CTIM-04. A 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) contribute to immunosuppression and treatment resistance in glioblastoma (GBM). A prior phase I study showed that phosphodiesterase-5 inhibition during chemoradiotherapy reduced peripheral MDSCs, particularly in patients with a baseline absolute lymphocyte count (ALC) <2000/mm3. Preclinical data suggest that inhibiting the receptor for advanced glycation end-products (RAGE) pathway with azeliragon, when combined with radiation therapy (RT), modulates MDSC accumulation in GBM and improves tumor control. CAN-401 (NCT05986851) is a phase II study evaluating the safety and preliminary efficacy of azeliragon with RT for newly diagnosed, MGMT-unmethylated GBM. METHODS In this multi-institutional, single-arm, open-label phase II trial, patients with unmethylated GBM received azeliragon with RT (60 Gy/30 fractions) without temozolomide or tumor-treating fields. Azeliragon was administered as a 30 mg BID for six days before RT, followed by 20 mg daily during and after RT. A six-patient safety run-in was conducted, with seamless accrual to a total of 30 patients. The primary hypothesis was that azeliragon plus RT would improve median progression-free survival (PFS) to 9.7 months compared to a historical control of 5.7 months (HR: 0.58). RESULTS From 12/2023 to 9/2024, 35 patients were screened, 30 enrolled, and 29 were evaluable. No dose-limiting toxicities, dose modifications, or discontinuations due to treatment-related adverse events were observed. At a median follow-up of 6.9 months, 22 patients had progressed, and 7 had died. Median PFS was 6.0 months (95% CI: 3.0-9.0), with a 6-month PFS rate of 48%. Patients with baseline ALC <2000/mm3 (n=19) had non-significantly longer PFS than those with ALC ≥2000/mm3 (median PFS 7.2 vs, 4.3 months; 6-month PFS 63% vs, 30%, p=0.18). CONCLUSIONS The combination of azeliragon and RT was well tolerated but did not improve PFS. Patients with lower baseline ALC may benefit from MDSC modulation, warranting further investigation.