First-in-Human, Phase I/II Dose Escalation and Expansion Study of Zelenectide Pevedotin in Patients With Advanced Solid Tumors: Results From Monotherapy Dose Escalation

作者：Capucine Baldini, Loïc Verlingue, Vincent Goldschmidt, Bernard Doger de Spéville, Julia Lostes, Antoîne Italiano, Sophie Cousin, Gerald S. Falchook, Andrea Necchi, Òscar Reig, Elisa Fontana, Louise Carter, Jordi Rodón, Jason R. Brown, Leslie R. DeMars, Kate Josephs, Amy L. Dickson, Cong Xu, Justin Bader, Carly Campbell, Rajiv Sharma, Meredith McKean · 发表于：Journal of Clinical Oncology · 年份：2025 · DOI：10.1200/jco-25-00559 · 被引用次数：11 · 研究领域：Cancer therapeutics and mechanisms、Enzyme function and inhibition、Cancer Treatment and Pharmacology

PURPOSE Zelenectide pevedotin (BT8009) is a Bicycle Drug Conjugate comprising a highly selective Nectin-4–targeting Bicycle peptide, linked to monomethyl auristatin E. We report monotherapy dose-escalation results from Duravelo-1 (Phase I/II; ClinicalTrials.gov identifier: NCT04561362 ). METHODS Adults with advanced/metastatic solid tumors associated with Nectin-4 expression received zelenectide pevedotin intravenously at 2.5, 5.0, or 7.5 mg/m 2 once weekly on a 28-day cycle; or 7.5 mg/m 2 on days 1 and 8 of a 21-day cycle; or 7.5 or 10.0 mg/m 2 once every 2 weeks on a 28-day cycle. Primary objectives were to evaluate safety and tolerability; antitumor activity and pharmacokinetic characterization were secondary objectives. RESULTS Forty-nine patients, most with urothelial carcinoma (UC; 25 of 49), received three previous lines of therapy (median). Common treatment-related adverse events (TRAEs) included nausea (49% [grade 3/4 2%]), likely because of a lack of prophylactic antiemetics during the dose-limiting toxicity period, and fatigue (39% [grade 3/4 6%]). The most common TRAEs of clinical interest were peripheral neuropathy (33% [grade 3/4 2%]), neutropenia (22% [grade 3/4 16%]), and skin reactions (22% [grade 3/4 2%]). The maximum tolerated dose was 7.5 mg/m 2 once every 2 weeks; the recommended phase 2 doses were 5.0 mg/m 2 once weekly and 7.5 mg/m 2 on days 1 and 8 of a 21-day cycle. Across doses (efficacy-evaluable; all tumor types), the objective response rate (ORR) ...