Presented at the 2026 ASCO Annual Meeting, Maria Martinez Garcia reported final results from the dose-finding phase of the CAN-201 NDG trial, evaluating azeliragon, a RAGE inhibitor, in combination with standard radiotherapy and temozolomide for patients with newly diagnosed glioblastoma.
Glioblastoma remains one of the most difficult primary brain tumors to treat. Standard first-line therapy includes maximal safe surgery followed by radiotherapy and temozolomide, but most patients eventually experience disease progression. This creates a major need for strategies that can improve the effectiveness of standard chemoradiotherapy.
The CAN-201 NDG trial explored whether targeting the RAGE receptor could help overcome resistance to radiotherapy and temozolomide in newly diagnosed glioblastoma.
Why RAGE Inhibition Is Being Studied in Glioblastoma
The RAGE receptor and its ligands may contribute to radiotherapy resistance in glioblastoma through several tumor-supporting mechanisms. These include chronic pro-tumorigenic inflammation, enhanced DNA damage repair pathways, and survival signaling in tumor cells exposed to hypoxia and stress.
Azeliragon is a RAGE inhibitor that has previously been extensively studied in Alzheimer’s disease. In this trial, investigators evaluated whether azeliragon could be safely combined with standard radiotherapy and temozolomide in patients with newly diagnosed IDH-wildtype glioblastoma.
CAN-201 NDG Trial Design
CAN-201 NDG is an open-label, single-arm, phase Ib/II trial conducted in Spain. The study enrolled patients with newly diagnosed IDH-wildtype glioblastoma.
Patients received azeliragon together with standard radiotherapy and temozolomide, followed by maintenance azeliragon therapy.
The trial included an initial dose-finding phase using a rolling six design, followed by a planned expansion phase of up to 14 additional patients at the recommended phase II dose.
Five azeliragon dose levels were evaluated: 5 mg/day, 10 mg/day, 20 mg/day, 30 mg/day, and 50 mg/day.
The primary objective was to determine the recommended phase II dose. This was defined as the dose at which fewer than 33% of patients experienced a dose-limiting toxicity within 28 days after starting treatment.
Secondary endpoints included progression-free survival, overall survival, and changes in corticosteroid requirements. Pharmacokinetic and translational analyses are ongoing.
Patient Population
From October 2023 to May 2025, the dose-finding phase enrolled 33 patients across the five dose levels, with 6 to 8 patients included at each level.
The median age was 56 years, with a range of 36 to 69 years. Most patients were male, accounting for 66.7% of the study population. ECOG performance status was 0–1 in 93.9% of patients.
MGMT promoter status showed that 54.5% of patients had unmethylated MGMT, a subgroup generally associated with poorer response to temozolomide-based treatment. Complete resection had been achieved in 45.5% of patients.
Safety Findings and Recommended Phase II Dose
No dose-limiting toxicities were reported across the dose levels tested. Based on these findings, azeliragon 50 mg/day was declared the recommended phase II dose.
Only one serious adverse event related to azeliragon was reported: a grade 3 maculopapular rash at the 50 mg/day dose level.
The most common grade 3–4 toxicities were thrombocytopenia, reported in 21.2%, and lymphopenia, reported in 9.1%. These events were attributed to radiotherapy or temozolomide.
The most common adverse events considered possibly related to azeliragon were mostly low grade. These included asthenia in 24.2%, nausea in 21.2%, anorexia in 9.1%, and diarrhea and dysgeusia in 6.1% each. All of these events were grade 1–2.
The median duration of azeliragon treatment was 7.4 months, with a range of 2.7 to 21.1 months.
Treatment was discontinued mainly because of disease progression, which occurred in 82.8% of patients. Treatment ended due to toxicity in 3.4% and due to death in 3.4%. Three patients treated at the 50 mg/day dose level remained on treatment at the time of analysis.
Early Efficacy Signals
At a median follow-up of 11 months, the median progression-free survival in the overall population was 7.9 months.
Outcomes differed by MGMT status. Median progression-free survival was 15.6 months in patients with MGMT-methylated tumors and 6.7 months in those with MGMT-unmethylated tumors.
Median overall survival had not yet been reached at the time of reporting. The 12-month overall survival rate was 61.5% in the overall study population.
By MGMT status, the 12-month overall survival rate was 74.2% among patients with MGMT-methylated disease and 51.1% among those with MGMT-unmethylated disease.
Why This Matters
The dose-finding phase of CAN-201 NDG shows that azeliragon can be combined with standard radiotherapy and temozolomide in newly diagnosed IDH-wildtype glioblastoma without dose-limiting toxicity.
The recommended phase II dose was established at 50 mg/day, and the safety profile appeared manageable. Most higher-grade toxicities were related to radiotherapy or temozolomide rather than azeliragon.
The early efficacy findings are preliminary, especially because this was a small, single-arm dose-finding study. However, the progression-free survival data and 12-month overall survival rates provide a basis for continued evaluation, particularly as more mature survival data become available.
These results support further follow-up and expansion of CAN-201 NDG to better understand whether RAGE inhibition can meaningfully improve outcomes when added to standard chemoradiotherapy in newly diagnosed glioblastoma.
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