CTLT-04 Safety and Preliminary Evidence of a Therapeutic Effect of Azeliragon Combined With Stereotactic Radiation Therapy in Patients With Brain Metastases: Phase 1 Study Results

Azeliragon is an oral, brain-penetrating small molecule inhibitor of the receptor for advanced glycation end-products (RAGE), reducing neuroinflammation by inhibiting peritumoral edema/vascular leakage and overcoming radiation resistance. This study evaluates the safety and tolerability of azeliragon plus stereotactic radiosurgery (SRS) substituting for peri-procedural corticosteroids (loading dose [LD] and corticosteroid taper [CT]) and assesses potential efficacy of this therapeutic combination. ADORATION (NCT05789589) is a single center, open-label, phase I/II trial enrolling adults with confirmed cancer diagnosis, brain metastasis diameter of ≤2 cm, and who have discontinued corticosteroids for at least 5 days. In phase I, participants were enrolled into sequential cohorts, starting with azeliragon + SRS + LD; depending on dose-limiting toxicities (DLTs). 3 patients were initially treated with azeliragon at 30 mg twice daily for 6 days followed by SRS+LD within 7 days of starting drug then a continuous dose of 20 mg daily for at least 8 weeks. As no DLTs were observed, the second cohort (n=3) was treated with azeliragon and SRS (no LD or CT). For the 6 evaluable patients treated to 46 brain metastases, at data cutoff (1/8/2025), the median follow-up was 4.9 months (3.8-9.4 months) and no DLTs were observed. Early response rate (RR) was assessed at 8 weeks, with a per-patient RANO RR of 100% (partial response [PR] for all 100%), and a per-lesion RANO RR for all RANO-defined target lesions (n=18) of 100% (PR 95.5%, complete response [CR] 4.5%). For all brain metastases treated (n=46) the RR was 93.5% (PR for 69.6% and CR for 23.9%). Neurocognitive function batteries, symptom inventories, and quality of life evaluations remained stable during this assessment period. Azeliragon was safely substituted for corticosteroids in this phase 1 study with no DLTs observed. The early response rate appears encouraging and accrual to the phase II cohort is ongoing.