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

Graft-versus-Host Disease Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01002742
• Other study ID #: BMTCTN0802
• Secondary ID: U01HL069294BMT C
• Status: Completed
• Phase: Phase 3
• Start date: January 2010
• Est. completion date: June 2013

Study information

• Verified date: December 2022
• Source: Medical College of Wisconsin
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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 Historical published and unpublished data from Johns Hopkins, M. D. Anderson, University of Michigan and others defined an expected 35%-53% complete response (CR) at Day +28 of corticosteroid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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 236
• Est. completion date: June 2013
• Est. primary completion date: January 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• Graft vs Host Disease
• Graft-versus-Host Disease
• Immune System Diseases
• Immune System Disorders

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	University of Michigan Medical Center	Ann Arbor	Michigan
United States	BMT Program at Northside Hospital	Atlanta	Georgia
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Maryland Medical Systems	Baltimore	Maryland
United States	Indiana BMT at Beech Grove	Beech Grove	Indiana
United States	Dana Farber Cancer Institute, Brigham & Women's Hospital	Boston	Massachusetts
United States	DFCI, Massachusetts General Hospital	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	University of North Carolina Hospital at Chapel Hill	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Levine Children's Hospital, Carolinas Medical Center	Charlotte	North Carolina
United States	Ann & Robert Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	Ohio State University	Columbus	Ohio
United States	Baylor University Medical Center	Dallas	Texas
United States	Colorado Blood Cancer Institute	Denver	Colorado
United States	City of Hope National Medical Center	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Florida College of Medicine	Gainesville	Florida
United States	Hackensack Univ. Medical Center	Hackensack	New Jersey
United States	University of Texas, MD Anderson Cancer Research Center	Houston	Texas
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University of California San Diego Medical Center	La Jolla	California
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota	Minneapolis	Minnesota
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Weill Cornell Medical College, NY Presbyterian Hospital	New York	New York
United States	University of Pennsylvania Cancer Center	Philadelphia	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University, Barnes Jewish Hospital	Saint Louis	Missouri
United States	Texas Transplant Institute	San Antonio	Texas
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Avera Hematology & Transplant Center	Sioux Falls	South Dakota
United States	Stanford Hospital and Clinics	Stanford	California

Sponsors (3)

Lead Sponsor	Collaborator
Medical College of Wisconsin	National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 st — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Incidence of Discontinuation of Immune Suppression Without Flare		Day 56, Day 180 and Day 360 post-treatment
Secondary	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
Secondary	Incidence of Topical/Non-absorbable Therapy		Day 56
Secondary	Overall GVHD-free Survival Post-randomization		Months 6 and 12
Secondary	Incidence of Chronic GVHD		12 months post-randomization
Secondary	Incidence of Systemic Infections	Number of participants that experienced at least one infection.	6 Months
Secondary	Incidence of Epstein-Barr Virus (EBV)-Associated Lymphoma		12 months
Secondary	Incidence of Cytomegalovirus (CMV) Reactivation		Year 1
Secondary	Cumulative Incidence of a Severe/Life-threatening/Fatal Infections		Year 1
Secondary	Disease-Free Survival (DFS) Post-Randomization	DFS includes death or progression/relapse of malignancy	Year 1
Secondary	Treatment Related Mortality (TRM)		Year 1
Secondary	Change in Patient Reported Outcomes From Enrollment to Day 56		Day 56

External Links

•   Blood and Marrow Transplant Clinical Trials Network