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

Study Overview
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Brief Summary
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This study is designed as a combined Phase II/III, randomized, open label, multicenter, prospective comparative study of sirolimus plus prednisone versus sirolimus/calcineurin-inhibitor plus prednisone for the treatment of chronic GVHD. Patients will be stratified by transplant center and will be randomized to an experimental arm of one of the two pre-specified experimental arms (sirolimus + prednisone or the comparator arm of sirolimus + calcineurin inhibitor + prednisone) in a 1:1 ratio.

Detailed Description
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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.

Official Title
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A Phase II/III Randomized, Multicenter Trial Comparing Sirolimus Plus Prednisone and Sirolimus/Calcineurin Inhibitor Plus Prednisone for the Treatment of Chronic Graft-versus-Host Disease (BMT CTN Protocol #0801)

Conditions
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Chronic GVHD

Intervention / Treatment
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* Drug: Sirolimus + calcineurin inhibitor + prednisone
* Drug: Sirolimus + prednisone


Participation Criteria
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Eligibility Criteria
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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.
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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: calcineurin inhibitor<br>Sirolimus + calcineurin inhibitor + prednisone | Drug: Sirolimus + calcineurin inhibitor + prednisone<br>* The target serum level for sirolimus is 3-12 ng/mL. The target serum level for tacrolimus is 5-10 ng/mL. The target serum level for cyclosporine is 120-200 ng/mL. Prednisone is administered initially as a single early morning dose of 1 mg/kg/day (or equivalent). If prednisone at a dose of 1 mg/kg/day (or equivalent) is contraindicated, patients may begin prednisone between 0.5-1 mg/kg/day.<br>* Other names: Gengraf;|
| Experimental: Sirolimus and prednisone<br>Sirolimus + prednisone | Drug: Sirolimus + prednisone<br>* The target serum level for sirolimus is 3-12 ng/mL. Prednisone is administered initially as a single early morning dose of 1 mg/kg/day (or equivalent). If prednisone at a dose of 1 mg/kg/day (or equivalent) is contraindicated, patients may begin prednisone between 0.5-1 mg/kg/day.<br>* Other names: Rapamune;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With Treatment Success | Treatment success was evaluated at 6 months in Phase II and is defined as a complete or partial response without secondary systemic immunosuppressive therapy and no recurrent malignancy or death. In Phase III, treatment success was evaluated at 24 months and is defined as a complete response without secondary systemic immunosuppressive therapy and no recurrent malignancy or death. | 6 months and 24 months post-randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Overall Survival | Overall survival is defined as survival of death from any cause. | 6 months and 24 months post-randomization | 
| Percentage of Participants With Progression-free Survival | Progression-free Survival is defined as survival without malignancy relapse. Relapse and death are considered failures for this endpoint. | 6 months and 24 months post-randomization | 
| Percentage of Participants With Failure-free Survival | Failure-free Survival is defined as survival without malignancy progression or initiation of secondary therapy for chronic GVHD. Progression, initiation of secondary therapy for chronic GVHD, and death are considered failures for this endpoint. | 6 months and 24 months post-randomization | 
| Percentage of Participants With Relapse | Relapse is defined as recurrence of the primary malignancy. Death is considered a competing risk for this endpoint. | 6 months and 24 months post-randomization | 
| Percentage of Participants With Secondary Immunosuppressive Therapy Initiated | The percentage of participants initiating secondary immunosuppressive therapy for chronic GVHD is described. Death is considered a competing risk for this endpoint. | 6 months and 24 months post-randomization | 
| Percentage of Participants With Discontinuation of Systemic Immunosuppressive Therapy at Two Years | The percentage of participants discontinuing all systemic immunosuppressive therapy by two years post-randomization is described. Death is considered a competing risk for this endpoint. | 2 years post-randomization | 
| Prednisone Dose | Daily dose of prednisone is described by treatment arm at baseline, 6 months, and 1 year post-randomization. | Baseline, 6 months, and 1 year post-randomization | 
| Change in Prednisone Dose From Baseline | Change in the daily dose of prednisone from baseline, the time of randomization, is described by treatment arm at 6 months and 1 year post-randomization. | 6 months and 1 year post-randomization | 
| Serum Creatinine Level | Creatinine level is described by treatment arm at baseline, 6 months, and 1 year post-randomization. | Baseline, 6 months, and 1 year post-randomization | 
| Change in Serum Creatinine Level From Baseline | Change in creatinine level from baseline, the time of randomization, is described by treatment arm at 6 months and 1 year post-randomization. | 6 months and 1 year post-randomization | 
| Patient-reported Chronic GVHD Severity | Each patient's perception of the severity of the chronic GVHD was collected at baseline and at 6 months, 1 year, and 2 years post-randomization. Severity is categorized as none, mild, moderate, and severe. | Baseline, 6 months, 1 year, and 2 years post-randomization | 
| Provider-reported Chronic GVHD Severity | Each patient's care provider's perception of the severity of the chronic GVHD was collected at baseline and at 6 months, 1 year, and 2 years post-randomization. Severity is categorized as none, mild, moderate, and severe. | Baseline, 6 months, 1 year, and 2 years post-randomization | 
| NIH Consensus Criteria Chronic GVHD Severity | Chronic GVHD severity was determined at baseline and at 6 months, 1 year, and 2 years post-randomization per the 2005 NIH Consensus Criteria (Filipovich et al. 2005). Severity is categorized as none, mild, moderate, and severe. | Baseline, 6 months, 1 year, and 2 years post-randomization | 
| SF-36 Physical Component Summary | The Medical Outcome Study SF-36 Physical Component Summary (PCS) is a subscale of the SF-36 intended to measure physical well-being. It is scored on a scale of 0-100, with higher scores indicating higher levels of well-being. | Baseline, 2 months, 6 months, 1 year, and 2 years post-randomization | 
| SF-36 Mental Component Summary | The Medical Outcome Study SF-36 Mental Component Summary (MCS) is a subscale of the SF-36 intended to measure mental well-being. It is scored on a scale of 0-100, with higher scores indicating higher levels of well-being. | Baseline, 2 months, 6 months, 1 year, and 2 years post-randomization | 
| FACT-BMT Score | The Functional Assessment of Cancer Therapy-Bone Marrow Transplant scale (FACT-BMT) is a quality of life instrument that assesses the effects of bone marrow transplantation (BMT) on a patient's physical, social/family, emotional, and functional well-being while taking into consideration BMT-specific concerns. The assessment has 37 questions, each scored on a Likert scale from 0-4. The overall score is computed by adding scores of the questions and falls in the range 0-148, with higher scores indicating higher levels of overall well-being. | Baseline, 2 months, 6 months, 1 year, and 2 years post-randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Graft-versus-Host Disease (cGVHD)