CTIM-26. PHASE II STUDY OF AZELIRAGON IN COMBINATION WITH RADIATION THERAPY IN NEWLY DIAGNOSED PATIENTS WITH MGMT-UNMETHYLATED GLIOBLASTOMA

Abstract BACKGROUND Myeloid-derived suppressor cells (MDSCs) exacerbate immunosuppression and immune exhaustion in glioblastoma (GBM) and promote resistance to chemoradiotherapy. Preclinical data demonstrate that inhibiting the receptor for advanced glycation end-products (RAGE) pathway using azeliragon, when combined with radiation therapy (RT), can modulate MDSC accumulation in the tumor microenvironment and improve tumor control. CAN-401 is a phase II study evaluating the safety and preliminary clinical efficacy of combining azeliragon with RT for newly diagnosed IDH-wildtype MGMT-unmethylated glioblastoma (GBM). METHODS This multi-institutional, single-arm, open-label phase II study combines azeliragon with RT (60 Gy/30 fractions). Azeliragon is administered orally with a loading dose of 30 mg twice daily for 6 days before RT, followed by 20 mg daily during and after RT. If more than one dose-limiting toxicity occurs during the safety run-in of 6 patients, additional patients will be treated at de-escalated dose levels using the rolling six design. The study hypothesizes that azeliragon and RT will improve median progression-free survival (PFS) to 9.7 months compared to historical control of 5.7 months, corresponding to a hazard ratio of 0.58. The study aims to enroll 30 evaluable patients. RESULTS From December 2023 to May 2024, 10 patients were enrolled and treated with 20 mg of azeliragon daily, including 6 patients in the safety run-in. No dose-limiting toxicity was observed, hence no dose de-escalation was needed. The most common treatment-related adverse events (AEs) were grade 1, including fatigue and lymphopenia. There were no dose modifications or discontinuations due to treatment-related AEs. Enrollment is ongoing, and updated clinical outcomes will be reported. CONCLUSIONS Azeliragon at 20 mg per day with concurrent RT is well tolerated in patients with GBM. The phase II study is currently enrolling across 8 institutions in the United States (NCT05986851).