Sirolimus as Secondary Therapy in Chronic Graft-Versus-Host Disease Not Responding To Prior Treatment

PRIMARY OBJECTIVES:

I. To assess the safety of sirolimus administered at a dose which provides steady-state, whole blood trough levels of 5-10 ng/mL in patients with chronic GVHD.

II. To determine whether administration of sirolimus provides benefit for patients with chronic GVHD that has not responded adequately to previous systemic treatment.

OUTLINE:

Patients receive sirolimus orally (PO) once daily (QD). Patients continue to receive prednisone and cyclosporine or tacrolimus at the discretion of the managing physician.

After completion of study treatment, patients are followed up periodically.

Inclusion criteria

• Biopsy-confirmed diagnosis of clinical extensive chronic GVHD with inadequate response to previous treatment and where secondary systemic therapy is indicated because of

• Clinical progression of signs and symptoms of chronic GVHD in a previously involved organ, or
• Development of signs and symptoms of chronic GVHD in a previously uninvolved organ, or
• Absence of improvement after 3 months of primary treatment, or
• Continued need for treatment with prednisone at doses >= 1.0 mg/kg/day for more than 2 months, without qualification for type of donor, graft or conditioning regimen
• Patient or guardian able and willing to provide informed consent
• Stated willingness to use contraception in women of child-bearing potential (Food and Drug Administration [FDA] requirement)
• Stated willingness of the patient to comply with study procedures and reporting requirements
• Stated willingness of the physician most involved in management of chronic GVHD (the "managing physician,") to comply with study procedures and reporting requirements

Exclusion criteria

• Fungal or viral infection with no radiographic evidence of improvement during continued appropriate antimicrobial therapy
• Cytomegalovirus (CMV) antigenemia unresponsive to antiviral therapy
• Active disseminated varicella zoster virus (VZV) infection with persistent non-crusted lesions
• Inability to tolerate oral medications
• Absolute neutrophil count (ANC) < 1500/uL
• Platelet count < 50,000/uL
• Persistent or recurrent malignancy, including histopathologic evidence of myeloma or lymphoma; patients with breakpoint cluster region-abelson (bcr/abl) detected by polymerase chain reaction (PCR) assay as the only evidence of persistent chronic myeloid leukemia may be enrolled
• Pregnancy
• Known history of hypersensitivity to sirolimus