Clinical trial NCT00412360: Single vs Double Umbilical Cord Blood Transplants in Children With High Risk Leukemia and Myelodysplasia (BMT CTN 0501)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Myelogenous Leukemia
Acute Lymphocytic Leukemia
Chronic Myelogenous Leukemia
Myelodysplastic Syndrome
Natural Killer Cell Lymphoblastic Leukemia/Lymphoma
Keywords: Double cord blood
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Blood and Marrow Transplant Clinical Trials Network
name: National Cancer Institute (NCI)
name: National Marrow Donor Program
First posted: 2006-12-18
Enrollment: 224
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants With Overall Survival
timeFrame: 1 year post-randomization
Secondary outcomes:
measure: Percentage of Participants With Disease-free Survival
timeFrame: 1 year post-randomization
measure: Percentage of Participants With Neutrophil and Platelet Engraftment
timeFrame: Days 42 and 100
measure: Time to Neutrophil and Platelet Engraftment
timeFrame: 2 years post-transplant
measure: Percentage of Participants With Acute Graft-versus-host Disease (GVHD)
timeFrame: Day 100 post-randomization
measure: Percentage of Participants With Chronic GVHD
timeFrame: 1 year post-randomization
measure: Number of Infections Per Participant
timeFrame: 2 years post-randomization
measure: Percentage of Participants With Relapse
timeFrame: 1 year post-randomization
measure: Percentage of Participants With Treatment-related Mortality
timeFrame: 1 year post-randomization
measure: Number of Participants With Engraftment Syndrome
timeFrame: Day 100 post-transplant
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Oakland
country: United States
facility: Childrens Hospital at Oakland
state: California
city: San Diego
country: United States
facility: UCSD/Rady Childrens Hospital
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco (Peds)
state: California
city: Denver
country: United States
facility: The Children's Hospital of Denver
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida College of Medicine (Shands)
state: Florida
city: Jacksonville
country: United States
facility: Nemours Childrens Clinic
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Saint Petersburg
country: United States
facility: All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University Medical Center
state: Indiana
city: Louisville
country: United States
facility: University of Louisville/Kosiar Children's Hospital
state: Kentucky
city: New Orleans
country: United States
facility: Children's of New Orleans
state: Louisiana
city: Boston
country: United States
facility: DFCI/Children's Hospital of Boston
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Institute/Children's Hospital of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi
state: Mississippi
city: Kansas City
country: United States
facility: Children's Mercy Hospital and Clinics
state: Missouri
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Children's Medical Center of Dallas
state: Texas
city: Fort Worth
country: United States
facility: Cook Childrens Medical Center
state: Texas
city: San Antonio
country: United States
facility: Texas Transplant Institute
state: Texas
city: Salt Lake City
country: United States
facility: Utah BMT/University of Utah Medical School
state: Utah
city: Richmond
country: United States
facility: Virgina Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Westmead
country: Australia
facility: Children's Hospital at Westmead
state: New South Wales
city: Vancouver
country: Canada
facility: BC Cancer Agency
state: British Columbia
Study officials:
affiliation: Center for International Blood and Marrow Transplant Research
name: Mary Horowitz, MD, MS
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.