Clinical trial NCT01339910: Reduced Intensity Regimen vs Myeloablative Regimen for Myeloid Leukemia or Myelodysplastic Syndrome (BMT CTN 0901)
Official title: A Randomized, Multi-Center, Phase III Study of Allogeneic Stem Cell Transplantation Comparing Regimen Intensity in Patients With Myelodysplastic Syndrome or Acute Myeloid Leukemia (BMT CTN #0901)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Leukemia, Myelocytic, Acute
Keywords: Acute Myelogenous Leukemia
Myelodysplastic Syndrome
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: National Cancer Institute (NCI)
name: Blood and Marrow Transplant Clinical Trials Network
name: National Marrow Donor Program
First posted: 2011-04-21
Enrollment: 272
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study is designed as a Phase III, multicenter trial comparing outcomes after allogeneic hematopoietic stem cell transplantation (HCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) between patients receiving myeloablative conditioning (MAC) versus reduced intensity conditioning (RIC) regimens.

Detailed description: Patients randomized to RIC will receive one of two regimen types: the combination of fludarabine (120-180 mg/m\^2) and busulfan (less than or equal to 8 mg/kg or IV equivalent) (Flu/Bu) or fludarabine (120-180 mg/m\^2) and melphalan (less than 150 mg/m\^2) (Flu/Mel). Patient randomized to MAC will receive one of three regimens: busulfan (16 mg/kg oral or 12.8 mg/kg IV equivalent) and cyclophosphamide (120 mg/kg) (Bu/Cy); or, busulfan (16 mg/kg PO or 12.8 mg/kg IV) and fludarabine (120-180 mg/m\^2) (Bu/Flu); or, cyclophosphamide (120 mg/kg) and total body irradiation (greater than 1200-1420cGy) (CyTBI). A total of 356 patients (178 to each arm) will be accrued on this study over a period of four years. Patients will be followed for up to 18 months from transplantation.

Eligibility criteria: Inclusion Criteria:

* Age equal or less than 65 years old and equal to or greater than 18 years old.
* Patients with the diagnosis of MDS or AML with fewer than 5% myeloblasts in the bone marrow and no leukemic myeloblasts in the peripheral blood on morphologic analysis performed within 30 days of start of the conditioning regimen enrollment.
* For patients receiving treatment of their MDS or AML prior to transplantation: a)Interval between the start of the most recent cycle of conventional cytotoxic chemotherapy and enrollment must be at least 30 days; b)Interval between completing treatment with a hypomethylating agent or other non-cytotoxic chemotherapy and enrollment must be at least 10 days.
* Patients must have a related or unrelated bone marrow or peripheral blood donor who is human leukocyte antigen (HLA)-matched at 7 or 8 of 8 HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing.
* HCT-Specific Comorbidity Index Score (HCT-CI) less than or equal to 4.
* Organ function: a) Cardiac function: Ejection fraction greater than or equal to 40%; b) Hepatic function: total bilirubin less than or equal to 2 times the upper limit of normal and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 3 times the upper limit of normal.; c)Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) greater than or equal to 40% and forced expiratory volume in one second (FEV1) greater than or equal to 50% (corrected for hemoglobin).
* Creatinine clearance greater than or equal to 50mL/min based on the Cockcroft-Gault formula.
* Signed informed consent.

Exclusion Criteria:

* Prior allograft or prior autograft.
* Symptomatic coronary artery disease.
* Leukemia involvement in the central nervous system (CNS) within 4 weeks of enrollment for patients with a history of prior CNS leukemia involvement (i.e., leukemic blasts previously detected in the cerebral spinal fluid).
* Karnofsky Performance Score less than 70.
* Patients receiving supplemental oxygen.
* Planned use of donor lymphocyte infusion (DLI) therapy.
* Patients with uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms).
* Patients seropositive for the human immunodeficiency virus (HIV).
* Patients with prior malignancies, except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent greater than 5 years previously. Cancer treated with curative intent less than 5 years previously will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs.
* Females who are pregnant or breastfeeding.
* Fertile men and women unwilling to use contraceptive techniques during and for 12 months following treatment.

Primary outcomes:
measure: Percentage of Participants With Overall Survival (OS)
timeFrame: 18 months post-randomization
Secondary outcomes:
measure: Percentage of Participants With Relapse-Free Survival (RFS)
timeFrame: 18 months post-randomization
measure: Percentage of Participants With Disease Relapse
timeFrame: 18 months post-randomization
measure: Percentage of Participants With Treatment-related Mortality
timeFrame: 18 months post-randomization
measure: Percentage of Participants With Neutrophil and Platelet Engraftment
timeFrame: Days 28 and 60 post-transplant
measure: Number of Participants With Donor Cell Engraftment
timeFrame: Days 28 and 100 and 18 months post-transplant
measure: Percentage of Participants With Acute Graft Versus Host Disease (GVHD)
timeFrame: Day 100 post-transplant
measure: Percentage of Participants With Chronic GVHD
timeFrame: 18 months post-transplant
measure: Number of Participants With Chronic GVHD Severity
timeFrame: 18 months post-transplant
measure: Number of Participants With Primary Graft Failure
timeFrame: 28 days post-transplant
measure: Number of Participants With Secondary Graft Failure
timeFrame: 18 months post-transplant
measure: Number of Participants With Maximum Grade 3-5 Toxicities
timeFrame: 18 months
measure: Infection Type
timeFrame: 18 months post-transplant
measure: Number of Participants With Infections
timeFrame: 18 months post-transplant
measure: Number of Participants With Cause of Death
timeFrame: 18 months post-randomization
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Phoenix
state: Arizona
city: La Jolla
country: United States
facility: University of California, San Diego Medical Center
state: California
city: Gainesville
country: United States
facility: University of Florida College of Medicine
state: Florida
city: Orlando
country: United States
facility: Florida Hospital Cancer Institute
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Atlanta
country: United States
facility: Blood and Marrow Transplant Program at Northside Hospital
state: Georgia
city: Kansas City
country: United States
facility: University of Kansas
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Boston
country: United States
facility: DFCI, Brigham & Women's Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University/Barnes Jewish Hospital
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Hospital at Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Jewish Hospital BMT Program
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals of Cleveland/Case Western
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Cancer Center
state: Pennsylvania
city: Dallas
country: United States
facility: Baylor University 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: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Morgantown
country: United States
facility: West Virginia University Hospital
state: West Virginia
city: Madison
country: United States
facility: University of Wisconsin Hospital & Clinics
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Center for International Blood and Marrow Transplant Research
name: Mary Horowitz, MD
role: STUDY_DIRECTOR
References:
citation: Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellstrom-Lindberg E, Tefferi A, Bloomfield CD. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009 Jul 30;114(5):937-51. doi: 10.1182/blood-2009-03-209262. Epub 2009 Apr 8.
citation: Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, Storer B. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005 Oct 15;106(8):2912-9. doi: 10.1182/blood-2005-05-2004. Epub 2005 Jun 30.
citation: Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56. doi: 10.1016/j.bbmt.2005.09.004.
citation: Copelan E, Casper JT, Carter SL, van Burik JA, Hurd D, Mendizabal AM, Wagner JE, Yanovich S, Kernan NA. A scheme for defining cause of death and its application in the T cell depletion trial. Biol Blood Marrow Transplant. 2007 Dec;13(12):1469-76. doi: 10.1016/j.bbmt.2007.08.047.
citation: Scott BL, Pasquini MC, Logan BR, Wu J, Devine SM, Porter DL, Maziarz RT, Warlick ED, Fernandez HF, Alyea EP, Hamadani M, Bashey A, Giralt S, Geller NL, Leifer E, Le-Rademacher J, Mendizabal AM, Horowitz MM, Deeg HJ, Horwitz ME. Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol. 2017 Apr 10;35(11):1154-1161. doi: 10.1200/JCO.2016.70.7091. Epub 2017 Feb 13.