Azeliragon, a RAGE inhibitor, in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: Preliminary results of phase Ib/II CAN-201 NDG trial.

2069 Background: Azeliragon is an orally available inhibitor of the receptor for advanced glycation end-products (RAGE). RAGE pathway promotes cell proliferation and angiogenesis, contributing to glioblastoma (GBM) progression and resistance to temozolomide (TMZ) and radiation (RT). Azeliragon has extensive clinical safety data in patients (pts) with Alzheimer’s disease. Our hypothesis was that azeliragon may enhance the efficacy of Stupp regimen in newly diagnosed GBM. Methods: CAN-201 NDG is an open-label, single arm, phase Ib/II trial in Spain. Newly diagnosed IDH wild-type pts with GBM, MGMT methylation locally available and with tumor resection were recruited. Pts received azeliragon in combination with standard radiotherapy and TMZ followed by maintenance with azeliragon. The trial consists of an initial dose finding phase in a 6 dose escalation strategy with a subsequent expansion phase (up to 14 additional pts) at the recommended phase 2 dose (RP2D). The dose levels were: 5 mg/day (L1), 10 mg/day (L2) and 20 mg/day (L3). The primary objective is to determine the RP2D, defined as the dose for which < 33% pts experience a dose limiting toxicity (DLT) within 28 days from initiation of dosing. Main secondary endpoints include progression-free survival (PFS), overall survival (OS) and changes in corticosteroid requirements. Results: From Oct 2023 to Jul 2024, 20 pts were included, 6 in L1, 8 in L2 and 6 in L3. The median age was 52 years (range: 40-69). Most pts were male (65%), ECOG 0-1 (95%) and MGMT unmethylated (60%). No DLTs were observed. Serious adverse events, all considered unrelated to azeliragon, were reported in 4 pts (20%), being hemiplegia, pyrexia, infectious meningoencephalitis, epilepsy and neurological decompensation. Non-serious Grade 3-4 adverse events (AE), also considered unrelated, were G3 hematological AEs in 33.3% in L1 and 37.5% in L2. G1-2 azeliragon-related AEs were reported in 33.3%, 25% and 66.7% of pts in L1, L2 and L3, respectively. Azeliragon treatment was ended due to progression in 83.3% and 62.5% of pts in L1 and L2, respectively. All pts on L3 are still on treatment. With a median follow-up time of 8.4 months, pts in L1 showed a median PFS of 5.2 months (95% CI, 4.4-Not Reached [NR]) and 9.8 months (95% CI, 6.2-NR) in L2. No progression of disease was observed in L3 with a range of follow-up of 4.9-7.0 months. Median OS in L1 was 11.1 months (95% CI, 9.4-NR). Data was not mature enough to calculate OS in L2 and L3. Conclusions: Azeliragon in combination with standard RT and TMZ is safe, with no dose-limiting toxicities reported so far at the initial three dose levels. To further explore the safety and efficacy profile of azeliragon, we are now expanding the study to include two additional dose levels of 30 mg/day (L4) and 50 mg/day (L5). Enrollment is currently open for level L4. Clinical trial information: NCT05635734 .