Azeliragon, a RAGE inhibitor, in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: Phase Ib/II CAN-201 NDG trial design.
Authors: Sepulveda José Manuel , Valiente Manuel , Vaz-Salgado Maria Ángeles , Pineda Estela , Martínez-García María , Ruiz Vico María , Velilla Gabriel , Mazariegos Manuel Alejandro , Valduvieco Izaskun , Castro-Henriques Maria , Cano Laia , Marcus Stephen Garrett 
Published: July 2024

TPS2096 Background: The receptor for advanced glycation end-products (RAGE) and its ligand high mobility group box 1 (HMGB1) promotes cell proliferation, invasion and angiogenesis through mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-κB), and Akt / mTOR signaling pathways and contributes to the rise of glioblastoma (GBM) resistance to temozolomide (TMZ). Direct inhibition of RAGE showed antitumor and antiangiogenic activity in cell-based and animal preclinical models of GBM. Azeliragon, an orally available small molecule RAGE inhibitor with extensive clinical experience in patients with Alzheimer's disease, may overcome TMZ resistance and lead to enhanced efficacy of the Stupp scheme in newly diagnosed GBM. Methods: CAN-201 NDG is an open-label, single arm, phase Ib/II trial in Spain. Newly diagnosed GBM pts will receive azeliragon in combination with standard radiotherapy (RT) / TMZ followed by maintenance with azeliragon monotherapy. Patients should be IDH wild type, have MGMT methylation available locally, ECOG ≤ 2, QTC of ≤ 480 msec, have had a gross total or subtotal resection and be treatment naïve. Corticosteroids are allowed if administered at stable or decreasing doses. Patients with other malignancies within 5 years, presence of active infections and use of CYP 2C8 inhibitors are not allowed. The trial consists of an initial dose finding phase, in which azeliragon is administered at three dose levels in a rolling 6 dose escalation strategy: 5 mg/day (level 1), 10 mg/day (level 2) and 20 mg/day (level 3). Before the start of RT / TMZ, these dose levels have an initial loading dose for 6 days at 15 mg daily, 15 mg twice a day and 30 mg twice a day, respectively. The subsequent expansion phase may include up to 14 additional patients at the recommended phase 2 dose (RP2D). The primary objective is to determine the RP2D, defined as the dose for which <33% patients experience a dose limiting toxicity (DLT) within 28 days from initiation of dosing. DLTs are defined as any grade ≥ 3 non-hematologic adverse event (except non clinically significant investigations, fatigue, nausea or vomiting), dose delays longer than 14 days, dose reductions or limitation to administer >80% of expected doses. Secondary endpoints include disease control, progression-free survival according to RANO criteria, overall survival, changes in Eastern cooperative oncology group (ECOG) performance status and changes in corticosteroid requirements. The predictive and prognostic value of molecular biomarkers such as S100A9 present in blood samples will be assessed by liquid biopsy. The study received regulatory approval and accrual started in September 2023. As of January 2024, recruitment in dose level 1 was completed with 6 patients and 3 patients were already included in dose level 2. Clinical trial information: NCT05635734 .