Sirolimus as Treatment of Steroid-Refractory or Steroid-Dependent Chronic Graft-Versus-Host Disease

A Phase II Trial of Sirolimus as Treatment of Steroid-Refractory or Steroid-Dependent Chronic Graft-Versus-Host Disease

To study the effectiveness of an immunosuppressive drug sirolimus, in the treatment of chronic graft versus host disease in combination with prednisone.

The purpose of this trial is to study the effectiveness of an immunosuppressive drug, sirolimus, in the treatment of chronic graft versus host disease in combination with prednisone. Graft versus host disease (GVHD) is a common complication in patients who have received blood or marrow transplantation from a related or unrelated donor. Chronic GVHD occurs approximately 100 days after transplantation and is the result of the donor immune system recognizing the patient's tissues as foreign and creating harmful effects on the patient's organs. We hope the use of sirolimus will decrease the significant disabling effects and deaths caused by chronic GVHD.

Inclusion Criteria:

• Age ≥ 13 years
• Weight ≥ 40 kg.
• Biopsy or clinical presentation diagnostic of chronic GVHD >100 days following allogeneic bone marrow/peripheral blood/umbilical cord blood transplantation that has failed prior corticosteroid therapy or corticosteroid taper. In the event that histological confirmation poses undue risk, clinical evaluation is sufficient.
• Women of child-bearing potential must have a negative pregnancy test before sirolimus administration and agree to use a medically acceptable contraceptive throughout the treatment period until 3 months after discontinuation of sirolimus.
• Any woman becoming pregnant during the treatment period must discontinue the use of sirolimus.
• Absolute neutrophil count (ANC) > 1000/mm³, unless receiving G-CSF to maintain neutrophil count > 500/mm³.
• At the time of initiating sirolimus the cyclosporine trough level is recommended to be < 100 mg/dl and FK506 level is recommended to be < 5 mg/dl. FK506 or cyclosporine is to be discontinued soon after initiation of sirolimus.
• Karnofsky performance score ≥ 50 during pre-study screening.
• Written, signed, and dated informed consent

Exclusion Criteria:

• Uncontrolled systemic infection
• Unstable disease states (i.e., hepatic failure, ventilatory-dependent respiratory failure, etc.)
• Serum creatinine ≥ 3.0 mg/dL
• Platelet count ≤ 50,000/mm³
• History of Post-transplant microangiopathic hemolytic anemia
• Uncontrolled hyperlipidemia
• Use of any investigational drug within 4 weeks of entry into the study
• Use of methotrexate or antibody therapies within 24 hours of sirolimus administration
• Inability to tolerate oral therapy for any reason
• Evidence of infiltrate, cavitation, or consolidation on chest x-ray during pre-study screening
• Known hypersensitivity to macrolide antibiotics