), Hematologic Malignancy
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.
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).
- Age: Subjects ≥ 18 and ≤ 70 years old
- Patients must have available both:
- 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.
- At least two potential umbilical cord blood units identified.
- 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.
- 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.
- Patients must have received either
- 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)
- Multi-agent chemotherapy (e.g. CVP+/-R, CHOP+/-R, ICE+/-R, DHAP+/-R, ESHAP+/-R, �)
- Chemotherapy regimens like those that are given as induction or consolidation of acute leukemia (7+3, HiDAc, mitoxantrone+etoposide, FLAG, FLIG, and others)
- Single drug alkylator agent (cyclophosphamide ≥1.5 g/m2 or equivalent)
- Single agent alemtuzumab or brentuximab vedotin
Antineoplastic agents that are not considered adequate cytotoxic chemotherapy include:
- Single agent steroids
- Single agent monoclonal antibody +/- steroids with the exception of alemtuzumab
- Single agent hypomethylating agent (e.g. azacytidine)
- Single agent antimetabolite +/- steroids (e.g. low dose methotrexate, low dose cytarabine)
- Single agent proteasome inhibitor +/- monoclonal antibody (except for alemtuzumab or brentuximab vedotin) +/- steroids
- Localized radiation therapy
- Autologous hematopoietic stem cell transplantation < 2 years prior to enrollment.
Please consult with the protocol chairs for any drugs or regimens not listed above.
- Acute Leukemias (includes T lymphoblastic lymphoma):
- 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:
- Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), other 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 first complete remission (CR1) (see remission definition in Chapter 3) 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 FLT3-ITD
- Normal karyotype with double mutated CEBPA
- APL in first molecular remission at end of consolidation
- Acute Leukemias in 2nd or subsequent CR (see remission definition in Chapter 3).
- 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 (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.
- Marginal zone B-cell lymphoma or follicular lymphoma that has progressed after at least two prior therapies (excluding single agent Rituxan).
- Performance status: Karnofsky score ≥ 70%.
- Patients with suitably matched related or unrelated donor, as defined per institutional practice.
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.
- Recipients of prior autologous hematopoietic stem cell transplantation are ineligible if disease recurrence occurred < 6 months from their autologous hematopoietic 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 hematopoietic stem cell transplant.
- 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. 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.
- Fertile men or women unwilling to use 2 effective forms of birth control or abstinence.
- 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.