Clinical trial NCT01106833: Chronic Graft-versus-Host Disease Treatment (BMT CTN 0801)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Chronic GVHD
Keywords: Chronic Graft-versus-Host Disease (cGVHD)
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: National Cancer Institute (NCI)
name: Blood and Marrow Transplant Clinical Trials Network
name: National Marrow Donor Program
First posted: 2010-04-20
Enrollment: 151
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Proportion of Participants With Treatment Success
timeFrame: 6 months and 24 months post-randomization
Secondary outcomes:
measure: Percentage of Participants With Overall Survival
timeFrame: 6 months and 24 months post-randomization
measure: Percentage of Participants With Progression-free Survival
timeFrame: 6 months and 24 months post-randomization
measure: Percentage of Participants With Failure-free Survival
timeFrame: 6 months and 24 months post-randomization
measure: Percentage of Participants With Relapse
timeFrame: 6 months and 24 months post-randomization
measure: Percentage of Participants With Secondary Immunosuppressive Therapy Initiated
timeFrame: 6 months and 24 months post-randomization
measure: Percentage of Participants With Discontinuation of Systemic Immunosuppressive Therapy at Two Years
timeFrame: 2 years post-randomization
measure: Prednisone Dose
timeFrame: Baseline, 6 months, and 1 year post-randomization
measure: Change in Prednisone Dose From Baseline
timeFrame: 6 months and 1 year post-randomization
measure: Serum Creatinine Level
timeFrame: Baseline, 6 months, and 1 year post-randomization
measure: Change in Serum Creatinine Level From Baseline
timeFrame: 6 months and 1 year post-randomization
measure: Patient-reported Chronic GVHD Severity
timeFrame: Baseline, 6 months, 1 year, and 2 years post-randomization
measure: Provider-reported Chronic GVHD Severity
timeFrame: Baseline, 6 months, 1 year, and 2 years post-randomization
measure: NIH Consensus Criteria Chronic GVHD Severity
timeFrame: Baseline, 6 months, 1 year, and 2 years post-randomization
measure: SF-36 Physical Component Summary
timeFrame: Baseline, 2 months, 6 months, 1 year, and 2 years post-randomization
measure: SF-36 Mental Component Summary
timeFrame: Baseline, 2 months, 6 months, 1 year, and 2 years post-randomization
measure: FACT-BMT Score
timeFrame: Baseline, 2 months, 6 months, 1 year, and 2 years post-randomization
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: La Jolla
country: United States
facility: University of California San Diego Medical Center
state: California
city: Stanford
country: United States
facility: Stanford Hospital and Clinics
state: California
city: Gainesville
country: United States
facility: University of Florida College of Medicine (Shands)
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Atlanta
country: United States
facility: Blood & Marrow Transplant Program at Northside Hospital
state: Georgia
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Hospital
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University, Barnes Jewish Hospital
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Rochester
country: United States
facility: Mayo Clinic
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Hospital at Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Jewish Hospital BMT Program
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals of Cleveland/ Case Western
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Medical Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health & Science University (A) and (P)
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Western Pennsylvania Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Houston
country: United States
facility: University of Texas/MD Anderson CRC
state: Texas
city: San Antonio
country: United States
facility: Texas Transplant Institute
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University/MCV Hospitals
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
Study officials:
affiliation: Center for International Blood and Marrow Transplant Research
name: Mary Horowitz, MD
role: STUDY_DIRECTOR
References:
citation: Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56. doi: 10.1016/j.bbmt.2005.09.004.
citation: Carpenter PA, Logan BR, Lee SJ, Weisdorf DJ, Johnston L, Costa LJ, Kitko CL, Bolanos-Meade J, Sarantopoulos S, Alousi AM, Abhyankar S, Waller EK, Mendizabal A, Zhu J, O'Brien KA, Lazaryan A, Wu J, Nemecek ER, Pavletic SZ, Cutler CS, Horowitz MM, Arora M; BMT CTN.. A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/ sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801. Haematologica. 2018 Nov;103(11):1915-1924. doi: 10.3324/haematol.2018.195123. Epub 2018 Jun 28.