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Single vs Double Umbilical Cord Blood Transplants in Children With High Risk Leukemia and Myelodysplasia (BMT CTN 0501)

13 octobre 2021 mis à jour par: 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.

Aperçu de l'étude

Statut

Complété

Les conditions

Intervention / Traitement

Description détaillée

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.

Type d'étude

Interventionnel

Inscription (Réel)

224

Phase

  • Phase 3

Contacts et emplacements

Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.

Lieux d'étude

  • Australie
    • New South Wales
      • Westmead, New South Wales, Australie, 2145
        • Children's Hospital at Westmead
  • Canada
    • British Columbia
      • Vancouver, British Columbia, Canada, V5Z 4E3
        • BC Cancer Agency
  • États-Unis
    • Alabama
      • Birmingham, Alabama, États-Unis, 35294
        • University of Alabama
    • Arizona
      • Phoenix, Arizona, États-Unis, 85016
        • Phoenix Children's Hospital
    • California
      • Duarte, California, États-Unis, 91010
        • City of Hope National Medical Center
      • Oakland, California, États-Unis, 94609
        • Childrens Hospital at Oakland
      • San Diego, California, États-Unis, 92123
        • UCSD/Rady Childrens Hospital
      • San Francisco, California, États-Unis, 94143
        • University of California, San Francisco (Peds)
    • Colorado
      • Denver, Colorado, États-Unis, 80218
        • The Children's Hospital of Denver
    • District of Columbia
      • Washington, District of Columbia, États-Unis, 20010
        • Children's National Medical Center
    • Florida
      • Gainesville, Florida, États-Unis, 32610
        • University of Florida College of Medicine (Shands)
      • Jacksonville, Florida, États-Unis, 32207
        • Nemours Childrens Clinic
      • Miami, Florida, États-Unis, 33136
        • University of Miami
      • Saint Petersburg, Florida, États-Unis, 33710
        • All Children's Hospital
    • Georgia
      • Atlanta, Georgia, États-Unis, 30322-1062
        • Children's Healthcare of Atlanta
    • Indiana
      • Indianapolis, Indiana, États-Unis, 46202
        • Indiana University Medical Center
    • Kentucky
      • Louisville, Kentucky, États-Unis, 40202
        • University of Louisville/Kosiar Children's Hospital
    • Louisiana
      • New Orleans, Louisiana, États-Unis, 70118
        • Children's of New Orleans
    • Massachusetts
      • Boston, Massachusetts, États-Unis, 02115
        • DFCI/Children's Hospital of Boston
    • Michigan
      • Ann Arbor, Michigan, États-Unis, 48109
        • University of Michigan Medical Center
      • Detroit, Michigan, États-Unis, 48201
        • Karmanos Cancer Institute/Children's Hospital of Michigan
    • Minnesota
      • Minneapolis, Minnesota, États-Unis, 55455
        • University of Minnesota
    • Mississippi
      • Jackson, Mississippi, États-Unis, 39216
        • University of Mississippi
    • Missouri
      • Kansas City, Missouri, États-Unis, 64108
        • Children's Mercy Hospital and Clinics
    • New York
      • Valhalla, New York, États-Unis, 10595
        • New York Medical College
    • North Carolina
      • Durham, North Carolina, États-Unis, 27705
        • Duke University Medical Center
    • Ohio
      • Columbus, Ohio, États-Unis, 43205-2696
        • Nationwide Children's Hospital
    • Oregon
      • Portland, Oregon, États-Unis, 97239
        • Oregon Health Sciences University
    • Pennsylvania
      • Philadelphia, Pennsylvania, États-Unis, 19104
        • Children's Hospital of Philadelphia
    • South Carolina
      • Charleston, South Carolina, États-Unis, 29425
        • Medical University of South Carolina
    • Tennessee
      • Nashville, Tennessee, États-Unis, 37232-7610
        • Vanderbilt University Medical Center
    • Texas
      • Dallas, Texas, États-Unis, 75235
        • Children's Medical Center of Dallas
      • Fort Worth, Texas, États-Unis, 76104
        • Cook Childrens Medical Center
      • San Antonio, Texas, États-Unis, 78229
        • Texas Transplant Institute
    • Utah
      • Salt Lake City, Utah, États-Unis, 84132
        • Utah BMT/University of Utah Medical School
    • Virginia
      • Richmond, Virginia, États-Unis, 23298
        • Virgina Commonwealth University
    • Washington
      • Seattle, Washington, États-Unis, 98109
        • Fred Hutchinson Cancer Research Center
    • Wisconsin
      • Milwaukee, Wisconsin, États-Unis, 53211
        • Medical College of Wisconsin

Critères de participation

Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.

Critère d'éligibilité

Âges éligibles pour étudier

1 an à 21 ans (Enfant, Adulte)

Accepte les volontaires sains

Non

Sexes éligibles pour l'étude

Tout

La description

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:

    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:

  • 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 d'étude

Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.

Comment l'étude est-elle conçue ?

Détails de conception

  • Objectif principal: Traitement
  • Répartition: Randomisé
  • Modèle interventionnel: Affectation à un seul groupe
  • Masquage: Aucun (étiquette ouverte)

Armes et Interventions

Groupe de participants / Bras
Intervention / Traitement
Expérimental: 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
Biologique: Single Umbilical Cord Blood Unit Transplant
Unrelated donor, single umbilical cord blood unit; conditioning regimen: TBI/cyclophosphamide/fludarabine; GVHD prophylaxis: cyclosporine/MMF
Radiation: 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.
Autres noms:
  • TCC
Médicament: 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.
Autres noms:
  • Cytoxan®
Médicament: 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.
Autres noms:
  • Fludara
Médicament: 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.
Autres noms:
  • ASC
Médicament: 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.
Autres noms:
  • MMF, Cellcept®
Expérimental: 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
Radiation: 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.
Autres noms:
  • TCC
Médicament: 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.
Autres noms:
  • Cytoxan®
Médicament: 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.
Autres noms:
  • Fludara
Médicament: 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.
Autres noms:
  • ASC
Médicament: 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.
Autres noms:
  • MMF, Cellcept®
Biologique: Double Umbilical Cord Blood Unit Transplant
Unrelated donor, double umbilical cord blood unit; Conditioning regimen: TBI/cyclophosphamide/fludarabine; GVHD prophylaxis: cyclosporine/MMF

Que mesure l'étude ?

Principaux critères de jugement

Mesure des résultats
Description de la mesure
Délai
Percentage of Participants With Overall Survival
Délai: 1 year post-randomization
Overall survival is defined as survival of death from any cause.
1 year post-randomization

Mesures de résultats secondaires

Mesure des résultats
Description de la mesure
Délai
Percentage of Participants With Disease-free Survival
Délai: 1 year post-randomization
Disease-free survival is defined as survival without relapse of the primary disease.
1 year post-randomization
Percentage of Participants With Neutrophil and Platelet Engraftment
Délai: Days 42 and 100
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.
Days 42 and 100
Time to Neutrophil and Platelet Engraftment
Délai: 2 years post-transplant
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.
2 years post-transplant
Percentage of Participants With Acute Graft-versus-host Disease (GVHD)
Délai: Day 100 post-randomization

Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995:

Skin stage:

0: No rash

  1. Rash <25% of body surface area
  2. Rash on 25-50% of body surface area
  3. Rash on > 50% of body surface area
  4. Generalized erythroderma with bullous formation

Liver stage (based on bilirubin level)*:

0: <2 mg/dL

  1. 2-3 mg/dL
  2. 3.01-6 mg/dL
  3. 6.01-15.0 mg/dL
  4. >15 mg/dL

GI stage*:

0: No diarrhea or diarrhea <500 mL/day

  1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD
  2. Diarrhea 1000-1499 mL/day
  3. Diarrhea >1500 mL/day
  4. Severe abdominal pain with or without ileus * If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1.

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
Percentage of Participants With Chronic GVHD
Délai: 1 year post-randomization
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.
1 year post-randomization
Number of Infections Per Participant
Délai: 2 years post-randomization
2 years post-randomization
Percentage of Participants With Relapse
Délai: 1 year post-randomization
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.
1 year post-randomization
Percentage of Participants With Treatment-related Mortality
Délai: 1 year post-randomization
Treatment related mortality is defined as death without relapse of the primary disease.
1 year post-randomization
Number of Participants With Engraftment Syndrome
Délai: Day 100 post-transplant
Day 100 post-transplant

Collaborateurs et enquêteurs

C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.

Parrainer

Medical College of Wisconsin

Collaborateurs

National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
National Marrow Donor Program
Blood and Marrow Transplant Clinical Trials Network

Publications et liens utiles

La personne responsable de la saisie des informations sur l'étude fournit volontairement ces publications. Il peut s'agir de tout ce qui concerne l'étude.

Publications générales

Liens utiles

Dates d'enregistrement des études

Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.

Dates principales de l'étude

Début de l'étude

1 décembre 2006

Achèvement primaire (Réel)

1 mars 2014

Achèvement de l'étude (Réel)

1 octobre 2014

Dates d'inscription aux études

Première soumission

14 décembre 2006

Première soumission répondant aux critères de contrôle qualité

14 décembre 2006

Première publication (Estimation)

18 décembre 2006

Mises à jour des dossiers d'étude

Dernière mise à jour publiée (Réel)

28 octobre 2021

Dernière mise à jour soumise répondant aux critères de contrôle qualité

13 octobre 2021

Dernière vérification

1 octobre 2021

Plus d'information

Termes liés à cette étude

Mots clés

Termes MeSH pertinents supplémentaires

Autres numéros d'identification d'étude

  • BMTCTN0501
  • 5U24CA076518 (Subvention/contrat des NIH des États-Unis)
  • 2U01HL069294 (Subvention/contrat des NIH des États-Unis)

Plan pour les données individuelles des participants (IPD)

Prévoyez-vous de partager les données individuelles des participants (DPI) ?

OUI

Description du régime IPD

Findings were published in a manuscript.

Délai de partage IPD

Within 6 months of official study closure at participating sites.

Critères d'accès au partage IPD

Available to the public.

Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .

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