Treatment for Acute Graft-Versus-Host Disease (BMT CTN 0302)
- Conditions
- Graft vs Host DiseaseImmune System Disorders
- Interventions
- Registration Number
- NCT00224874
- Brief Summary
The study is a randomized Phase II, four arm treatment trial. The primary purpose of the study is to define new agents with promising activity against acute graft-versus-host disease (GVHD) suitable for testing against corticosteroids alone in a subsequent Phase III trial.
- Detailed Description
BACKGROUND:
Acute graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic stem cell (HSC) transplantation. Acute GVHD produces significant morbidity and complicates patient management resulting in organ toxicity, frequent infections, malnutrition, and substantial delay in recovery from transplantation. Corticosteroids have been the primary therapy for acute GVHD for over three decades. Various additional immunosuppressive strategies have been tested as GVHD therapy but neither anti-thymocyte globulin (ATG), CD5-immunotoxins, IL-1 antagonists nor other agents have been demonstrably helpful in either control of GVHD symptoms or improvement in survival. Published response rates of complete response (CR) to acute GVHD therapy with corticosteroids range from 25-41%. These rates will be used as benchmarks for assessing efficacy of promising new agents. New immunosuppressive agents and strategies are required to improve the management of GVHD and decrease the toxicities of the immunosuppressive regimens.
DESIGN NARRATIVE:
In this trial, patients with newly diagnosed acute GVHD will be randomly assigned to receive corticosteroids plus one of four new agents (etanercept, MMF, denileukin diftitox \[Ontak\], and pentostatin). A control arm of only corticosteroids will not be employed. Each agent will be assessed for safety and efficacy (at least 35% complete remission \[CR\] rate at Day 28 of therapy can be expected from previously untreated patients).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 180
- Prior allogeneic hematopoietic stem cell transplant using either bone marrow, peripheral blood stem cells, or cord blood
- De novo acute GVHD diagnosed within 48 hours prior to enrollment; biopsy confirmation of GVHD is strongly recommended but not required; enrollment should not be delayed awaiting biopsy or pathology results; the patient must have had no previous systemic immune suppressive therapy given for treatment of acute GVHD except for a maximum 48 hours of prior corticosteroid therapy (at least 1 mg/kg/day methylprednisolone)
- Patients that have undergone a scheduled donor lymphocyte infusion (DLI) as part of their original transplant therapy plan
- Absolute neutrophil count (ANC) greater than 500/µL
- Clinical status at enrollment to allow tapering of steroids to not less than 1 mg/kg/day methylprednisolone (1.4 mg/kg/day prednisone) at Day 28 of therapy (e.g., persisting malignant disease suggesting the need for accelerated taper of immunosuppression)
- Estimated creatinine clearance greater than 30 mL/minute
- Assent and educational materials provided to, and reviewed with, patients under the age of 18
- ONTAK, pentostatin, or etanercept given within 7 days of enrollment
- Active uncontrolled infection
- Patients that have undergone an unscheduled DLI, or DLI that was not part of their original transplant therapy plan
- If any prior steroid therapy (for indication other than GVHD), treatment at doses of at least 0.5 mg/kg/day methylprednisolone within 7 days prior to onset of GVHD
- Patients unlikely to be available at the transplant center on Day 28 and 56 of therapy
- A clinical syndrome resembling de novo chronic GVHD developing at any time after allotransplantation (see Chapter 2 of the BMT CTN Manual of Procedures for details of de novo chronic GVHD)
- Other investigational therapeutics for GVHD within 30 days, including agents used for GVHD prophylaxis
- Patients who are pregnant, breast feeding, or if sexually active, unwilling to use effective birth control for the duration of the study
- Adults unable to provide informed consent
- Patients with a history of intolerance to any of the study drugs
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Pentostatin Pentostatin Enroll within 48 hours of new onset acute GVHD and randomize to Pentostatin Mycophenolate Mofetil Mycophenolate Mofetil Enroll within 48 hours of new onset acute GVHD and randomize to Mycophenolate Mofetil Etanercept Etanercept Enroll within 48 hours of new onset acute GVHD and randomize to Etanercept Denileukin Diftitox Denileukin Diftitox Enroll within 48 hours of new onset acute GVHD and randomize to Denileukin Diftitox
- Primary Outcome Measures
Name Time Method Number of Complete Response (CR) at Day 28 of Therapy Measured at Day 28 Complete response at day 28 after randomization. CR was defined as resolution of all signs and symptoms of Graft-Versus-Host Disease (GVHD) in all evaluable organs in comparison to Day 1 scoring.
- Secondary Outcome Measures
Name Time Method Number of Patients With Acute Graft-versus-host Disease (GVHD) Flares at Day 90 Measured at Day 90 Flares were defined as any increase in symptoms of or therapy for acute GVHD after an initial response (i.e., progression from an earlier CR or PR).
Number of Patients With Chronic Graft-versus-host Disease (GVHD) Measured at 9 months Number of patients with limited and extensive chronic GVHD at 9 months
Cumulative Incidence of Systemic Infections Measured at Day 270 Number of Partial Response (PR), Mixed Response (MR), and Progression Measured at Day 28 Partial response, mixed response, and progression at Day 28 after randomization. Partial response was defined as improvement in one or more organs involved with Graft-Versus-Host Disease (GVHD) symptoms without progression in others. Mixed response was defined as improvement in one or more organs with deterioration in another organ manifesting symptoms of GVHD or development of symptoms of GVHD in a new organ. Progression was defined as deterioration in at least one organ without any improvement in others.
Number of Patients Surviving at 6 and 9 Months Post Randomization Measured at 6 and 9 months Incidence of Epstein-Barr Virus (EBV)-Associated Lymphoma Measured at 9 months Proportion of Treatment Failure Measured at Day 56 Number of Patients Discontinuing Immune Suppression Without Flare Measured at Days 90, 180, and 270 post-treatment Immunosuppression discontinuation was defined as the discontinuation of corticosteroids and all additional immunosuppressives, except cyclosporine or tacrolimus, for treatment of acute GVHD without subsequent flare by Day 90 post-initiation of therapy and later by discontinuation of all immunosuppressive medications, including cyclosporine or tacrolimus.
Trial Locations
- Locations (19)
DFCI/Brigham & Women's Hospital
🇺🇸Boston, Massachusetts, United States
Fred Hutchinson Cancer Research Center
🇺🇸Seattle, Washington, United States
Washington University/Barnes Jewish Hospital
🇺🇸Saint Louis, Missouri, United States
City of Hope National Medical Center
🇺🇸Duarte, California, United States
Texas Transplant Institute
🇺🇸San Antonio, Texas, United States
Stanford Hospital and Clinics
🇺🇸Stanford, California, United States
Duke University Medical Center (Peds)
🇺🇸Durham, North Carolina, United States
University of Florida College of Medicine (Shands)
🇺🇸Gainesville, Florida, United States
University of Michigan Medical Center
🇺🇸Ann Arbor, Michigan, United States
Johns Hopkins/SKCCC
🇺🇸Baltimore, Maryland, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸New York, New York, United States
University Hospitals of Cleveland/Case Western
🇺🇸Cleveland, Ohio, United States
Oregon Health Sciences University
🇺🇸Portland, Oregon, United States
University of California
🇺🇸San Diego, California, United States
University of Pennsylvania Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
University of Texas/MD Anderson CRC
🇺🇸Houston, Texas, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States