Investigating belumosudil in children with refractory moderate-to-severe chronic graft-versus-host disease: Design of a phase 1/2 study

Abstract Background: Chronic graft-versus-host disease (cGvHD) is a significant complication in children who have undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT), contributing to long-term morbidity. Belumosudil, a selective rho-associated coiled-coil–containing protein kinase 2 (ROCK2) inhibitor, has demonstrated efficacy in adult cGvHD but pediatric data are lacking. This trial aims to establish the recommended pediatric equivalent dose (RPED) of belumosudil and assess its safety and efficacy in children aged 1 to less than 18 years old. Methods and study design: SchoolROCK is an open-label, multicenter, Phase 1/2, single-arm study investigating a daily orally administered liquid formulation of belumosudil in children with moderate-to-severe cGvHD, which is refractory to or has recurred after 2-5 prior lines of systemic therapy. In Phase 1, participants aged 1 to <12 years will receive a belumosudil dose estimated to mimic the exposure observed in adults after the administration of belumosudil 200 mg tablets once daily. After actual RPED is determined, Phase 2 will assess the overall response rate (ORR) by Week 24 in participants aged 1 to <18 years. Treatment will continue until clinically significant disease progression; relapse of the underlying disease; initiation of new systemic therapy for cGvHD; unacceptable toxicity; or study completion. The study also included a 4-week post-treatment safety follow-up, plus long-term follow-up until death or end of study, whichever occur first. Eligibility Criteria: Key inclusion criteria: Age 1 to <18 years; prior allo-HSCT; moderate-to-severe cGvHD requiring systemic therapy as defined by the 2014 National Institutes of Health (NIH) consensus criteria; prior treatment with 2-5 lines of systemic GvHD therapy; Lansky or Karnofsky performance status ≥60; and body weight ≥8 kg. Key exclusion criteria: Progressive underlying disease; prior exposure to belumosudil; severe pulmonary dysfunction (forced expiratory volume in 1 second ≤39% or lung score of 3); active, uncontrolled infections; significant organ dysfunction; and current use of restricted medications (e.g., strong CYP3A4 inducers, proton pump inhibitors [PPIs] during Phase 1). Participants with progressive underlying disease or post-transplant lymphoproliferative disease within 4 weeks prior to the first dose of belumosudil, active viral hepatitis B and C, history of another malignancy (within 3 years) are excluded. Endpoints:Primary endpoints: RPED determination (Phase 1); ORR by Week 24 (Phase 2)Secondary endpoints: Safety, PK parameters, duration of response, organ-specific response, failure-free survival, overall survival, and time to response Status: The study is in progress. RPED determination in Phase 1 will provide dosing details for Phase 2. Enrollment and follow-ups are also in progress.