A first-in-human phase I study to evaluate the pan-PI3K inhibitor GDC-0941 administered QD or BID in patients with advanced solid tumors.

Abstract

2541 Background: The PI3K-PTEN-AKT signaling pathway is deregulated in a wide variety of cancers. GDC-0941 is a potent and selective oral pan-inhibitor of the class I PI3K, which demonstrates broad activity in breast, ovarian, lung, and prostate cancer in in vitro and in vivo (xenograft) models. Methods: A phase I dose-escalation study using a 3+3 design was initiated in patients (pts) with solid tumors to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety characteristics of GDC-0941. GDC-0941 was given on day 1, followed by a 1-week (wk) washout to study single-dose PK and PD markers. GDC-0941 was then dosed QD on a 3-wks on, 1-wk off, schedule. Steady-state PK and PD were evaluated after 1 wk of continuous dosing. A separate concurrent dose-escalation arm with BID dosing was initiated after the third QD cohort. Results: Thirty-six pts have been enrolled in 9 successive dose-escalation cohorts in the QD arm, with dose levels up to 245 mg daily. Twenty-three pts have been enrolled in 8 cohorts in the BID arm at total daily doses (TDD) up to 180 mg daily. Day 1 and day 15 PK data suggest GDC-0941 is rapidly absorbed and displays dose-proportional increases in mean Cmax and AUC0-inf, with a mean apparent half-life that supports either QD or BID dosing regimens. The most frequently reported drug-related adverse events were grade (Gr) 1–2 nausea, fatigue, diarrhea, and dysgeusia. Three dose-limiting toxicities have been reported: Gr 3 headache at 80 mg QD, Gr 3 pleural effusion at 80 mg TDD, and Gr 3 decreased DLCO at 180 mg TDD . A partial response has been observed in one breast cancer pt (130 mg QD) by RECIST. Other signs of anti-tumor activity have also been observed in 3 ovarian pts: one (30 mg BID) was on-study >450 days with a best response of 23% decrease in measured disease and 2.8-fold decrease in CA-125, the second (60 mg QD) was on-study >170 days with stable disease (SD) and the third (130 mg TDD) was on study for >230 days with SD. Analysis of archival tissue for PI3K pathway alterations is ongoing. Conclusions: GDC-0941 is generally well tolerated, with signs of antitumor activity. Preliminary PK data suggest dose-proportional increases in exposure across the dose levels evaluated. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Roche Genentech