Acute Graft-versus-Host Disease Treatment (BMT CTN 0802)

A Multi-Center, Randomized, Double Blind, Phase III Trial Evaluating Corticosteroids With Mycophenolate Mofetil vs. Corticosteroids With Placebo as Initial Systemic Treatment of Acute Graft-Vs-Host-Disease (BMT CTN #0802)

The study is a Phase III, randomized double blind, placebo controlled, and trial evaluating the addition of Mycophenolate mofetil (MMF) vs. placebo to systemic corticosteroids as initial therapy for acute Graft Vs Host Disease (GVHD). The primary endpoint will be GVHD free survival at Day 56 post randomization.

Study Overview

• Status: Completed
• Conditions: Graft-versus-Host Disease; Immune System Disorders
• Intervention / Treatment: Drug: Placebo; Drug: Mycophenolate Mofetil

Detailed Description

Corticosteroids have been used as primary therapy for acute GVHD for many years. Historical published and unpublished data from Johns Hopkins, M. D. Anderson, University of Michigan and others defined an expected 35%-53% complete response (CR) at Day +28 of corticosteroid therapy for previously untreated patients with acute GVHD.

BMT CTN study 0302 (NCT00224874)was a randomized Phase II study evaluating etanercept, mycophenolate mofetil, denileukin diftitox or pentostatin in addition to corticosteroids. The results of that study suggested that mycophenolate mofetil produced the highest rates of CR at Day 28 and overall survival, supporting its evaluation in a Phase III study. Day 56 GVHD-free survival for the four treatment arms (all combining corticosteroids with one of the four study drugs) ranged from 39-71% across the four study arms.

• Study Type: Interventional
• Enrollment (Actual): 236
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
    • La Jolla, California, United States, 92093
      • University of California San Diego Medical Center
    • Stanford, California, United States, 94305
      • Stanford Hospital and Clinics
  • Colorado
    • Denver, Colorado, United States, 80218
      • Colorado Blood Cancer Institute
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida College of Medicine
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • BMT Program at Northside Hospital
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60611
      • Ann & Robert Lurie Children's Hospital of Chicago
  • Indiana
    • Beech Grove, Indiana, United States, 46107
      • Indiana BMT at Beech Grove
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins University
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Systems
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02114
      • DFCI, Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute, Brigham & Women's Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University, Barnes Jewish Hospital
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack Univ. Medical Center
  • New York
    • New York, New York, United States, 10021
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10065
      • Weill Cornell Medical College, NY Presbyterian Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7305
      • University of North Carolina Hospital at Chapel Hill
    • Charlotte, North Carolina, United States, 28232
      • Levine Children's Hospital, Carolinas Medical Center
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Cancer Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Avera Hematology & Transplant Center
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Houston, Texas, United States, 77030
      • University of Texas, MD Anderson Cancer Research Center
    • San Antonio, Texas, United States, 78229
      • Texas Transplant Institute
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53211
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Acute GVHD developing after allogeneic hematopoietic stem cell transplant using either bone marrow, peripheral blood stem cells or cord blood. Recipients of non-myeloablative and myeloablative transplants are eligible.
• Acute GVHD after planned donor lymphocyte infusion or planned T cell add back are eligible.
• De novo acute GVHD requiring systemic therapy. GVHD is defined as the presence of skin rash and/or persistent nausea, vomiting, and/or diarrhea and/or cholestasis presenting in a context in which acute GVHD is likely to occur and where other etiologies such as drug rash, enteric infection, or hepatotoxic syndromes are unlikely or have been ruled out. Note that patients with stage I and II skin only (overall grade I) or isolated upper gastrointestinal (GI) involvement are eligible if the treating physician deems that systemic high-dose corticosteroid treatment is indicated.
• The patient must have had no previous systemic immune suppressive therapy for treatment of acute GVHD except for a maximum 72 hours of prior corticosteroid therapy at >0.5mg/kg methylprednisolone or equivalent after the onset of acute GVHD.
• Clinical status at enrollment to allow tapering of steroids to not less than 0.25 mg/kg/day prednisone (0.2 mg/kg/day methylprednisolone) at Day 28 of therapy.
• Absolute neutrophil count (ANC) greater than 500/µL.
• Written informed consent and/or assent from patient, parent or guardian.
• Documentation that the assent document and education materials have been provided to, and reviewed with, patients between the ages of 7 and 17.
• Patients of all ages are eligible.
• Biopsy confirmation of GVHD is recommended, but not required. Enrollment should not be delayed for biopsy or pathology results unless these are to be used to decide about whether to treat for GVHD.

Exclusion Criteria:

• Patients receiving mycophenolate mofetil or mycophenolic acid (Myfortic) within seven days of screening for enrollment.
• Patients with uncontrolled infections will be excluded. If a bacterial or viral infection is present, patients must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to enrollment. If a fungal infection is present, patients must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to enrollment. Progressing infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
• Relapsed/persistent malignancy requiring rapid immune suppression withdrawal.
• Patients with GVHD after an unplanned Donor Lymphocyte Infusion (DLI), i.e., DLI that was not part of their original transplant therapy plan, or DLI given for treatment of persistent or recurrent malignancy after transplantation.
• Patients unlikely to be available at the transplantation center on Day 28 and 56 of therapy.
• A clinical syndrome resembling de novo chronic GVHD developing at any time after allotransplantation.
• Patients receiving other drugs for the treatment of GVHD.
• Patients receiving methylprednisolone > 0.5 mg/kg/day (or 0.6 mg/kg/day prednisone) within 7 days before the onset of acute GVHD. If steroid therapy has been administered for treatment of a non-GVHD related condition and tapered to ≤ 0.5 mg/kg/day methylprednisolone (0.6 mg/kg/day prednisone) for seven or more days before the onset of acute GVHD, the patient is eligible.
• Patients who are pregnant, breast feeding, or, if sexually active, unwilling to use effective birth control for the duration of the study. Available evidence and/or expert consensus is inconclusive or is inadequate for determining infant risk when used during breastfeeding, therefore breast feeding patients are not eligible.
• Adults unable to provide informed consent.
• Patients on dialysis.
• Patients with severe hepatic Veno-Occlusive Disease (VOD) or sinusoidal obstruction syndrome who in the judgement of the treating physician are not expected to have normalized bilirubin by Day 56 after enrollment.
• Patients with a history of intolerance/allergy to MMF.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Placebo; Corticosteroids with placebo	Drug: Placebo; Oral dosing should be delivered in 250 mg units blinded placebo. For those < 40 kg, IV dosing should be within ± 10% of the exact dose. Intravenous doses are infused over a two-hour period.; Patients who weight > 60 kg should receive placebo 1 gm PO/IV every 8 hours.; Patients who weight between 40-60 kg should receive 750 mg PO/IV every 8 hours.; Patients who weight <40 kg should receive 20 mg/kg IV or PO every 8 hours.; Other Names: Inactive drug
Experimental: Mycophenolate Mofetil; Corticosteroids with Mycophenolate Mofetil	Drug: Mycophenolate Mofetil; Oral dosing should be delivered in 250 mg units. For those < 40 kg, IV dosing should be within ± 10% of the exact dose. Intravenous doses are infused over a two-hour period.; Patients who weight > 60 kg should receive MMF 1 gm PO/IV every 8 hours.; Patients who weight between 40-60 kg should receive 750 mg PO/IV every 8 hours.; Patients who weight <40 kg should receive 20 mg/kg IV or PO every 8 hours.; Other Names: MMF; Cellcept®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
GVHD-free Survival	Success is defined as alive and free of GVHD at day 56 after randomization, all others are considered to be a study failure.	Day 56

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Surviving Participants With Complete Response (CR)	CR is defined as a score of 0 for the GVHD grading in all evaluable organs.	Days 14, 28, and 56
Incidence of GVHD Flares Requiring Increased Therapy	Flares are defined as any progression of acute GVHD after an initial response (i.e., earlier CR or PR) that requires re-escalation of steroid dosing, or initiation of additional topical or systemic therapy.	Day 90
Incidence of Discontinuation of Immune Suppression Without Flare		Day 56, Day 180 and Day 360 post-treatment
Cumulative Steroid Dose	The cumulative steroid dose for each patient will be calculated by adding the doses (end of each week's dose) for each of the first four weeks of treatment, divided by the number of days of survival during this interval. The cumulative steroid dose was calculated for all patients per treatment arm and compared.	Days 28 and 56
Incidence of Topical/Non-absorbable Therapy		Day 56
Overall GVHD-free Survival Post-randomization		Months 6 and 12
Incidence of Chronic GVHD		12 months post-randomization
Incidence of Systemic Infections	Number of participants that experienced at least one infection.	6 Months
Incidence of Epstein-Barr Virus (EBV)-Associated Lymphoma		12 months
Incidence of Cytomegalovirus (CMV) Reactivation		Year 1
Cumulative Incidence of a Severe/Life-threatening/Fatal Infections		Year 1
Disease-Free Survival (DFS) Post-Randomization	DFS includes death or progression/relapse of malignancy	Year 1
Treatment Related Mortality (TRM)		Year 1
Change in Patient Reported Outcomes From Enrollment to Day 56		Day 56

Collaborators and Investigators

• Sponsor: Medical College of Wisconsin
• Collaborators: National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

General Publications

• Bolanos-Meade J, Logan BR, Alousi AM, Antin JH, Barowski K, Carter SL, Goldstein SC, Hexner EO, Horowitz MM, Lee SJ, Levine JE, MacMillan ML, Martin PJ, Mendizabal AM, Nakamura R, Pasquini MC, Weisdorf DJ, Westervelt P, Ho VT. Phase 3 clinical trial of steroids/mycophenolate mofetil vs steroids/placebo as therapy for acute GVHD: BMT CTN 0802. Blood. 2014 Nov 20;124(22):3221-7; quiz 3335. doi: 10.1182/blood-2014-06-577023. Epub 2014 Aug 28.
• Shah O, Tamaresis JS, Kenyon LJ, Xu L, Zheng P, Gupta P, Rangarajan K, Lee S, Spellman S, Nikiforow S, Zehnder J, Meyer EH. Analysis of the Whole CDR3 T Cell Receptor Repertoire after Hematopoietic Stem Cell Transplantation in 2 Clinical Cohorts. Biol Blood Marrow Transplant. 2020 Jun;26(6):1050-1070. doi: 10.1016/j.bbmt.2020.01.020. Epub 2020 Feb 18.

Helpful Links

• Blood and Marrow Transplant Clinical Trials Network

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2010
• Primary Completion (Actual): January 1, 2012
• Study Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: October 23, 2009
• First Submitted That Met QC Criteria: October 23, 2009
• First Posted (Estimate): October 27, 2009

Study Record Updates

• Last Update Posted (Actual): January 4, 2023
• Last Update Submitted That Met QC Criteria: December 7, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: GVHD
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Mycophenolic Acid
• Other Study ID Numbers: BMTCTN0802; U01HL069294 (U.S. NIH Grant/Contract); 5U24CA076518 (U.S. NIH Grant/Contract); U01HL069294-06 (U.S. NIH Grant/Contract); BMT CTN 0802 (Other Identifier: Blood and Marrow Transplant Clinical Trials Network)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Findings will be published in a manuscript.
• IPD Sharing Time Frame: Within 6 months of official study closure at participating sites.
• IPD Sharing Access Criteria: Available to the public