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

13 października 2021 zaktualizowane przez: 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.

Przegląd badań

Status

Zakończony

Warunki

Interwencja / Leczenie

Szczegółowy opis

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.

Typ studiów

Interwencyjne

Zapisy (Rzeczywisty)

224

Faza

  • Faza 3

Kontakty i lokalizacje

Ta sekcja zawiera dane kontaktowe osób prowadzących badanie oraz informacje o tym, gdzie badanie jest przeprowadzane.

Lokalizacje studiów

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

Kryteria uczestnictwa

Badacze szukają osób, które pasują do określonego opisu, zwanego kryteriami kwalifikacyjnymi. Niektóre przykłady tych kryteriów to ogólny stan zdrowia danej osoby lub wcześniejsze leczenie.

Kryteria kwalifikacji

Wiek uprawniający do nauki

1 rok do 21 lat (Dziecko, Dorosły)

Akceptuje zdrowych ochotników

Nie

Płeć kwalifikująca się do nauki

Wszystko

Opis

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 studiów

Ta sekcja zawiera szczegółowe informacje na temat planu badania, w tym sposób zaprojektowania badania i jego pomiary.

Jak projektuje się badanie?

Szczegóły projektu

  • Główny cel: Leczenie
  • Przydział: Randomizowane
  • Model interwencyjny: Zadanie dla jednej grupy
  • Maskowanie: Brak (otwarta etykieta)

Broń i interwencje

Grupa uczestników / Arm
Interwencja / Leczenie
Eksperymentalny: 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
Biologiczny: Single Umbilical Cord Blood Unit Transplant
Unrelated donor, single umbilical cord blood unit; conditioning regimen: TBI/cyclophosphamide/fludarabine; GVHD prophylaxis: cyclosporine/MMF
Promieniowanie: 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.
Inne nazwy:
  • TBI
Lek: 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.
Inne nazwy:
  • Cytoxan®
Lek: 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.
Inne nazwy:
  • Fludara
Lek: 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.
Inne nazwy:
  • CSA
Lek: 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.
Inne nazwy:
  • MMF, Cellcept®
Eksperymentalny: 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
Promieniowanie: 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.
Inne nazwy:
  • TBI
Lek: 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.
Inne nazwy:
  • Cytoxan®
Lek: 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.
Inne nazwy:
  • Fludara
Lek: 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.
Inne nazwy:
  • CSA
Lek: 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.
Inne nazwy:
  • MMF, Cellcept®
Biologiczny: Double Umbilical Cord Blood Unit Transplant
Unrelated donor, double umbilical cord blood unit; Conditioning regimen: TBI/cyclophosphamide/fludarabine; GVHD prophylaxis: cyclosporine/MMF

Co mierzy badanie?

Podstawowe miary wyniku

Miara wyniku
Opis środka
Ramy czasowe
Percentage of Participants With Overall Survival
Ramy czasowe: 1 year post-randomization
Overall survival is defined as survival of death from any cause.
1 year post-randomization

Miary wyników drugorzędnych

Miara wyniku
Opis środka
Ramy czasowe
Percentage of Participants With Disease-free Survival
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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)
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 2 years post-randomization
2 years post-randomization
Percentage of Participants With Relapse
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: Day 100 post-transplant
Day 100 post-transplant

Współpracownicy i badacze

Tutaj znajdziesz osoby i organizacje zaangażowane w to badanie.

Sponsor

Medical College of Wisconsin

Współpracownicy

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

Publikacje i pomocne linki

Osoba odpowiedzialna za wprowadzenie informacji o badaniu dobrowolnie udostępnia te publikacje. Mogą one dotyczyć wszystkiego, co jest związane z badaniem.

Publikacje ogólne

Przydatne linki

Daty zapisu na studia

Daty te śledzą postęp w przesyłaniu rekordów badań i podsumowań wyników do ClinicalTrials.gov. Zapisy badań i zgłoszone wyniki są przeglądane przez National Library of Medicine (NLM), aby upewnić się, że spełniają określone standardy kontroli jakości, zanim zostaną opublikowane na publicznej stronie internetowej.

Główne daty studiów

Rozpoczęcie studiów

1 grudnia 2006

Zakończenie podstawowe (Rzeczywisty)

1 marca 2014

Ukończenie studiów (Rzeczywisty)

1 października 2014

Daty rejestracji na studia

Pierwszy przesłany

14 grudnia 2006

Pierwszy przesłany, który spełnia kryteria kontroli jakości

14 grudnia 2006

Pierwszy wysłany (Oszacować)

18 grudnia 2006

Aktualizacje rekordów badań

Ostatnia wysłana aktualizacja (Rzeczywisty)

28 października 2021

Ostatnia przesłana aktualizacja, która spełniała kryteria kontroli jakości

13 października 2021

Ostatnia weryfikacja

1 października 2021

Więcej informacji

Terminy związane z tym badaniem

Słowa kluczowe

Dodatkowe istotne warunki MeSH

Inne numery identyfikacyjne badania

  • BMTCTN0501
  • 5U24CA076518 (Grant/umowa NIH USA)
  • 2U01HL069294 (Grant/umowa NIH USA)

Plan dla danych uczestnika indywidualnego (IPD)

Planujesz udostępniać dane poszczególnych uczestników (IPD)?

TAK

Opis planu IPD

Findings were published in a manuscript.

Ramy czasowe udostępniania IPD

Within 6 months of official study closure at participating sites.

Kryteria dostępu do udostępniania IPD

Available to the public.

Te informacje zostały pobrane bezpośrednio ze strony internetowej clinicaltrials.gov bez żadnych zmian. Jeśli chcesz zmienić, usunąć lub zaktualizować dane swojego badania, skontaktuj się z register@clinicaltrials.gov. Gdy tylko zmiana zostanie wprowadzona na stronie clinicaltrials.gov, zostanie ona automatycznie zaktualizowana również na naszej stronie internetowej .

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