Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors

Abstract

Taselisib is a potent and selective tumor growth inhibitor through PI3K pathway suppression. Thirty-four patients with locally advanced or metastatic solid tumors were treated (phase I study, modified 3+3 dose escalation; 5 cohorts; 3-16 mg taselisib once-daily capsule). Taselisib pharmacokinetics were dose-proportional; mean half-life was 40 hours. Frequent dose-dependent, treatment-related adverse events included diarrhea, hyperglycemia, decreased appetite, nausea, rash, stomatitis, and vomiting. At 12 and 16 mg dose levels, dose-limiting toxicities (DLT) were observed, with an accumulation of higher-grade adverse events after the cycle 1 DLT assessment window. Pharmacodynamic findings showed pathway inhibition at ≥3 mg in patient tumor samples, consistent with preclinical <i>PIK3CA</i>-mutant tumor xenograft models. Confirmed response rate was 36% for <i>PIK3CA</i>-mutant tumor patients with measurable disease [5/14: 4 breast cancer (3 patients at 12 mg); 1 non-small cell lung cancer], where responses started at 3 mg, and 0% in patients with tumors without known <i>PIK3CA</i> hotspot mutations (0/15).<b>Significance:</b> Preliminary data consistent with preclinical data indicate increased antitumor activity of taselisib in patients with <i>PIK3CA</i>-mutant tumors (in comparison with patients with tumors without known activating <i>PIK3CA</i> hotspot mutations) starting at the lowest dose tested of 3 mg, thereby supporting higher potency for taselisib against <i>PIK3CA</i>-mutant tumors. <i>Cancer Discov; 7(7); 704-15. ©2017 AACR.</i><i>See related commentary by Rodon and Tabernero, p. 666</i><i>This article is highlighted in the In This Issue feature, p. 653</i>.