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Treatment for Acute Graft-Versus-Host Disease (BMT CTN 0302)

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ClinicalTrials.gov Identifier: NCT00224874
Recruitment Status : Completed
First Posted : September 23, 2005
Results First Posted : April 9, 2010
Last Update Posted : November 1, 2021
National Cancer Institute (NCI)
Blood and Marrow Transplant Clinical Trials Network
Information provided by (Responsible Party):
National Heart, Lung, and Blood Institute (NHLBI)

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.

Condition or disease Intervention/treatment Phase
Graft vs Host Disease Immune System Disorders Drug: Etanercept Drug: Mycophenolate Mofetil Drug: Denileukin Diftitox Drug: Pentostatin Phase 2

Detailed Description:


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.


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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 180 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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 Start Date : September 2005
Actual Primary Completion Date : January 2009
Actual Study Completion Date : June 2012

Arm Intervention/treatment
Experimental: Etanercept
Enroll within 48 hours of new onset acute GVHD and randomize to Etanercept
Drug: Etanercept
Etanercept [25 mg subcutaneously twice weekly for up to 4 weeks; discontinue if in complete response by 4 weeks].
Other Name: ENBREL®

Experimental: Mycophenolate Mofetil
Enroll within 48 hours of new onset acute GVHD and randomize to Mycophenolate Mofetil
Drug: Mycophenolate Mofetil
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 Name: CellCept®

Experimental: Denileukin Diftitox
Enroll within 48 hours of new onset acute GVHD and randomize to Denileukin Diftitox
Drug: Denileukin Diftitox
Denileukin Diftitox (ONTAK®) [9 mcg/kg intravenously Days 1, 3, 5, 15, 17, 19].
Other Name: ONTAK®

Experimental: Pentostatin
Enroll within 48 hours of new onset acute GVHD and randomize to Pentostatin
Drug: Pentostatin
Pentostatin [1.5 mg/m2 daily for 3 days; Days 1-3 and repeat Days 15-17
Other Name: Nipent®

Primary Outcome Measures :
  1. Number of Complete Response (CR) at Day 28 of Therapy [ Time Frame: 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 :
  1. Number of Partial Response (PR), Mixed Response (MR), and Progression [ Time Frame: 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.

  2. Proportion of Treatment Failure [ Time Frame: Measured at Day 56 ]
  3. Number of Patients With Acute Graft-versus-host Disease (GVHD) Flares at Day 90 [ Time Frame: 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).

  4. Number of Patients Discontinuing Immune Suppression Without Flare [ Time Frame: 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.

  5. Number of Patients With Chronic Graft-versus-host Disease (GVHD) [ Time Frame: Measured at 9 months ]
    Number of patients with limited and extensive chronic GVHD at 9 months

  6. Number of Patients Surviving at 6 and 9 Months Post Randomization [ Time Frame: Measured at 6 and 9 months ]
  7. Cumulative Incidence of Systemic Infections [ Time Frame: Measured at Day 270 ]
  8. Incidence of Epstein-Barr Virus (EBV)-Associated Lymphoma [ Time Frame: Measured at 9 months ]

Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00224874

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Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
Blood and Marrow Transplant Clinical Trials Network
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Study Director: Mary Horowitz, MD Center for International Blood and Marrow Transplant Research
  Study Documents (Full-Text)

Documents provided by National Heart, Lung, and Blood Institute (NHLBI):
Additional Information:
Publications of Results:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier: NCT00224874    
Obsolete Identifiers: NCT00253656, NCT00474149
Other Study ID Numbers: BMTCTN0302
BMT CTN 0302 ( Other Identifier: Blood and Marrow Transplant Clinicial Trials Network )
U01HL069294-05 ( U.S. NIH Grant/Contract )
285 ( Other Identifier: National Heart, Lung, and Blood Institute )
First Posted: September 23, 2005    Key Record Dates
Results First Posted: April 9, 2010
Last Update Posted: November 1, 2021
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc where indicated).
Supporting Materials: Study Protocol
Informed Consent Form (ICF)
Time Frame: Within 6 months of official study closure at participating sites.
Access Criteria: Available to the public
URL: https://biolincc.nhlbi.nih.gov/home/
Keywords provided by National Heart, Lung, and Blood Institute (NHLBI):
Acute Graft vs Host Disease
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases
Mycophenolic Acid
Denileukin diftitox
Antibiotics, Antineoplastic
Antineoplastic Agents
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Gastrointestinal Agents
Immunosuppressive Agents
Immunologic Factors
Adenosine Deaminase Inhibitors