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

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

Detailed Description
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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.

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

Conditions
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Graft vs Host Disease

Intervention / Treatment
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* Drug: Sirolimus
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 13 Years

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sirolimus Therapy<br>Administration of Sirolimus and Prednisone | Drug: Sirolimus<br>* Patients will receive sirolimus at 2 mg/day orally with monitoring of trough drug levels weekly for 2 weeks to achieve trough drug levels 7-12 ng/ml. Along with prednisone therapy.<br>* Other names: Rapamune;Drug: Prednisone<br>* Prednisone therapy will remain at the dose the patient received at the time sirolimus was begun. Withdrawal of prednisone will began after first evidence of improvement of chronic GVHD.<br>* Other names: Deltasone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Activity | Determined by discontinuation of immunosuppression with resolution of all reversible CGVHD manifestations. Evaluated at 2 years after enrollment | 3 month intervals after the initiation of sirolimus until 2 years after the initiation of sirolimus | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Administration of Sirolimus and Prednisone | 3 month intervals after the initiation of sirolimus until 2 years after the initiation of sirolimus | 

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