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).

Abstract

2022 Background: 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. The primary objective of this study is to evaluate the safety and tolerability of azeliragon plus stereotactic radiosurgery (SRS) for patients with brain metastasis substituting for peri-procedural corticosteroids (loading dose [LD] and corticosteroid taper [CT]) and secondarily to assess the potential efficacy of this novel therapeutic combination. Methods: ADORATION (NCT05789589) is a single center, open-label, phase I/II trial. Eligible adults have a confirmed cancer diagnosis within 5 years, maximum brain metastasis diameter of ≤2 cm, and have discontinued corticosteroids at least 5 days prior to SRS. In phase I, participants were enrolled into sequential cohorts, starting with azeliragon + SRS + LD; depending on dose-limiting toxicities (DLTs), the next cohorts could be either azeliragon + SRS or azeliragon + SRS + LD + CT. A DLT was defined as any CNS-specific Grade ≥ 2 toxicity requiring corticosteroid treatment or any Grade ≥ 3 events not clearly due to the underlying disease or extraneous causes. Results: In the completed phase 1 portion, 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 of 3 patients was treated with azeliragon and SRS without any corticosteroids (LD or CT). Of the 6 evaluable patients treated to 46 brain metastases, the most common primary histology was lung adenocarcinoma (n = 4). 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) to the combination therapy was assessed at week 8, 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 the 8-week early assessment period. Conclusions: 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 expansion cohort (n = 40) with a primary endpoint of objective response rate is ongoing. Clinical trial information: NCT05789589 .