Trial in progress: A phase 3, randomized, double-blind, placebo-controlled study of axatilimab and corticosteroids as initial treatment for moderate to severe chronic graft-versus-host disease

Abstract Introduction: Chronic graft-versus-host disease (cGVHD) is an immune-mediated complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) that affects multiple organs with inflammatory and fibrotic pathology. cGVHD occurs in 50% of patients who have received allo-HSCT and is a major cause of morbidity and nonrelapse mortality. Current first-line treatment options, primarily systemic corticosteroids, are often insufficient, as disease recurrence is frequent: 50%–60% of patients progress to second-line therapy within 2 years, and failure-free survival after second-line therapy is approximately 20%. cGVHD is mediated by colony-stimulating factor 1 receptor (CSF-1R) signaling-dependent monocytes and macrophages that lead to tissue damage and organ impairment. Axatilimab, an intravenous anti–CSF-1R monoclonal antibody, was approved by the US Food and Drug Administration for treatment of cGVHD after ≥2 lines of therapy based on results from a phase 2, randomized, open-label, multicenter study (AGAVE-201; NCT04710576) at a dose of 0.3 mg/kg every 2 weeks (Q2W). In AGAVE-201, patients with relapsed/refractory cGVHD achieved an overall response rate (ORR) of 74% with the 0.3 mg/kg Q2W dose, which was generally well tolerated, with adverse events leading to discontinuation occurring in 6% of patients. Aims: To describe the design of a phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy, clinical benefit, and safety of axatilimab in combination with corticosteroids versus corticosteroids alone as first-line therapy for moderate to severe cGVHD (NCT06585774). Methods: Approximately 240 patients will provide informed consent and enroll in this study. Eligible patients are aged ≥12 years with new-onset moderate to severe cGVHD following allo-HSCT. Exclusion criteria include receipt of ≥2 prior allo-HSCT, overlap cGVHD, receipt of any other systemic treatment for cGVHD, or an inability to begin at the starting dose of corticosteroids. Patients will be randomized in a 1:1 ratio to intravenous axatilimab 0.3 mg/kg Q2W or placebo, in combination with prednisone at a starting dose of 1.0 mg/kg/day (or equivalent dose of methylprednisolone or prednisolone), with a recommended tapering schedule starting at Week 2. Treatment will continue until discontinuation criteria are met (eg, disease progression requiring new systemic therapy, unacceptable toxicity, or relapse of primary hematologic disease) for a maximum period of 24 months. If patients achieve protocol-specified response criteria, axatilimab/placebo dosing can be changed to 0.6 mg/kg every 4 weeks or tapered as clinically appropriate. Patients will have a safety follow-up period of up to 30 (±7) days after the last dose of axatilimab/placebo. The primary endpoint is event-free survival. Key secondary endpoints include ORR at 6 months, defined as complete or partial response per 2014 National Institutes of Health consensus criteria, and the proportion of patients with a ≥7-point improvement in modified Lee Symptom Scale total score. Safety will be assessed by monitoring the frequency and severity of adverse events. Trial status: Recruiting.Conclusion: This phase 3 study will provide insight into the efficacy and safety of axatilimab with systemic corticosteroids as first-line therapy for patients aged ≥12 years with moderate to severe cGVHD.