Double Cord Versus Haploidentical (BMT CTN 1101)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Multi-Center, Phase III, Randomized Trial of RIC and Transplantation of (dUCB) Versus HLA-Haplo Related Bone Marrow for Patients With Hematologic Malignancies.(BMT CTN #1101)

Conditions
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Acute Lymphocytic Leukemia, Acute Myelogenous Leukemia, Burkitt's Lymphoma, Follicular Lymphoma, Hodgkin Lymphoma, Mantle Cell Lymphoma, Non-Hodgkin Lymphoma

Intervention / Treatment
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* Biological: Haploidentical Bone Marrow Transplant
* Biological: Double Umbilical Cord Blood Transplant


Participation Criteria
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Eligibility Criteria
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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: Patients must have available two UCB units fulfilling the following criteria: 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. 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). Additional graft selection criteria specified in section 2.5 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Haploidentical Bone Marrow Transplant<br>Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen. | Biological: Haploidentical Bone Marrow Transplant<br>* 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<br>|
| Experimental: Double Umbilical Cord Blood Transplant<br>Participants will receive a double umbilical cord blood transplant using a reduced intensity conditioning regimen. | Biological: Double Umbilical Cord Blood Transplant<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Progression Free Survival (PFS) | The primary endpoint is PFS at 2 years post-randomization. Death or disease relapse/progression will be considered as events. The time to event is defined as the time interval from randomization to relapse/progression, to death or to last follow-up, whichever comes first. Relapse is defined by either morphological or cytogenetic evidence of acute leukemia consistent with pre-transplant features, or radiologic evidence of progressive lymphoma. Minimal residual disease will not be considered evidence of relapse, however, minimal residual disease that progresses will be considered as relapse and the date of relapse will be the date of detection of minimal residual disease that prompted an intervention by the treating physician. Finally, institution of any therapy to treat persistent, progressive or relapsed disease, including withdrawal of immunosuppressive therapy or DLI, will be considered evidence of relapse/progression regardless of whether the criteria described above are met. | Year 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With PFS by Treatment Arms in Subgroups | Participants' primary diagnosis was categorized into two large groups: leukemia versus lymphoma. Age was dichotomized into two large groups: age <= 59 versus age > 59. The Kaplan-Meier estimate for PFS at 2 years post-randomization are provided for each subgroup. | Year 2 | 
| Percentage of Participants With Neutrophil Recovery | 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. | Day 56 | 
| Percentage of Participants With Platelet Recovery | 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. | Day 100 | 
| Participants With Primary Graft Failure | Primary graft failure is defined as less than 5% donor chimerism on all measurements up to and including Day 56. | Day 56 | 
| Percentage of Participants With Secondary Graft Failure | Secondary graft failure is defined as initial donor chimerism ≥ 5% declining to < 5% on subsequent measurements with time to secondary graft failure beginning at the first day of primary engraftment. | Year 2 | 
| Percentage of Participants With Acute Graft-versus-Host Disease (aGVHD) | The cumulative incidences of grade II - IV and III - IV acute aGVHD will be determined. | Day 180 | 
| Percentage of Participants With Chronic Graft-versus-Host Disease (cGHVD) | The cumulative incidence of cGVHD from the time of transplant will be determined. Data were collected directly from providers and chart review according to the recommendations of the NIH Consensus Conference. | Year 2 | 
| Percentage of Participants With Overall Survival | 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. The time interval between date of transplant and death from any cause or for surviving patients, to last follow-up are also analyzed. | Year 2 | 
| Percentage of Participants With Treatment-related Mortality (TRM) | The cumulative incidence of TRM will be estimated, event for this endpoint is death without evidence of disease progression or recurrence. | Day 100, Day 180, Year 1, and Year 2 | 
| Percentage of Participants With Relapse/Progression | Incidence of relapse/progression will be estimated using cumulative incidence function, treating death in remission as a competing risk. Relapse is defined by either morphological or cytogenetic evidence of acute leukemia consistent with pre-transplant features, or radiologic evidence of progressive lymphoma. When in doubt, the diagnosis of recurrent or progressive lymphoma should be documented by tissue biopsy. Minimal residual disease will not be considered evidence of relapse, however, minimal residual disease that progresses will be considered as relapse and the date of relapse will be the date of detection of minimal residual disease that prompted an intervention by the treating physician. Finally, institution of any therapy to treat persistent, progressive or relapsed disease, including withdrawal of immunosuppressive therapy or DLI, will be considered evidence of relapse/progression regardless of whether the criteria described above are met. | Year 1, year 2 | 
| Toxicities | They are all Grade ≥ 3 toxicities based on NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4. | Day 28, Day 56, Day 180, 1 year, and 2 years | 
| Participants With Infections | All Grade 2 and 3 infections will be reported. Grade 1 CMV infections through Day 56 will also be reported. | Up to 2 years | 
| Hospital Admission and Length of Stay | Total Time Alive and Not Hospitalized within 6 Months Post Randomization | Month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Haplo identical transplant, Cord blood transplant, Reduced intensity conditioning regimen, Lymphoma, Leukemia