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

• Phase II: Proportion of subjects with CR/PR [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Phase III: Proportion of subjects with CR; resolution of GVHD manifestations [ Time Frame: 24 months ] [ Designated as safety issue: No ]

• Phase II: Avg. daily dose % reduction of prednisone [ Time Frame: 6 and 12 months ] [ Designated as safety issue: No ]
• Phase II: Cumulative incidence of treatment failure [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• Phase II: Prevalence of active symptomatic chronic GVHD [ Time Frame: 1 and 2 years ] [ Designated as safety issue: No ]
• Phase II: Incidence of discontinuation of all systemic immunosuppressive therapy [ Time Frame: 1 and 2 years ] [ Designated as safety issue: No ]
• Phase II: Overall and cancer progression-free survival [ Time Frame: 1 and 2 years ] [ Designated as safety issue: No ]
• Phase II: Serum biomarkers of chronic GVHD [ Time Frame: baseline, 2 and 6 months ] [ Designated as safety issue: No ]
• Phase III: Avg. daily dose % reduction of prednisone [ Time Frame: 6, 12 and 24 months ] [ Designated as safety issue: No ]
• Phase III: Cumulative incidence of treatment failure [ Time Frame: 1 and 2 years ] [ Designated as safety issue: No ]
• Phase III: Prevalence of active symptomatic chronic GVHD [ Time Frame: 1 and 2 years ] [ Designated as safety issue: No ]
• Phase III: Incidence of discontinuation of all systemic immunosuppressive therapy [ Time Frame: 1 and 2 years ] [ Designated as safety issue: No ]
• Phases III: Overall and cancer progression-free survival [ Time Frame: 1 and 2 years ] [ Designated as safety issue: No ]
• Phase III: Serum biomarkers of chronic GVHD [ Time Frame: baseline, 1 and 2 years ] [ Designated as safety issue: No ]

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.

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.

• Drug: Sirolimus + calcineurin inhibitor + prednisone

  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.

  Other Names:

  • Rapamune
  • Prograf
  • Neorall
  • Gengraf
• Drug: Sirolimus + prednisone

  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.

  Other Name: Rapamune

• Active Comparator: Sirolimus + calcineurin inhibitor + prednisone
  Intervention: Drug: Sirolimus + calcineurin inhibitor + prednisone
• Experimental: Sirolimus + prednisone
  Intervention: Drug: Sirolimus + prednisone

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); b)Previously treated but inadequately responding after ≤ 16 weeks of initial therapy with prednisone and/or 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 < 12 years). Adults: eCCr (mL/min/1.73 m^2) = (140 - age) x mass (kg) x (0.85 if female)/72 x serum creatinine (mg/dL; 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.

• National Heart, Lung, and Blood Institute (NHLBI)
• National Cancer Institute (NCI)
• Blood and Marrow Transplant Clinical Trials Network