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

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 proportional. BT5528 has a short half-life (0.4-0.7 hours), and the half-life of MMAE is longer (35-47 hours). CONCLUSION BT5528 was well tolerated and demonstrated favorable and preliminary antitumor activity. We believe these data provide preliminary validation of a Bicycle Toxin Conjugate approach to EphA2 tumor antigen. The study is ongoing and is evaluating BT5528 as monotherapy at a RP2D of 6.5 mg/m 2 once every 2 weeks.