Clinical trial NCT01002742: Acute Graft-versus-Host Disease Treatment (BMT CTN 0802)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Graft-versus-Host Disease
Immune System Disorders
Keywords: GVHD
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: National Cancer Institute (NCI)
First posted: 2009-10-27
Enrollment: 236
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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 Historical published and unpublished data from Johns Hopkins, M. D. Anderson, University of Michigan and others defined an expected 35%-53% complete response (CR) at Day +28 of corticosteroid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

Eligibility criteria: 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.

Primary outcomes:
measure: GVHD-free Survival
timeFrame: Day 56
Secondary outcomes:
measure: Percentage of Surviving Participants With Complete Response (CR)
timeFrame: Days 14, 28, and 56
measure: Incidence of GVHD Flares Requiring Increased Therapy
timeFrame: Day 90
measure: Incidence of Discontinuation of Immune Suppression Without Flare
timeFrame: Day 56, Day 180 and Day 360 post-treatment
measure: Cumulative Steroid Dose
timeFrame: Days 28 and 56
measure: Incidence of Topical/Non-absorbable Therapy
timeFrame: Day 56
measure: Overall GVHD-free Survival Post-randomization
timeFrame: Months 6 and 12
measure: Incidence of Chronic GVHD
timeFrame: 12 months post-randomization
measure: Incidence of Systemic Infections
timeFrame: 6 Months
measure: Incidence of Epstein-Barr Virus (EBV)-Associated Lymphoma
timeFrame: 12 months
measure: Incidence of Cytomegalovirus (CMV) Reactivation
timeFrame: Year 1
measure: Cumulative Incidence of a Severe/Life-threatening/Fatal Infections
timeFrame: Year 1
measure: Disease-Free Survival (DFS) Post-Randomization
timeFrame: Year 1
measure: Treatment Related Mortality (TRM)
timeFrame: Year 1
measure: Change in Patient Reported Outcomes From Enrollment to Day 56
timeFrame: Day 56
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: La Jolla
country: United States
facility: University of California San Diego Medical Center
state: California
city: Stanford
country: United States
facility: Stanford Hospital and Clinics
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: Gainesville
country: United States
facility: University of Florida College of Medicine
state: Florida
city: Atlanta
country: United States
facility: BMT Program at Northside Hospital
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert Lurie Children's Hospital of Chicago
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Beech Grove
country: United States
facility: Indiana BMT at Beech Grove
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Baltimore
country: United States
facility: University of Maryland Medical Systems
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: DFCI, Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute, Brigham & Women's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University, Barnes Jewish Hospital
state: Missouri
city: Hackensack
country: United States
facility: Hackensack Univ. Medical Center
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College, NY Presbyterian Hospital
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Hospital at Chapel Hill
state: North Carolina
city: Charlotte
country: United States
facility: Levine Children's Hospital, Carolinas Medical Center
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Cancer Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Sioux Falls
country: United States
facility: Avera Hematology & Transplant Center
state: South Dakota
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Houston
country: United States
facility: University of Texas, MD Anderson Cancer Research Center
state: Texas
city: San Antonio
country: United States
facility: Texas Transplant Institute
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Center for International Blood and Marrow Transplant Research
name: Mary Horowitz, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.