A Phase II Study of Azeliagon in Combination With Radiation Therapy in Newly Diagnosed Patients With MGMT-Unmethylated Glioblastoma

Document Type

Conference Proceeding

Publication Date

11-2025

Publication Title

Neuro-Oncology

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.

Volume

27

Issue

Suppl 5

First Page

v114

Last Page

v114

Comments

World Federation of Neuro-Oncology Societies AND Society for NeuroOncology Annual Meeting, November 19-23, 2025, Honolulu, HI

DOI

10.1093/neuonc/noaf201.0461

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