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
Bashir, B. Wang, J. S. Falchook, G. Fontana, E. Arkenau, H. T. Carter, Louise Galot, R. Basu, B. Greystoke, A. Subbiah, V.
Bashir, B.
Wang, J. S.
Falchook, G.
Fontana, E.
Arkenau, H. T.
Carter, Louise
Galot, R.
Basu, B.
Greystoke, A.
Subbiah, V.
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Abstract
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.
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Date
2024
Publisher
Collections
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Type
Article
Citation
Bashir B, Wang JS, Falchook G, Fontana E, Arkenau HT, Carter L, et al. 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. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2024 Oct 10;42(29):3443-52. PubMed PMID: 39231383. Epub 2024/09/04. eng.