Results From First-in-Human Phase I Dose-Escalation Study of a Novel Bicycle Toxin Conjugate Targeting EphA2 (BT5528) in Patients With Advanced Solid Tumors

作者：Babar Bashir, Judy S. Wang, Gerald S. Falchook, Elisa Fontana, Hendrik‐Tobias Arkenau, Louise Carter, Rachel Galot, Bristi Basu, Alastair Greystoke, Vivek Subbiah, Debra L. Richardson, Hanna Orr, Gavin Bennett, Rajiv Sharma, Hongmei Xu, Paola Paganoni, Cong Xu, Carly Campbell, Meredith McKean · 发表于：Journal of Clinical Oncology · 年份：2024 · DOI：10.1200/jco.23.01107 · 被引用次数：23 · 研究领域：Axon Guidance and Neuronal Signaling、Hippo pathway signaling and YAP/TAZ、Angiogenesis and VEGF in Cancer

PURPOSE BT5528 is a Bicycle Toxin Conjugate, a novel class of chemically synthesized molecules, comprising a bicyclic peptide targeting EphA2 tumor antigen, linked to a cytotoxin (monomethyl auristatin E [MMAE]). EphA2 is overexpressed in many solid tumors and contributes to oncogenesis, tumor-associated angiogenesis, and metastasis. MATERIALS AND METHODS The primary objectives were to investigate the safety and tolerability of BT5528 and to define the maximum-tolerated dose, if observed, and recommended phase II dose (RP2D)/expansion dose. Dose escalation exploring once every week or once every 2 weeks administration of BT5528 employed a 3 + 3 dose-escalation design for the first two dose levels, followed by a Bayesian logistic regression model. Secondary and exploratory end points included preliminary efficacy and the pharmacokinetics of BT5528 and MMAE. RESULTS Forty-five patients were enrolled and received BT5528 doses between 2.2 mg/m 2 once every week to 10.0 mg/m 2 once every 2 weeks within the dose-escalation stage of the study. The most frequent BT5528-related adverse events (AEs) were nausea (44.4%), diarrhea (35.6%), and fatigue (33.3%), and the most common grade ≥3 BT5528-related AE was neutropenia/neutrophil count decrease (22.2%). Dose level 6.5 mg/m 2 once every 2 weeks was selected as a RP2D. At 6.5 mg/m 2 once every 2 weeks, the overall response rate was 6.7%, and the disease control rate was 20.0%. BT5528 and MMAE pharmacokinetics are generally dose proporti...