A phase I dose-escalation study to evaluate GDC-0941, a pan-PI3K inhibitor, administered QD or BID in patients with advanced or metastatic solid tumors.

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3052^ Background: The PI3K-PTEN-AKT signaling pathway is deregulated in a wide variety of cancers. GDC-0941 is a potent, oral, selective pan-inhibitor of class I PI3K with IC50 against the isoforms of p110 ranging from 3 nM (p110α) to 75 nM (p110γ) in vitro. Methods: A 2-stage phase I dose-escalation study (GDC4255g) using a 3+3 design was initiated in patients (pts) with solid tumors to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety of GDC-0941. Stage 2 is an expansion phase at MTD enrolling pts with solid tumors and pts with PIK3CA mutant (mt) breast cancer. GDC-0941 was given on Day 1, followed by a 1-week (wk) washout for single-dose PK and PD markers. GDC-0941 was then dosed QD or BID on a 21/28 schedule. Archival tissue was assayed for PI3K mt/amplification and PTEN status. Results: Forty-nine pts were enrolled in 12 cohorts (15-450 mg) in the QD arm. Thirty-six pts have been enrolled in 8 cohorts in the BID arm at total daily doses (TDD) from 60-450 mg. The MTD was exceeded at 450 mg with dose limiting toxicities (DLT) of grade (Gr) 3 macular rash and Gr 3 asymptomatic T-wave inversion on ECG in the QD arm and Gr 3 thrombocytopenia and Gr 4 hyperglycemia in the BID arm. Other significant drug-related AEs at 450 mg were Gr 3 increased ALT and AST in the BID arm and Gr 3 fatigue in the QD arm. Drug-related AEs reported in ³10% of pts were similar in both arms with nausea, diarrhea, vomiting, fatigue, decreased appetite, dysgeusia, and rash. Two patients have exhibited partial responses (PR) by RECIST: an endocervical cancer (PIK3CA mt E545K) pt treated at 330 mg TDD in the BID arm who also had a 80% decrease in tumor FDG avidity by PET scan and continues on-study > 8 mo and an ER+, HER2- breast cancer pt treated at 130 mg QD who was on-study for ~5 mo. Additional signs of anti-tumor activity include CA-125 responses in 3 pts with ovarian cancer; one with known high PIK3CA gene copy number who was on-study for 15 mo and had a 23% decrease in target lesion by RECIST. Conclusions: GDC-0941 is generally well tolerated administered either QD or BID at doses below 450 mg with similar PK exposures and safety profiles. Clinical activity was observed below 450 mg with 2 PRs by RECIST.