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

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies the side effects and how well sirolimus works as secondary therapy in treating patients with chronic graft-versus-host disease (GVHD) that did not respond to prior treatment. Sirolimus may be an effective treatment for chronic GVHD

Detailed Description
-----------------
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.

Official Title
-----------------
A Phase II Clinical Trial to Evaluate the Safety and Efficacy of Sirolimus for Secondary Treatment of Chronic Graft-versus-Host Disease

Conditions
-----------------
Graft Versus Host Disease

Intervention / Treatment
-----------------
* Drug: sirolimus


Participation Criteria
=================
Eligibility Criteria
-----------------
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
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sirolimus<br>Study participants receive sirolimus added once daily to their baseline combination therapy of prednisone plus either cyclosporine or tacrolimus at the discretion of the managing physician. Treatment other than cyclosporine (or tacrolimus) and prednisone must be discontinued when administration of sirolimus is started. Topical therapy, including psoralen and UVA irradiation (PUVA), glucocorticoid creams, topical tacrolimus, oral beclomethasone, topical azathioprine and ophthalmic glucocorticoids may be given at the discretion of the managing physician in consultation with the transplant center. | Drug: sirolimus<br>* Given PO<br>* Other names: SLM;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Treatment Success | Defined as the absence of any immunosuppressive treatment, including sirolimus, with resolution of all reversible manifestations of chronic GVHD and no additional systemic therapy. | Approximately 7 years | 
| Number of Participants Experiencing Treatment Failure | Defined as the initiation of additional systemic therapy, development of bronchiolitis obliterans, or death from causes other than recurrent malignancy during primary treatment for chronic GVHD, whichever occurs first. | Approximately 7 years | 
| Number of Participants Needing Additional Systemic Therapy | Includes any intervention intended to control chronic GVHD through an immunosuppressive effect from oral or parenteral administration of any systemic medication not originally given under auspices of this protocol. | Approximately 7 years | 
| Number of Participants With Recurrent Malignancy | Defined as clinical or histopathologic evidence demonstrating the presence of any malignancy considered as the indication for transplant. Recurrent malignancy will also be defined as any post-transplant intervention not routinely used to prevent the development of overt recurrence, prompted by laboratory evidence of persisting malignant cells but without clinical or histopathologic evidence of recurrence. | Approximately 7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Who Discontinue Administration of Sirolimus Because of Toxicity |  | Approximately 7 years | 
| Proportion With Infections Categorized by Organism |  | Approximately 7 years | 
| Secondary Malignancies | Proportion of participants who developed at least one secondary malignancy by 7 years | Up to 7 years | 
| Duration of Treatment With Prednisone |  | Approximately 7 years | 
| Probability of Survival Without Recurrent Malignancy | Kaplan-Meier estimate assessed at 7 years for probability of survival without recurrent malignancy. | Approximately 7 years | 
| Probability of Overall Survival | Kaplan-Meier estimate assessed at 7 years | Approximately 7 years | 
| Probability of Cumulative Incidence of Death Without Recurrent Malignancy | Analyzed with recurrent malignancy as a competing risk factor. Assessed at 7 years. | Approximately 7 years | 
| Probability of Cumulative Incidence of Recurrent Malignancy | Analyzed with death as a competing risk factor. Assessed at 7 years. | Approximately 7 years |