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

This study has been completed.
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Information provided by (Responsible Party):
Medical College of Wisconsin
ClinicalTrials.gov Identifier:
NCT00412360
First received: December 14, 2006
Last updated: June 27, 2016
Last verified: May 2016

December 14, 2006
June 27, 2016
December 2006
March 2014   (final data collection date for primary outcome measure)
Overall Survival [ Time Frame: Year 1 ] [ Designated as safety issue: No ]
Overall survival (measured 1 year after study entry)
Complete list of historical versions of study NCT00412360 on ClinicalTrials.gov Archive Site
  • Disease-free Survival [ Time Frame: Year 1 ] [ Designated as safety issue: No ]
    Disease-free survival is defined as the minimum time interval of the times to relapse/recurrence, to death or to last follow-up.
  • Neutrophil Engraftment [ Time Frame: Day 180 ] [ Designated as safety issue: No ]
    Neutrophil engraftment is defined as achieving an ANC ≥ 500/mm3 for three consecutive measurements on different days. The first of the three days will be designated the day of neutrophil engraftment.
  • Acute Graft-versus-host Disease (GVHD) [ Time Frame: Day 100 ] [ Designated as safety issue: No ]
    Incidences of grade II - IV and III - IV acute GVHD at Day 100 will be graded according to the BMT CTN Manual of Procedures (MOP).
  • Chronic GVHD [ Time Frame: Year 1 ] [ Designated as safety issue: No ]
    Incidences of chronic GVHD will be scored according to the BMT CTN MOP.
  • Treatment-related Mortality [ Time Frame: Year 1 ] [ Designated as safety issue: Yes ]
  • Infections [ Time Frame: Year 2 ] [ Designated as safety issue: No ]
  • Relapse [ Time Frame: Year 1 ] [ Designated as safety issue: No ]
    Testing for recurrent malignancy in the blood, marrow or other sites will be used to assess relapse after transplantation. For the purpose of this study, relapse is defined by either morphological or cytogenetic evidence of AML, ALL, CML, or MDS consistent with pre-transplant features.
  • Platelet Engraftment [ Time Frame: Day 180 ] [ Designated as safety issue: No ]
    Platelet engraftment to 50,000/mL
  • Engraftment Syndrome [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
  • Chimerism [ Time Frame: 28, 42, 60, 180, 365 days ] [ Designated as safety issue: No ]
  • Immune Reconstitution [ Time Frame: 100 days, 6 months, 1 and 2 years ] [ Designated as safety issue: No ]
  • Disease-free Survival
  • Incidences of neutrophil and platelet engraftment
  • Chimerism
  • Acute Graft-versus-host Disease (GVHD)
  • Chronic GVHD
  • Transplant-related mortality
  • Infections
  • Immune Reconstitution
  • Relapse (measured 1 year after study entry)
Not Provided
Not Provided
 
Single vs Double Umbilical Cord Blood Transplants in Children With High Risk Leukemia and Myelodysplasia (BMT CTN 0501)
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.

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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Acute Myelogenous Leukemia
  • Acute Lymphocytic Leukemia
  • Chronic Myelogenous Leukemia
  • Myelodysplastic Syndrome
  • Natural Killer Cell Lymphoblastic Leukemia/Lymphoma
  • Biological: Single Umbilical Cord Blood Unit Transplant
    Unrelated donor, single umbilical cord blood unit; conditioning regimen: TBI/cyclophosphamide/fludarabine; GVHD prophylaxis: cyclosporine/MMF
  • Biological: Double Umbilical Cord Blood Unit Transplant
    Unrelated donor, double 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.
    Other Name: TBI
  • Drug: 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.
    Other Name: Cytoxan®
  • Drug: 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.
    Other Name: Fludara
  • Drug: 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.
    Other Name: CSA
  • Drug: 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 Name: MMF, Cellcept®
  • 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
    Interventions:
    • Biological: Single Umbilical Cord Blood Unit Transplant
    • Radiation: Total Body Irradiation
    • Drug: Cyclophosphamide
    • Drug: Fludarabine
    • Drug: Cyclosporine A
    • Drug: Mycophenolate Mofetil
  • 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
    Interventions:
    • Biological: Double Umbilical Cord Blood Unit Transplant
    • Radiation: Total Body Irradiation
    • Drug: Cyclophosphamide
    • Drug: Fludarabine
    • Drug: Cyclosporine A
    • Drug: Mycophenolate Mofetil
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
224
October 2014
March 2014   (final data collection date for primary outcome measure)

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
Both
1 Year to 21 Years   (Child, Adult)
No
Contact information is only displayed when the study is recruiting subjects
United States,   Australia,   Canada
 
NCT00412360
BMTCTN0501, 2U01HL069294, 5U24CA076518
Yes
Yes
Findings were published in a manuscript.
Medical College of Wisconsin
Medical College of Wisconsin
  • National Heart, Lung, and Blood Institute (NHLBI)
  • Blood and Marrow Transplant Clinical Trials Network
  • National Cancer Institute (NCI)
  • National Marrow Donor Program
Study Director: Mary Horowitz, MD, MS Center for International Blood and Marrow Transplant Research
Medical College of Wisconsin
May 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP