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

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published and unpublished data from Johns Hopkins, M. D. Anderson, University of Michigan and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.

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.