Clinical trial NCT01597778: Double Cord Versus Haploidentical (BMT CTN 1101)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Lymphocytic Leukemia
Acute Myelogenous Leukemia
Burkitt's Lymphoma
Follicular Lymphoma
Hodgkin Lymphoma
Mantle Cell Lymphoma
Non-Hodgkin Lymphoma
Keywords: Haplo identical transplant
Cord blood transplant
Reduced intensity conditioning regimen
Lymphoma
Leukemia
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: National Cancer Institute (NCI)
name: Blood and Marrow Transplant Clinical Trials Network
name: National Marrow Donor Program
First posted: 2012-05-14
Enrollment: 368
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants With Progression Free Survival (PFS)
timeFrame: Year 2
Secondary outcomes:
measure: Percentage of Participants With PFS by Treatment Arms in Subgroups
timeFrame: Year 2
measure: Percentage of Participants With Neutrophil Recovery
timeFrame: Day 56
measure: Percentage of Participants With Platelet Recovery
timeFrame: Day 100
measure: Participants With Primary Graft Failure
timeFrame: Day 56
measure: Percentage of Participants With Secondary Graft Failure
timeFrame: Year 2
measure: Percentage of Participants With Acute Graft-versus-Host Disease (aGVHD)
timeFrame: Day 180
measure: Percentage of Participants With Chronic Graft-versus-Host Disease (cGHVD)
timeFrame: Year 2
measure: Percentage of Participants With Overall Survival
timeFrame: Year 2
measure: Percentage of Participants With Treatment-related Mortality (TRM)
timeFrame: Day 100, Day 180, Year 1, and Year 2
measure: Percentage of Participants With Relapse/Progression
timeFrame: Year 1, year 2
measure: Toxicities
timeFrame: Day 28, Day 56, Day 180, 1 year, and 2 years
measure: Participants With Infections
timeFrame: Up to 2 years
measure: Hospital Admission and Length of Stay
timeFrame: Month 6
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Arizona Cancer Center
state: Arizona
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Los Angeles
country: United States
facility: University of California at Los Angeles
state: California
city: Stanford
country: United States
facility: Stanford Hospital and Clinics
state: California
city: Gainesville
country: United States
facility: University of Florida College of Medicine (Shands)
state: Florida
city: Orlando
country: United States
facility: Florida Hospital Cancer Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Atlanta
country: United States
facility: BMT Program at Northside Hospital
state: Georgia
city: Kansas City
country: United States
facility: University of Kansas Hospital
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: DFCI Massachustts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: DFCI Brigham & Women's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Institute/BMT
state: Michigan
city: Minneapolis
country: United States
facility: Univeristy of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Buffalo
country: United States
facility: Roswell Park Cancer Center
state: New York
city: New York
country: United States
facility: Mt. Sinai Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Hospital at Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Jewish Hospital BMT Program
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals of Cleveland, Case Western
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Ohio State / Arthur G. James Cancer Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Medical Center
state: Oklahoma
city: Hershey
country: United States
facility: Penn State College of Medicine - The Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania Cancer Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Univesity of Texas, MD Anderson CRC
state: Texas
city: San Antonio
country: United States
facility: Texas Transplant Institute
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Morgantown
country: United States
facility: West Virginia University
state: West Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Center for International Blood and Marrow Transplant Research (CIBMTR), Medical College of Wisconsin
name: Mary Horowitz, MD, MS
role: STUDY_DIRECTOR
References:
citation: Eapen M, O'Donnell P, Brunstein CG, Wu J, Barowski K, Mendizabal A, Fuchs EJ. Mismatched related and unrelated donors for allogeneic hematopoietic cell transplantation for adults with hematologic malignancies. Biol Blood Marrow Transplant. 2014 Oct;20(10):1485-92. doi: 10.1016/j.bbmt.2014.05.015. Epub 2014 May 23.
citation: Roth JA, Bensink ME, O'Donnell PV, Fuchs EJ, Eapen M, Ramsey SD. Design of a cost-effectiveness analysis alongside a randomized trial of transplantation using umbilical cord blood versus HLA-haploidentical related bone marrow in advanced hematologic cancer. J Comp Eff Res. 2014 Mar;3(2):135-44. doi: 10.2217/cer.13.95.
citation: Brunstein CG, DeFor TE, Fuchs EJ, Karanes C, McGuirk JP, Rezvani AR, Eapen M, O'Donnell PV, Weisdorf DJ; Blood and Marrow Transplant Clinical Trials Network. Engraftment of Double Cord Blood Transplantation after Nonmyeloablative Conditioning with Escalated Total Body Irradiation Dosing to Facilitate Engraftment in Immunocompetent Patients. Transplant Cell Ther. 2021 Oct;27(10):879.e1-879.e3. doi: 10.1016/j.jtct.2021.07.006. Epub 2021 Jul 15.
citation: Fuchs EJ, O'Donnell PV, Eapen M, Logan B, Antin JH, Dawson P, Devine S, Horowitz MM, Horwitz ME, Karanes C, Leifer E, Magenau JM, McGuirk JP, Morris LE, Rezvani AR, Jones RJ, Brunstein CG. Double unrelated umbilical cord blood vs HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial. Blood. 2021 Jan 21;137(3):420-428. doi: 10.1182/blood.2020007535.