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

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 Historical published and unpublished data from Johns Hopkins, M. D. Anderson, University of Michigan and others defined an expected 35%-53% complete response (CR) at Day +28 of corticosteroid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

Official Title
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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)

Conditions
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Graft-versus-Host Disease, Immune System Disorders

Intervention / Treatment
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* Drug: Mycophenolate Mofetil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo<br>Corticosteroids with placebo | Drug: Placebo<br>* 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.<br>* Other names: Inactive drug;|
| Experimental: Mycophenolate Mofetil<br>Corticosteroids with Mycophenolate Mofetil | Drug: Mycophenolate Mofetil<br>* 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.<br>* Other names: MMF;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GVHD