A phase I/II study to assess safety and preliminary evidence of a therapeutic effect of azeliragon combined with stereotactic radiation therapy in patients with brain metastases (ADORATION).

TPS2093 Background: The receptor for advanced glycation end-products (RAGE) is a multifunctional receptor which stimulates proliferation, invasion, resistance to chemotherapy and radiotherapy, and metastatic spread when activated. One of the RAGE ligands preferentially associated with brain metastasis, S100A9, has been recently identified as a specific mediator of radiotherapy resistance. RAGE also mediates neuroinflammatory pathways in the brain associated with peri-tumoral edema and cancer-related cognitive decline. Azeliragon is an oral small molecule agent that crosses the blood-brain barrier and inhibits RAGE interactions with its ligands, including S100A9. Consequently, the purpose of this study is to evaluate a new treatment paradigm with Azeliragon + stereotactic radiosurgery (SRS) for patients with brain metastasis to evaluate the safety and tolerability of the combined approach with the goal of minimizing the use of peri-procedural corticosteroids (loading dose LD and corticosteroid taper CT) as well was evaluating the potential radiosensitizing efficacy of this therapeutic combination. Methods: ADORATION is a single center, open-label, phase I/II cohort expansion trial to determine if azeliragon can be substituted for peri-procedural corticosteroids in patients undergoing SRS for brain metastasis. Eligible adults will have a confirmed cancer diagnosis in the last 5 years, a maximum tumor diameter of the largest brain metastasis ≤ 2 cm, and have discontinued corticosteroids at least 5 days prior to SRS. In phase I (n=up to 9), participants are enrolled into sequential cohorts, starting with azeliragon + SRS + LD. Depending on dose-limiting toxicities (DLTs) within 28 days of SRS, the next cohort will receive azeliragon + SRS alone or azeliragon + SRS + LD + CT. The phase II expansion cohort (n=up to 40 including the phase I cohort) will subsequently open with a primary endpoint of response rate. Azeliragon dosing includes a loading dose for 6 days followed by a continuous dose for at least 8 weeks, and SRS within 7 days of starting drug. Safety endpoints include number of DLTs and number of CNS treatment-related adverse events. Response endpoints include early brain metastasis response at 8 weeks, intracranial response at 6 and 12 months, and lesion specific local control. Neurocognitive batteries, symptom inventories, and quality-of-life questionnaires will also be administered. Three participants have been enrolled in the starting cohort and are pending DLT assessment. Clinical trial information: NCT05789589 .