Biomarker research
First-in-human phase Ia study of the covalent TEAD palmitoylation inhibitor BPI-460372 in patients with advanced solid tumors: pharmacokinetics, exposure-limited dosing, and early antitumor activity
By Liang H, Xu Y, Zhao J and 7 others.
Abstract
Background
The Hippo pathway is a critical regulator of tumor development and progression, dysregulation of the Hippo pathway drives tumorigenesis in multiple malignancies. BPI-460,372 is a first‑in‑class covalent irreversible inhibitor of transcriptional enhanced associated domain (TEAD) palmitoylation. This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of BPI-460,372 in patients with advanced solid tumors.
Methods
This open-label, multicenter, single-arm phase Ia dose-escalation study enrolled patients with advanced solid tumors who had progressed after standard therapies or lacked available standard treatment options. A modified 3 + 3 design with accelerated titration was used. BPI-460,372 was administered orally once daily under fasting conditions, with dose escalation from 10 mg to 240 mg daily. Additional cohorts evaluated twice-daily dosing (80 mg and 120 mg) and postprandial administration (80 mg and 160 mg) to characterize exposure optimization strategies. Primary endpoints were safety, tolerability, dose-limiting toxicities (DLTs), and the maximum tolerated dose (MTD). Secondary endpoints included pharmacokinetics (PK) and preliminary antitumor efficacy. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; modified criteria were applied for malignant pleural mesothelioma.