Safety, pharmacokinetics, and preliminary activity of the α-specific PI3K inhibitor BYL719: Results from the first-in-human study.
2017
2531 Background: BYL719 is an oral small-molecule inhibitor of the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), which is encoded by the PIK3CA gene, one of the most commonly mutated genes in human cancers. BYL719 inhibits proliferation of PI3Kα-driven cancer cell lines in vitro and causes regression of PIK3CA-mutant tumor models in vivo. Methods: This Ph I study was performed in patients (pts) with advanced solid tumors carrying a somatic mutation of PIK3CA. Dose escalation used an adaptive Bayesian logistic regression model with overdose control. Following determination of the maximum tolerated dose (MTD), an expansion cohort was opened at the MTD to evaluate safety, pharmacokinetics (PK), and clinical activity in pts with PIK3CA-mutant advanced solid tumors, including estrogen receptor-positive (ER+) metastatic breast cancer (mBC). Results: During dose escalation 36 pts received doses up to 450 mg/d, where 4/9 pts had dose-limiting toxicities (DLTs). The MTD for once-daily dosing was...
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