Single vs Double Umbilical Cord Blood Transplants in Children With High Risk Leukemia and Myelodysplasia (BMT CTN 0501)
13 de octubre de 2021 actualizado por: Medical College of Wisconsin
Multi-center, Open Label, Randomized Trial Comparing Single Versus Double Umbilical Cord Blood (UCB) Transplantation in Pediatric Patients With High Risk Leukemia and Myelodysplasia (BMT CTN #0501)
This study is a Phase III, randomized, open-label, multi-center, prospective study of single umbilical cord blood (UCB) transplantation versus double UCB transplantation in pediatric patients with hematologic malignancies.
Descripción general del estudio
Estado
Terminado
Condiciones
Descripción detallada
BACKGROUND:
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.
Tipo de estudio
Intervencionista
Inscripción (Actual)
224
Fase
- Fase 3
Contactos y Ubicaciones
Esta sección proporciona los datos de contacto de quienes realizan el estudio e información sobre dónde se lleva a cabo este estudio.
Ubicaciones de estudio
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New South Wales
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Westmead, New South Wales, Australia, 2145
- Children's Hospital at Westmead
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British Columbia
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Vancouver, British Columbia, Canadá, V5Z 4E3
- BC Cancer Agency
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Alabama
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Birmingham, Alabama, Estados Unidos, 35294
- University of Alabama
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Arizona
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Phoenix, Arizona, Estados Unidos, 85016
- Phoenix Children's Hospital
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California
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Duarte, California, Estados Unidos, 91010
- City of Hope National Medical Center
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Oakland, California, Estados Unidos, 94609
- Childrens Hospital at Oakland
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San Diego, California, Estados Unidos, 92123
- UCSD/Rady Childrens Hospital
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San Francisco, California, Estados Unidos, 94143
- University of California, San Francisco (Peds)
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Colorado
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Denver, Colorado, Estados Unidos, 80218
- The Children's Hospital of Denver
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District of Columbia
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Washington, District of Columbia, Estados Unidos, 20010
- Children's National Medical Center
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Florida
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Gainesville, Florida, Estados Unidos, 32610
- University of Florida College of Medicine (Shands)
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Jacksonville, Florida, Estados Unidos, 32207
- Nemours Childrens Clinic
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Miami, Florida, Estados Unidos, 33136
- University of Miami
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Saint Petersburg, Florida, Estados Unidos, 33710
- All Children's Hospital
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Georgia
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Atlanta, Georgia, Estados Unidos, 30322-1062
- Children's Healthcare of Atlanta
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Indiana
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Indianapolis, Indiana, Estados Unidos, 46202
- Indiana University Medical Center
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Kentucky
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Louisville, Kentucky, Estados Unidos, 40202
- University of Louisville/Kosiar Children's Hospital
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Louisiana
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New Orleans, Louisiana, Estados Unidos, 70118
- Children's of New Orleans
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Massachusetts
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Boston, Massachusetts, Estados Unidos, 02115
- DFCI/Children's Hospital of Boston
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Michigan
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Ann Arbor, Michigan, Estados Unidos, 48109
- University of Michigan Medical Center
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Detroit, Michigan, Estados Unidos, 48201
- Karmanos Cancer Institute/Children's Hospital of Michigan
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Minnesota
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Minneapolis, Minnesota, Estados Unidos, 55455
- University of Minnesota
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Mississippi
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Jackson, Mississippi, Estados Unidos, 39216
- University of Mississippi
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Missouri
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Kansas City, Missouri, Estados Unidos, 64108
- Children's Mercy Hospital and Clinics
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New York
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Valhalla, New York, Estados Unidos, 10595
- New York Medical College
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North Carolina
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Durham, North Carolina, Estados Unidos, 27705
- Duke University Medical Center
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Ohio
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Columbus, Ohio, Estados Unidos, 43205-2696
- Nationwide Children's Hospital
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Oregon
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Portland, Oregon, Estados Unidos, 97239
- Oregon Health Sciences University
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Pennsylvania
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Philadelphia, Pennsylvania, Estados Unidos, 19104
- Children's Hospital of Philadelphia
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South Carolina
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Charleston, South Carolina, Estados Unidos, 29425
- Medical University of South Carolina
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Tennessee
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Nashville, Tennessee, Estados Unidos, 37232-7610
- Vanderbilt University Medical Center
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Texas
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Dallas, Texas, Estados Unidos, 75235
- Children's Medical Center of Dallas
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Fort Worth, Texas, Estados Unidos, 76104
- Cook Childrens Medical Center
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San Antonio, Texas, Estados Unidos, 78229
- Texas Transplant Institute
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Utah
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Salt Lake City, Utah, Estados Unidos, 84132
- Utah BMT/University of Utah Medical School
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Virginia
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Richmond, Virginia, Estados Unidos, 23298
- Virgina Commonwealth University
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Washington
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Seattle, Washington, Estados Unidos, 98109
- Fred Hutchinson Cancer Research Center
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Wisconsin
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Milwaukee, Wisconsin, Estados Unidos, 53211
- Medical College of Wisconsin
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Criterios de participación
Los investigadores buscan personas que se ajusten a una determinada descripción, denominada criterio de elegibilidad. Algunos ejemplos de estos criterios son el estado de salud general de una persona o tratamientos previos.
Criterio de elegibilidad
Edades elegibles para estudiar
1 año a 21 años (Niño, Adulto)
Acepta Voluntarios Saludables
No
Géneros elegibles para el estudio
Todos
Descripción
Inclusion Criteria:
- Two partially HLA-matched UCB units. Units must be HLA-matched minimally at 4 of 6 HLA-A and B (at intermediate resolution by molecular typing) and DRB1 (at high resolution by molecular typing) loci with the patient, and the units must be HLA-matched at 3 of 6 HLA- A, B, DRB1 loci with each other (using same resolution of molecular typing as indicated above). 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 at least 1.5 x 10^7 per kilogram.
Acute myelogenous leukemia (AML) at the following stages:
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
- Second or greater CR
- First relapse with less than 25% blasts in bone marrow
- 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:
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.
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.
- 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:
- Cardiac: Left ventricular ejection fraction greater than 40% or shortening fraction greater than 26%
- 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)
- 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
- 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:
- Pregnant (β-positive human chorionic gonadotropin [HCG]) or breastfeeding
- 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
Plan de estudios
Esta sección proporciona detalles del plan de estudio, incluido cómo está diseñado el estudio y qué mide el estudio.
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación de un solo grupo
- Enmascaramiento: Ninguno (etiqueta abierta)
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
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Experimental: 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
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Unrelated donor, single umbilical cord blood unit; conditioning regimen: TBI/cyclophosphamide/fludarabine; GVHD prophylaxis: cyclosporine/MMF
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.
Otros nombres:
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.
Otros nombres:
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.
Otros nombres:
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.
Otros nombres:
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.
Otros nombres:
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Experimental: 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
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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.
Otros nombres:
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.
Otros nombres:
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.
Otros nombres:
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.
Otros nombres:
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.
Otros nombres:
Unrelated donor, double umbilical cord blood unit; Conditioning regimen: TBI/cyclophosphamide/fludarabine; GVHD prophylaxis: cyclosporine/MMF
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Percentage of Participants With Overall Survival
Periodo de tiempo: 1 year post-randomization
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Overall survival is defined as survival of death from any cause.
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1 year post-randomization
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Percentage of Participants With Disease-free Survival
Periodo de tiempo: 1 year post-randomization
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Disease-free survival is defined as survival without relapse of the primary disease.
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1 year post-randomization
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Percentage of Participants With Neutrophil and Platelet Engraftment
Periodo de tiempo: Days 42 and 100
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Neutrophil engraftment is defined as achieving an absolute neutrophil count greater than 500x10^6/liter for three consecutive measurements on different days.
The first of the three days will be designated the day of neutrophil engraftment.
Platelet engraftment is defined as achieving platelet counts greater than 50,000/microliter for consecutive measurements over 7 days without requiring platelet transfusions.
The first of the 7 days will be designated the day of platelet engraftment.
Subjects must not have had platelet transfusions during the preceding 7 days.
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Days 42 and 100
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Time to Neutrophil and Platelet Engraftment
Periodo de tiempo: 2 years post-transplant
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Platelet engraftment is defined as achieving platelet counts greater than 50,000/microliter for consecutive measurements over 7 days without requiring platelet transfusions.
The first of the 7 days will be designated the day of platelet engraftment.
Subjects must not have had platelet transfusions during the preceding 7 days.
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2 years post-transplant
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Percentage of Participants With Acute Graft-versus-host Disease (GVHD)
Periodo de tiempo: Day 100 post-randomization
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Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995: Skin stage: 0: No rash
Liver stage (based on bilirubin level)*: 0: <2 mg/dL
GI stage*: 0: No diarrhea or diarrhea <500 mL/day
GVHD grade: 0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4 |
Day 100 post-randomization
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Percentage of Participants With Chronic GVHD
Periodo de tiempo: 1 year post-randomization
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Incidences of chronic GVHD will be graded per Shulman et al. 1980.
This reference categorizes chronic GVHD as either limited or extensive.
For this outcome, participants developing either type are considered to have a chronic GVHD event.
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1 year post-randomization
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Number of Infections Per Participant
Periodo de tiempo: 2 years post-randomization
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2 years post-randomization
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Percentage of Participants With Relapse
Periodo de tiempo: 1 year post-randomization
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Relapse is defined by either morphological or cytogenetic evidence of AML, ALL, CML, or MDS consistent with pre-transplant features.
Testing for recurrent malignancy in the blood, marrow or other sites will be used to assess relapse after transplantation.
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1 year post-randomization
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Percentage of Participants With Treatment-related Mortality
Periodo de tiempo: 1 year post-randomization
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Treatment related mortality is defined as death without relapse of the primary disease.
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1 year post-randomization
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Number of Participants With Engraftment Syndrome
Periodo de tiempo: Day 100 post-transplant
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Day 100 post-transplant
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Colaboradores e Investigadores
Aquí es donde encontrará personas y organizaciones involucradas en este estudio.
Publicaciones y enlaces útiles
La persona responsable de ingresar información sobre el estudio proporciona voluntariamente estas publicaciones. Estos pueden ser sobre cualquier cosa relacionada con el estudio.
Publicaciones Generales
- 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.
Fechas de registro del estudio
Estas fechas rastrean el progreso del registro del estudio y los envíos de resultados resumidos a ClinicalTrials.gov. Los registros del estudio y los resultados informados son revisados por la Biblioteca Nacional de Medicina (NLM) para asegurarse de que cumplan con los estándares de control de calidad específicos antes de publicarlos en el sitio web público.
Fechas importantes del estudio
Inicio del estudio
1 de diciembre de 2006
Finalización primaria (Actual)
1 de marzo de 2014
Finalización del estudio (Actual)
1 de octubre de 2014
Fechas de registro del estudio
Enviado por primera vez
14 de diciembre de 2006
Primero enviado que cumplió con los criterios de control de calidad
14 de diciembre de 2006
Publicado por primera vez (Estimar)
18 de diciembre de 2006
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
28 de octubre de 2021
Última actualización enviada que cumplió con los criterios de control de calidad
13 de octubre de 2021
Última verificación
1 de octubre de 2021
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Enfermedades del sistema inmunológico
- Neoplasias por tipo histológico
- Neoplasias
- Trastornos linfoproliferativos
- Enfermedades linfáticas
- Trastornos inmunoproliferativos
- Enfermedades de la médula ósea
- Enfermedades hematológicas
- Trastornos mieloproliferativos
- Leucemia Linfoide
- Síndromes mielodisplásicos
- Leucemia
- Leucemia Mieloide
- Leucemia Mieloide Aguda
- Leucemia-linfoma linfoblástico de células precursoras
- Leucemia, Mielógena, Crónica, BCR-ABL Positivo
- Efectos fisiológicos de las drogas
- Mecanismos moleculares de acción farmacológica
- Agentes antiinfecciosos
- Inhibidores de enzimas
- Agentes antirreumáticos
- Agentes antineoplásicos
- Agentes inmunosupresores
- Factores inmunológicos
- Agentes antineoplásicos, alquilantes
- Agentes alquilantes
- Agonistas mieloablativos
- Agentes dermatológicos
- Agentes antibacterianos
- Antibióticos, Antineoplásicos
- Agentes antifúngicos
- Agentes antituberculosos
- Antibióticos, Antituberculosos
- Inhibidores de calcineurina
- Ciclofosfamida
- Fludarabina
- Ácido micofenólico
- Ciclosporina
- Ciclosporinas
Otros números de identificación del estudio
- BMTCTN0501
- 5U24CA076518 (Subvención/contrato del NIH de EE. UU.)
- 2U01HL069294 (Subvención/contrato del NIH de EE. UU.)
Plan de datos de participantes individuales (IPD)
¿Planea compartir datos de participantes individuales (IPD)?
SÍ
Descripción del plan IPD
Findings were published in a manuscript.
Marco de tiempo para compartir IPD
Within 6 months of official study closure at participating sites.
Criterios de acceso compartido de IPD
Available to the public.
Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .