- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00224874
Treatment for Acute Graft-Versus-Host Disease (BMT CTN 0302)
Initial Systemic Treatment of Acute GVHD: A Phase II Randomized Trial Evaluating Etanercept, Mycophenolate Mofetil (MMF), Denileukin Diftitox (ONTAK), and Pentostatin in Combination With Corticosteroids (BMT CTN #0302)
Study Overview
Status
Conditions
Intervention / Treatment
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).
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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California
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Duarte, California, United States, 91010
- City of Hope National Medical Center
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San Diego, California, United States, 92093
- University of California
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Stanford, California, United States, 94305
- Stanford Hospital and Clinics
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Florida
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Gainesville, Florida, United States, 32610
- University of Florida College of Medicine (Shands)
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Maryland
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Baltimore, Maryland, United States, 21231
- Johns Hopkins/SKCCC
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Massachusetts
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Boston, Massachusetts, United States, 02114
- DFCI/Brigham & Women's Hospital
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Michigan
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Ann Arbor, Michigan, United States, 48109
- University of Michigan Medical Center
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Minnesota
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Minneapolis, Minnesota, United States, 55455
- University of Minnesota
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Missouri
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Saint Louis, Missouri, United States, 63110
- Washington University/Barnes Jewish Hospital
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Nebraska
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Omaha, Nebraska, United States, 68198
- University of Nebraska Medical Center
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New Jersey
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Hackensack, New Jersey, United States, 07601
- Hackensack University Medical Center
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New York
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New York, New York, United States, 10021
- Memorial Sloan-Kettering Cancer Center
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North Carolina
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Durham, North Carolina, United States, 27705
- Duke University Medical Center (Peds)
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Ohio
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Cleveland, Ohio, United States, 44106
- University Hospitals of Cleveland/Case Western
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Oregon
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Portland, Oregon, United States, 97239
- Oregon Health Sciences University
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Pennsylvania
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Philadelphia, Pennsylvania, United States, 19104
- University of Pennsylvania Cancer Center
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Texas
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Houston, Texas, United States, 77030
- University of Texas/MD Anderson CRC
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San Antonio, Texas, United States, 78229
- Texas Transplant Institute
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Washington
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Seattle, Washington, United States, 98109
- Fred Hutchinson Cancer Research Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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 Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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EXPERIMENTAL: Etanercept
Enroll within 48 hours of new onset acute GVHD and randomize to Etanercept
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Etanercept [25 mg subcutaneously twice weekly for up to 4 weeks; discontinue if in complete response by 4 weeks].
Other Names:
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EXPERIMENTAL: Mycophenolate Mofetil
Enroll within 48 hours of new onset acute GVHD and randomize to Mycophenolate Mofetil
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Mycophenolate mofetil (MMF) [20 mg/kg (maximum 1 gm) orally or intravenously twice daily; continue through prednisone taper, then taper MMF over 4 weeks].
Other Names:
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EXPERIMENTAL: Denileukin Diftitox
Enroll within 48 hours of new onset acute GVHD and randomize to Denileukin Diftitox
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Denileukin Diftitox (ONTAK®) [9 mcg/kg intravenously Days 1, 3, 5, 15, 17, 19].
Other Names:
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EXPERIMENTAL: Pentostatin
Enroll within 48 hours of new onset acute GVHD and randomize to Pentostatin
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Pentostatin [1.5 mg/m2 daily for 3 days; Days 1-3 and repeat Days 15-17
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Complete Response (CR) at Day 28 of Therapy
Time Frame: Measured at Day 28
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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.
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Measured at Day 28
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Partial Response (PR), Mixed Response (MR), and Progression
Time Frame: Measured at Day 28
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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.
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Measured at Day 28
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Proportion of Treatment Failure
Time Frame: Measured at Day 56
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Measured at Day 56
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Number of Patients With Acute Graft-versus-host Disease (GVHD) Flares at Day 90
Time Frame: Measured at Day 90
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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).
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Measured at Day 90
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Number of Patients Discontinuing Immune Suppression Without Flare
Time Frame: Measured at Days 90, 180, and 270 post-treatment
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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.
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Measured at Days 90, 180, and 270 post-treatment
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Number of Patients With Chronic Graft-versus-host Disease (GVHD)
Time Frame: Measured at 9 months
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Number of patients with limited and extensive chronic GVHD at 9 months
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Measured at 9 months
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Number of Patients Surviving at 6 and 9 Months Post Randomization
Time Frame: Measured at 6 and 9 months
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Measured at 6 and 9 months
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Cumulative Incidence of Systemic Infections
Time Frame: Measured at Day 270
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Measured at Day 270
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Incidence of Epstein-Barr Virus (EBV)-Associated Lymphoma
Time Frame: Measured at 9 months
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Measured at 9 months
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Collaborators and Investigators
Publications and helpful links
General Publications
- Alousi AM, Weisdorf DJ, Logan BR, Bolanos-Meade J, Carter S, Difronzo N, Pasquini M, Goldstein SC, Ho VT, Hayes-Lattin B, Wingard JR, Horowitz MM, Levine JE; Blood and Marrow Transplant Clinical Trials Network. Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network. Blood. 2009 Jul 16;114(3):511-7. doi: 10.1182/blood-2009-03-212290. Epub 2009 May 14.
- Jacobson PA, Huang J, Wu J, Kim M, Logan B, Alousi A, Grimley M, Bolanos-Meade J, Ho V, Levine JE, Weisdorf D. Mycophenolate pharmacokinetics and association with response to acute graft-versus-host disease treatment from the Blood and Marrow Transplant Clinical Trials Network. Biol Blood Marrow Transplant. 2010 Mar;16(3):421-9. doi: 10.1016/j.bbmt.2009.11.010.
- Levine JE, Logan B, Wu J, Alousi AM, Ho V, Bolanos-Meade J, Weisdorf D; Blood and Marrow Transplant Clinical Trials Network. Graft-versus-host disease treatment: predictors of survival. Biol Blood Marrow Transplant. 2010 Dec;16(12):1693-9. doi: 10.1016/j.bbmt.2010.05.019. Epub 2010 Jun 9.
- Levine JE, Logan BR, Wu J, Alousi AM, Bolanos-Meade J, Ferrara JL, Ho VT, Weisdorf DJ, Paczesny S. Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a Blood and Marrow Transplant Clinical Trials Network study. Blood. 2012 Apr 19;119(16):3854-60. doi: 10.1182/blood-2012-01-403063. Epub 2012 Mar 1.
Helpful Links
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Immune System Diseases
- Graft vs Host Disease
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Peripheral Nervous System Agents
- Enzyme Inhibitors
- Analgesics
- Sensory System Agents
- Anti-Inflammatory Agents, Non-Steroidal
- Analgesics, Non-Narcotic
- Anti-Inflammatory Agents
- Antirheumatic Agents
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Gastrointestinal Agents
- Anti-Bacterial Agents
- Antibiotics, Antineoplastic
- Antitubercular Agents
- Antibiotics, Antitubercular
- Adenosine Deaminase Inhibitors
- Etanercept
- Mycophenolic Acid
- Denileukin diftitox
- Pentostatin
Other Study ID Numbers
- BMTCTN0302
- U01HL069294-05 (NIH)
- BMT CTN 0302 (OTHER: Blood and Marrow Transplant Clinicial Trials Network)
- 285 (National Heart, Lung, and Blood Institute)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- ICF
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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