Azeliragon, a RAGE inhibitor, plus temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: Final results from a dose-finding phase in the CAN-201 NDG trial.

2015 Background: Radiotherapy (RT) plus temozolomide (TMZ) is the standard of care for patients (pts) with newly diagnosed glioblastoma (GBM). However, most eventually progress. The RAGE receptor and its ligands may contribute to RT resistance in GBM by sustaining chronic pro-tumorigenic inflammation, enhancing DNA damage repair pathways, and promoting survival signaling in hypoxic and stressed tumor cells. Azeliragon, an extensively studied RAGE inhibitor in Alzheimer’s disease, may enhance overcome RT-TMZ resistance in newly diagnosed GBM. Methods: The CAN-201 NDG is an open-label, single-arm, phase Ib/II trial in Spain recruiting pts with newly diagnosed IDH-wildtype GBM. Pts received azeliragon in combination with standard RT-TMZ, followed by maintenance therapy with azeliragon. The trial consists of an initial dose-finding phase with a rolling six design and a subsequent expansion phase (up to 14 additional pts) at the recommended phase 2 dose (RP2D). The dose levels were 5 (L1), 10 (L2), 20 (L3), 30 (L4), and 50 (L5) mg/day. The primary objective was to determine the RP2D, defined as the dose for which <33% of pts experience dose-limiting toxicity (DLT) within 28 days of the initiation of dosing. Main secondary endpoints include progression-free survival (PFS), overall survival (OS), and changes in corticosteroid requirements. Pharmacokinetic and translational research is ongoing. Results: From Oct 2023 to May 2025, 33 pts were included across L1-L5 levels (6-8 pts per level). Median age was 56 years (range: 36-69). Most pts were male (66.7%), with ECOG 0-1 (93.9%), MGMT unmethylated (54.5%) and complete resection (45.5%). No DLTs occurred, and L5 (50 mg/day) was declared RP2D. One grade 3 maculopapular rash at L5 was the only serious adverse event related to azeliragon. Most common grade 3-4 toxicities were thrombocytopenia (21.2%) and lymphopenia (9.1%), all RT or TMZ-related. Most common possibly azeliragon-related AEs were asthenia (24.2%), nausea (21.2%), anorexia (9.1%), diarrhoea and dysgeusia (6.1% each), all grade 1-2. Median azeliragon treatment duration was 7.4 m (range: 2.7-21.1). Treatment ended due to disease progression (82.8%), toxicity (3.4%), and exitus (3.4%). Three pts at L5 remain on treatment. With median follow-up of 11 m (95% CI: 8.2-16.4), median PFS was 7.9 m (95% CI: 6.2-12.2) overall, 15.6 m (95% CI: 6.1-NR) and 6.7 m (95% CI: 5.0-10.9) for methylated and unmethylated MGMT, respectively. Median OS was not reached, 12m OS rate was 61.5% (95% CI: 4.4-85.3), with rates of 74.2% (95% CI: 52.4-100) and 51.1% (95% CI: 29.3-88.8) for methylated and unmethylated MGMT, respectively. Conclusions: Azeliragon at 50 mg/day in combination with standard RT / TMZ is safe, with no DLTs reported. More mature OS data will be presented. Further follow-up with a larger number of pts is required to assess preliminary efficacy. Clinical trial information: NCT05635734 .