Single vs Double Umbilical Cord Blood Transplants in Children With High Risk Leukemia and Myelodysplasia (BMT CTN 0501)
NCT ID: NCT00412360
Last Updated: 2021-10-28
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
224 participants
INTERVENTIONAL
2006-12-31
2014-10-31
Brief Summary
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Detailed Description
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In nearly every large single center or registry analysis of outcomes after UCB transplantation, cell dose is identified as an important factor influencing the incidence and rate of hematopoietic recovery, risk of transplant-related mortality, and probability of survival. Pilot data suggest that infusion of two partially human leukocyte antigen (HLA)-matched UCB units, which always augments the graft cell dose, is safe and may improve neutrophil recovery and survival. To determine whether the infusion of two UCB units enhances survival, a multi-center, open-label, randomized trial is proposed. As adequate single UCB units can be identified for more than 80% of pediatric recipients (in contrast to less than 30% for adults), this study will be open only to pediatric patients. The population will be restricted to patients with high-risk hematologic malignancy, the most common indication of UCB transplantation in children.
DESIGN NARRATIVE:
Participants will include patients 1 to 21 years of age with a diagnosis of hematological malignancy and with two partially HLA-matched UCB units. Units must be HLA-matched at 3 of 6 HLA-A and B (intermediate resolution molecular typing) and DRB1 (high resolution molecular typing) with each other and 4 of 6 with the recipient. Two appropriately HLA-matched units must be available such that one unit delivers a pre-cryopreserved, nucleated cell dose of at least 2.5 x 10\^7 per kilogram and the second unit delivers at least 1.5 x 10\^7 per kilogram.
Patients will be randomized no more than 14 days prior to initiation of conditioning. UCB units will be shipped prior to initiation of conditioning.
The preparative regimen will consist of the following:
* Fludarabine: 25 mg/m2/day IV on Days -10, -9, and -8.
* Total Body Irradiation (TBI): 165 cGy twice daily on Days -7, -6, -5, and -4.
* Cyclophosphamide: 60 mg/kg/day x 2 on Days -3 and -2.
* Day 0 will be the day of the UCB transplant. The Graft-vs-Host-Disease (GVHD) prophylaxis regimen will be mycophenolate mofetil (MMF) 15 mg/kg IV BID on Day -3 to Day + 45 and cyclosporine A (CSA) to maintain level 200-400 ng/mL beginning on Day -3.
Patients will be followed for at least 24 months post-transplant.
Conditions
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Keywords
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Study Design
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RANDOMIZED
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Single Cord Blood Transplant
Unrelated donor, single umbilical cord blood unit transplant; conditioning regimen: Total Body Irradiation/cyclophosphamide/fludarabine; GVHD prophylaxis: Cyclosporine A/Mycophenolate Mofetil
Single Umbilical Cord Blood Unit Transplant
Unrelated donor, single umbilical cord blood unit; conditioning regimen: TBI/cyclophosphamide/fludarabine; GVHD prophylaxis: cyclosporine/MMF
Total Body Irradiation
The TBI will be delivered from either a linear accelerator or cobalt source at a dose rate of between 4 and 26 cGy/minute using energies of between 1 and 25 MV.
Cyclophosphamide
Cyclophosphamide 60 mg/kg/day will be administered as a 2 hour intravenous infusion with a high volume fluid flush on Days -3 and -2.
Fludarabine
Fludarabine 25 mg/m2/day will be administered over 30-60 minutes intravenous infusion on Days -10 through -8. Fludarabine will not be dose adjusted for body weight.
Cyclosporine A
CSA will be administered beginning on Day -3 and doses will be adjusted to maintain a level of 200-400 ng/mL by TDX method (or 100-250 ng/mL by Tandem MS or equivalent level for other CSA testing methods). CSA can be administered per institutional practice.
Mycophenolate Mofetil
MMF will be given at a dose of 1 gram IV q 8 hours if \> 50 kg or 15 mg/kg IV q 8 hours if \< 50 kg beginning the morning of Day -3.
Double Cord Blood Transplant
Unrelated donor, double umbilical cord blood unit transplant; Conditioning regimen: Total Body Irradiation/cyclophosphamide/fludarabine; GVHD prophylaxis: Cyclosporine A/Mycophenolate Mofetil
Double Umbilical Cord Blood Unit Transplant
Unrelated donor, double umbilical cord blood unit; Conditioning regimen: TBI/cyclophosphamide/fludarabine; GVHD prophylaxis: cyclosporine/MMF
Total Body Irradiation
The TBI will be delivered from either a linear accelerator or cobalt source at a dose rate of between 4 and 26 cGy/minute using energies of between 1 and 25 MV.
Cyclophosphamide
Cyclophosphamide 60 mg/kg/day will be administered as a 2 hour intravenous infusion with a high volume fluid flush on Days -3 and -2.
Fludarabine
Fludarabine 25 mg/m2/day will be administered over 30-60 minutes intravenous infusion on Days -10 through -8. Fludarabine will not be dose adjusted for body weight.
Cyclosporine A
CSA will be administered beginning on Day -3 and doses will be adjusted to maintain a level of 200-400 ng/mL by TDX method (or 100-250 ng/mL by Tandem MS or equivalent level for other CSA testing methods). CSA can be administered per institutional practice.
Mycophenolate Mofetil
MMF will be given at a dose of 1 gram IV q 8 hours if \> 50 kg or 15 mg/kg IV q 8 hours if \< 50 kg beginning the morning of Day -3.
Interventions
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Single Umbilical Cord Blood Unit Transplant
Unrelated donor, single umbilical cord blood unit; conditioning regimen: TBI/cyclophosphamide/fludarabine; GVHD prophylaxis: cyclosporine/MMF
Double Umbilical Cord Blood Unit Transplant
Unrelated donor, double umbilical cord blood unit; Conditioning regimen: TBI/cyclophosphamide/fludarabine; GVHD prophylaxis: cyclosporine/MMF
Total Body Irradiation
The TBI will be delivered from either a linear accelerator or cobalt source at a dose rate of between 4 and 26 cGy/minute using energies of between 1 and 25 MV.
Cyclophosphamide
Cyclophosphamide 60 mg/kg/day will be administered as a 2 hour intravenous infusion with a high volume fluid flush on Days -3 and -2.
Fludarabine
Fludarabine 25 mg/m2/day will be administered over 30-60 minutes intravenous infusion on Days -10 through -8. Fludarabine will not be dose adjusted for body weight.
Cyclosporine A
CSA will be administered beginning on Day -3 and doses will be adjusted to maintain a level of 200-400 ng/mL by TDX method (or 100-250 ng/mL by Tandem MS or equivalent level for other CSA testing methods). CSA can be administered per institutional practice.
Mycophenolate Mofetil
MMF will be given at a dose of 1 gram IV q 8 hours if \> 50 kg or 15 mg/kg IV q 8 hours if \< 50 kg beginning the morning of Day -3.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Acute myelogenous leukemia (AML) at the following stages:
1. High risk first complete remission (CR1), defined as the following:
* Having preceding myelodysplasia (MDS)
* High risk cytogenetics (high risk cytogenetics: del (5q) -5, -7, abn (3q), t (6;9) complex karyotype \[at least 5 abnormalities\],)the presence of a high FLT3 ITD-AR (\> 0.4)
* Requiring more than 1 cycle of chemotherapy to obtain complete remission (CR);
* FAB M6
2. Second or greater CR
3. First relapse with less than 25% blasts in bone marrow
4. Morphologic complete remission with incomplete blood count recovery
* Therapy-related AML for which prior malignancy has been in remission for at least 12 months
* Acute lymphocytic leukemia (ALL) at the following stages:
1. High risk first remission, defined as one of the following conditions:
* Philadelphia chromosome-positive adult lymphoblastic leukemia (Ph+ ALL)
* Mixed lineage leukemia (MLL) rearrangement with slow early response (defined as having M2 \[5-25% blasts\] or M3 \[more than 25% blasts on bone marrow examination on Day 14 of induction therapy\])
* Hypodiploidy (less than 44 chromosomes or DNA index less than 0.81)
* End of induction M3 bone marrow
* End of induction M2 with M2-3 at Day 42
* Evidence of minimal residual disease (MRD). If a patient's only high risk criterion is MRD, approval by a protocol chair or protocol officer is required for enrollment. For COG centers, this will only be for MRD greater than 1 percent by flow MRD at the end of extended induction.
2. High risk second remission, defined as one of the following conditions:
* Philadelphia chromosome-positive adult lymphoblastic leukemia (Ph+ ALL)
* Bone marrow relapse less than 36 months from induction
* T-lineage relapse at any time
* Very early isolated central nervous system (CNS) relapse (6 months from diagnosis)
* Slow reinduction (M2-3 at Day 28) after relapse at any time
* Evidence of minimal residual disease (MRD). If a patient's only high risk criterion is MRD, approval by a protocol chair or protocol officer is required for enrollment. For COG centers, this will only be for MRD greater than 1 percent by flow MRD at the end of extended induction.
3. Any third or subsequent CR
* NK cell lymphoblastic leukemia in any CR
* Biphenotypic or undifferentiated leukemia in any CR or if in first relapse must have less than 25% blasts in bone marrow (BM)
* Myelodysplastic syndrome (MDS) at any stage
* Chronic myelogenous leukemia (CML) in chronic or accelerated phase
* All patients with evidence of CNS leukemia must be treated and be in CNS CR to be eligible for study.
* Patients 16 years old or older must have a Karnofsky score of at least 70% and patients younger than 16 years old must have a Lansky score of at least 70%.
* Patients with adequate physical function as measured by:
1. Cardiac: Left ventricular ejection fraction greater than 40% or shortening fraction greater than 26%
2. Hepatic: Bilirubin no more than 2.5 mg/dL; alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) no more than 5 times the upper limit of normal (ULN)
3. Renal: Serum creatinine within normal range for age, or if serum creatinine is outside normal range for age, then renal function (creatinine clearance or GFR) greater than 70 mL/min/1.73 m\^2
4. Pulmonary: Diffusing capacity of the lung for carbon monoxide (DLCO), forced expiratory volume in one second (FEV1), or forced vital capacity (FVC) greater than 50% of predicted value (corrected for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation greater than 92% of room air
Exclusion Criteria
* Evidence of HIV infection or HIV positive serology
* Current uncontrolled bacterial, viral, or fungal infection (currently taking medication and progression of clinical symptoms)
* Autologous transplant less than 12 months prior to enrollment
* Prior autologous transplant for the disease for which the UCB transplant will be performed
* Prior allogeneic hematopoietic stem cell transplant
* Active malignancy other than the one for which the UCB transplant is being performed within 12 months of enrollment
* Inability to receive TBI
* Requirement of supplemental oxygen
* HLA-matched related donor able to donate
1 Year
21 Years
ALL
No
Sponsors
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National Heart, Lung, and Blood Institute (NHLBI)
NIH
Blood and Marrow Transplant Clinical Trials Network
NETWORK
National Cancer Institute (NCI)
NIH
National Marrow Donor Program
OTHER
Medical College of Wisconsin
OTHER
Responsible Party
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Principal Investigators
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Mary Horowitz, MD, MS
Role: STUDY_DIRECTOR
Center for International Blood and Marrow Transplant Research
Locations
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University of Alabama
Birmingham, Alabama, United States
Phoenix Children's Hospital
Phoenix, Arizona, United States
City of Hope National Medical Center
Duarte, California, United States
Childrens Hospital at Oakland
Oakland, California, United States
UCSD/Rady Childrens Hospital
San Diego, California, United States
University of California, San Francisco (Peds)
San Francisco, California, United States
The Children's Hospital of Denver
Denver, Colorado, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
University of Florida College of Medicine (Shands)
Gainesville, Florida, United States
Nemours Childrens Clinic
Jacksonville, Florida, United States
University of Miami
Miami, Florida, United States
All Children's Hospital
St. Petersburg, Florida, United States
Children's Healthcare of Atlanta
Atlanta, Georgia, United States
Indiana University Medical Center
Indianapolis, Indiana, United States
University of Louisville/Kosiar Children's Hospital
Louisville, Kentucky, United States
Children's of New Orleans
New Orleans, Louisiana, United States
DFCI/Children's Hospital of Boston
Boston, Massachusetts, United States
University of Michigan Medical Center
Ann Arbor, Michigan, United States
Karmanos Cancer Institute/Children's Hospital of Michigan
Detroit, Michigan, United States
University of Minnesota
Minneapolis, Minnesota, United States
University of Mississippi
Jackson, Mississippi, United States
Children's Mercy Hospital and Clinics
Kansas City, Missouri, United States
New York Medical College
Valhalla, New York, United States
Duke University Medical Center
Durham, North Carolina, United States
Nationwide Children's Hospital
Columbus, Ohio, United States
Oregon Health Sciences University
Portland, Oregon, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Medical University of South Carolina
Charleston, South Carolina, United States
Vanderbilt University Medical Center
Nashville, Tennessee, United States
Children's Medical Center of Dallas
Dallas, Texas, United States
Cook Childrens Medical Center
Fort Worth, Texas, United States
Texas Transplant Institute
San Antonio, Texas, United States
Utah BMT/University of Utah Medical School
Salt Lake City, Utah, United States
Virgina Commonwealth University
Richmond, Virginia, United States
Fred Hutchinson Cancer Research Center
Seattle, Washington, United States
Medical College of Wisconsin
Milwaukee, Wisconsin, United States
Children's Hospital at Westmead
Westmead, New South Wales, Australia
BC Cancer Agency
Vancouver, British Columbia, Canada
Countries
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References
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Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE, Hackman R, Tsoi MS, Storb R, Thomas ED. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med. 1980 Aug;69(2):204-17. doi: 10.1016/0002-9343(80)90380-0.
Wagner JE Jr, Eapen M, Carter S, Wang Y, Schultz KR, Wall DA, Bunin N, Delaney C, Haut P, Margolis D, Peres E, Verneris MR, Walters M, Horowitz MM, Kurtzberg J; Blood and Marrow Transplant Clinical Trials Network. One-unit versus two-unit cord-blood transplantation for hematologic cancers. N Engl J Med. 2014 Oct 30;371(18):1685-94. doi: 10.1056/NEJMoa1405584.
Provided Documents
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Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form
Other Identifiers
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