Chronic Graft-versus-Host Disease Treatment (BMT CTN 0801)

Background: Chronic GVHD is a medical condition that can become very serious. Chronic GVHD is
a common development after allogeneic transplant that occurs when the donor cells attack and
damage tissues. The primary purpose of this study is to compare treatment regimens that
contain sirolimus without a calcineurin inhibitor to a comparator regimen of sirolimus with a
calcineurin inhibitor and evaluate how well chronic GVHD responds to treatment. The
combinations of medications in this study are:

- Sirolimus + calcineurin inhibitor + prednisone

- Sirolimus + prednisone

The goal is to select a treatment regimen for further comparison in the Phase III trial.

Design Narrative: The intent is to enroll subjects at the start of initial therapy for
chronic GVHD, or before their chronic GVHD is refractory to glucocorticoid therapy, or is
chronically dependent upon glucocorticoid therapy and multiple secondary systemic
immunosuppressive agents. Patients will be stratified by transplant center and will be
randomized to one of two arms.

Inclusion Criteria:

- Suitable candidates are patients with classic chronic GVHD or overlap syndrome
(classic chronic plus acute GVHD)that is: a)Previously untreated (newly diagnosed) as
defined by having received < 14 days of prednisone (or equivalent) before
enrollment/randomization to study therapy; b)Previously treated but inadequately
responding after ≤ 16 weeks of initial therapy with prednisone and/or calcineurin
inhibitor (CNI) ± additional non-sirolimus agent (started at the time of chronic GVHD
diagnosis).

- Patient or guardian willing and able to provide informed consent.

- Stated willingness to use contraception in women of childbearing potential.

- Stated willingness of patient to comply with study procedures and reporting
requirements.

Exclusion Criteria:

- Patients with late persistent acute GVHD or recurrent acute GVHD only.

- Inability to begin prednisone therapy at a dose of greater than 0.5 mg/kg/day.

- Receiving sirolimus for treatment of chronic GVHD (sirolimus for prophylaxis or
treatment of acute GVHD is acceptable).

- Already receiving sirolimus (for prophylaxis or treatment of acute GVHD) with
prednisone at ≥ 0.25 mg/kg/day (or equivalent) ± additional agents.

- Receiving therapy for chronic GVHD for more than 16 weeks.

- Invasive fungal or viral infection not responding to appropriate antifungal or
antiviral therapies.

- Inadequate renal function defined as measured creatinine clearance less than 50
mL/min/1.73 m^2 based on the Cockcroft-Gault formula (adults) or Schwartz formula (age
less than or equal to 12 years). Adults: estimated creatinine clearance rate (eCCr)
(mL/min/) = (140 - age) x mass (kg) x (0.85 if female)/72 x serum creatinine (mg/dL;
Creatinine clearance (mL/min/1.73m^2) = eCCr x 1.73/Body Surface Area (BSA) (m^2);
Children: eCCr (mL/min/1.73 m^2) = k x height (cm) / serum creatinine (mg/dL) k = 0.33
(pre-term), 0.45 (full term to 1 year old), 0.55 (age 1-12 years).

- Inability to tolerate oral medications.

- Absolute neutrophil count less than 1500 per microliter.

- Requirement for platelet transfusions.

- Pregnancy (positive serum β-HCG) or breastfeeding.

- Receiving any treatment for persistent, progressive or recurrent malignancy.

- Progressive or recurrent malignancy defined other than by quantitative molecular
assays.

- Known hypersensitivity to sirolimus.