First-in-human phase I study of BPI-9016M, a dual MET/Axl inhibitor, in patients with non-small cell lung cancer

作者：Xingsheng Hu, Xin Zheng, Sheng Yang, Lin Wang, Xuezhi Hao, Xinge Cui, Lieming Ding, Li Mao, Pei Hu, Yuankai Shi · 发表于：Journal of Hematology & Oncology · 年份：2020 · DOI：10.1186/s13045-019-0834-2 · 被引用次数：25 · 研究领域：Liver physiology and pathology、Phagocytosis and Immune Regulation、FOXO transcription factor regulation

Abstract Background BPI-9016M is a novel small-molecule inhibitor that simultaneously targets both c-Met and AXL tyrosine kinases. This phase I study aimed to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of BPI-9016M in Chinese patients with advanced non-small cell lung cancer (NSCLC). Methods Over the dose range of 100 mg to 800 mg, eligible patients were administered with a single dose of 9016M tablet and received 7 days of pharmacokinetics evaluation, followed by continuous dose administration (QD dosing, 28 days). Standard “3 + 3” dose escalations were performed. Results Twenty NSCLC patients were treated. All patients experienced at least one adverse event (AE), of which treatment-related adverse events (TRAEs) were reported in 17 (85.0%) patients. The most common TRAEs were alanine transaminase (ALT) elevation (60%), bilirubin increased (40%), dysgeusia (40%), constipation (30%), hypertension (25%), and palmar-plantar erythrodysesthesia syndrome (15%). The TRAEs of grade 3 or higher during treatment were hypertension (15%), pulmonary embolism (5%), and laryngeal pain (5%). No dose-limiting toxicity (DLT) was observed, and the MTD was not reached. The median time to C max ranged from 2.0 to 3.5 h, and the plasma concentration of BPI-9016M declined rapidly after T max fitting a single-compartment model. The mean AUC 0–72 h of M1 and M2-2, main metabolites of BPI-9016M, were 4.8–6.6 folds and 4.1–9.8 folds higher than that of...