452MO - Early experience with azeliragon, a RAGE inhibitor, in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: Phase Ib/II CAN-201 NDG trial

Background

The receptor for advanced glycation end-products (RAGE) pathway cell proliferation and contributes to the rise of glioblastoma (GBM) resistance to temozolomide (TMZ). Azeliragon (AZE), an orally available RAGE inhibitor with extensive clinical experience in patients (pts) with Alzheimer's disease, may overcome TMZ resistance and lead to enhanced efficacy of the Stupp scheme in newly diagnosed GBM.

Methods

This is an open-label, single arm, phase Ib/II trial in Spain including pts with GBM, IDH wild type, MGMT methylation available locally, treatment-naive, with a gross total or subtotal resection. AZE in combination with standard radiotherapy (RT) / TMZ followed by maintenance with AZE monotherapy. The trial consists of an initial dose finding phase, with 3 dose levels (L) using a rolling 6 dose escalation strategy: 5 mg/day (L1), 10 mg/day (L2) and 20 mg/day (L3). The subsequent expansion phase may include up to 14 additional pts at the recommended phase II dose (RP2D). The primary objective is to determine the RP2D: <33% pts with dose limiting toxicity (DLT). Here we focus on the safety data from the first two dose levels completed.

Results

From Oct 2023 to Mar 2024, 12 pts were included, 6 in both L1 and L2. The median age was 54 years (range: 40-69). Most pts were male (58%) and ECOG 0-1 (92%). No DLTs were observed. Serious adverse events (AEs) were reported in 2 pts (16%), being paralysis and encephalitis. Grade 3 AEs were hematologic AEs in 2 pts (16%), meningo-encephalitis in 1 pts (8%), and hemiplegia in 1 pts (8%). No grade 3 AEs related to AZE were reported. One pts (8%) had asthenia G1 and anorexia G1 and another had transaminitis G1 related to AZE at L1. One pts (8%) had asthenia G2, anorexia G2 and nausea G2 related to AZE at L2. AZE treatment was administered for a median of 2.6 months (95% CI: 0.9 - 3.1). No temporary interruptions were required. All pts completed concomitant phase with RDT administered at a median total dose of 60 Gy. Treatment was discontinued in 3 pts at L1 due to disease progression (PD). All other pts are on treatment, without PD and alive at data cutoff.

Conclusions

AZE was safely administered in the first two dose levels. Recruitment continues in the higher dose level.

Clinical trial identification

EudraCT: 2022-002801-36 / NCT05635734.

Editorial acknowledgement

We acknowledge MFAR Clinical Research staff for their assistance in the development of this abstract.

Legal entity responsible for the study

CANTEX Pharmaceuticals, Inc.

Funding

CANTEX Pharmaceuticals, Inc.

Disclosure

E. Pineda: Financial Interests, Personal, Advisory Role: Novocure, Novartis; Financial Interests, Personal, Speaker’s Bureau: Novocure; Non-Financial Interests, Personal, Leadership Role, President of GEINO: GEINO; Non-Financial Interests, Personal, Membership or affiliation: EANO, GEINO, SEOM. J.M. Sepúlveda: Financial Interests, Personal, Advisory Role: BMS, Cantex Pharma, Servier, MSD; Financial Interests, Personal, Speaker’s Bureau: GSK, Servier; Financial Interests, Personal, Research Funding: Pfizer, CANTEX Pharmaceuticals, IDP Phara, Tilray Pharma; Financial Interests, Personal, Other, Travel, Accomodation expenses: AstraZeneca, Pfizer. M. Valiente: Financial Interests, Personal, Research Funding, The content of the funded research is not connected to the clinical trial presented: AstraZeneca; Non-Financial Interests, Personal, Leadership Role: canSERV IRB, EARC Panel of Reviewers, MRS, EANO, RENACER, ESMO faculty of CNS tumors. M. Martínez-García: Financial Interests, Personal, Advisory Role: Novocure, Boehringer Ingelheim, Gilead, Seagen; Financial Interests, Personal, Speaker’s Bureau: Novocure, Eli Lilly; Financial Interests, Personal, Other, Honoraria: Eli Lilly; Financial Interests, Personal, Other, Honoraria, Travel accommodation expenses: AstraZeneca, Pfizer; Financial Interests, Personal, Other, travel/accommodation expenses: Gilead, Daiichi Sankyo; Financial Interests, Personal, Other, Honoraria (public speaking): Reddy Pharma. M. Ruiz Vico: Financial Interests, Institutional, Research Grant: Astellas Pharma Europe Ltd; Financial Interests, Personal, Research Grant, No financial interest,2-year: Spanish Soctiey of Medical Oncology (SEOM); Financial Interests, Personal, Other, grant for training in translational research in reference centres abroad. Spanish Society of Medical Oncology (SEOM). Awarded in 2018: FSEOM; Non-Financial Interests, Personal, Project Lead: Astellas Pharma Europe Ltd. G. Velilla: Financial Interests, Personal, Other, Invited Speaker: Neuraxpharm Spain S.L. M. Castro-Henriques: Financial Interests, Personal, Advisory Role, 2023: Genomic Health; Financial Interests, Personal, Speaker’s Bureau, 2023: Daiichi, Pfizer; Financial Interests, Personal, Speaker’s Bureau, 2023 & 2024: Novartis; Financial Interests, Personal, Speaker’s Bureau, 2024: Gilead; Non-Financial Interests, Personal, Other, Cooperative group for young oncologists: AstraZeneca; Non-Financial Interests, Personal, Membership or affiliation: ESMO, SEOM, SOLTI; Financial Interests, Personal, Other, Travel expenses and congress assistance: Lilly, Pfizer, Daiichi, Novartis; Financial Interests, Personal, Advisory Role, Advisory for development of a technology platform for patient journey: Roche. S.G. Marcus: Financial Interests, Personal, Full or part-time Employment: CANTEX Pharmaceuticals, Inc.; Financial Interests, Personal, Leadership Role: CANTEX Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks or ownership: CANTEX Pharmaceuticals, Inc.; Financial Interests, Personal, Other, Honoraria: CANTEX Pharmaceuticals, Inc.; Financial Interests, Personal, Advisory Role: CANTEX Pharmaceuticals, Inc.; Financial Interests, Personal, Other, Travel, Accomodation expenses: CANTEX Pharmaceuticals, Inc.; Financial Interests, Personal, Research Funding: CANTEX Pharmaceuticals, Inc.; Financial Interests, Personal, Royalties: CANTEX Pharmaceuticals, Inc. All other authors have declared no conflicts of interest.