Background: The PI3K-AKT-mTOR signaling pathway is deregulated in a wide variety of cancers. GDC-0980 is a potent, selective, oral inhibitor of class I PI3K and mTOR kinase with in vitro IC₅₀ of 4.8 nM for p110α/p85α and apparent Ki of 17.3 nM for human mTOR. GDC-0980 demonstrates broad activity in xenograft cancer models (breast, ovarian, lung, and prostate). Methods: A phase I dose-escalation study (PIM4604g) using a 3+3 design was initiated in patients (pts) with solid tumors. GDC-0980 was given on Day 1, followed by 1 wk washout to study single-dose pharmacokinetic (PK) and pharmacodynamic (PD) markers. GDC-0980 was then dosed QD on a 21/28-day schedule. Steady-state PK and PD were evaluated after 1 wk of QD dosing. Objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT), evaluate PD endpoints (pAKT in platelet-rich plasma [PRP] and tumor FDG avidity by PET scan [FDG-PET]), and describe anti-tumor activity. Results: Thirty-three pts have been enrolled in 7 cohorts (2-70 mg QD). GDC-0980 demonstrates dose-proportional increases in fasting mean Cmax and AUC. Preliminary PD data show >90% inhibition of pAKT levels assayed in PRP at ≥16 mg GDC-0980. Drug-related adverse events reported in ≥10% of pts were fatigue, diarrhea, decreased appetite, nausea, rash, mucositis, hyperglycemia, vomiting, and constipation. The MTD was exceeded at 70 mg with DLT of Grade (Gr) 3 maculopapular rash and symptomatic Gr 3 hyperglycemia. Three pts at 70 mg experienced Gr 2-3 pneumonitis at the end of Cycle 2. One pt at 70 mg developed Gr 3 mucositis in Cycle 2. In all cases, symptoms associated with pneumonitis resolved with drug cessation and medical management. Anti-tumor activity was observed in 3 pts with mesothelioma treated at 8, 32, or 50 mg with 23 to 28% decreases by RECIST. Five of 6 patients evaluated by FDG-PET had a response (29 to 64% decreases) by SUVmax. A pt with GIST treated at 50 mg obtained a 58% decrease in tumor FDG-PET and continued on-study for >6 mo and a pt with adrenal cell carcinoma pt continues on-study for >1 year. Conclusions: GDC-0980 is generally well tolerated at doses below 70 mg QD. PK data support QD dosing. PD and anti-tumor activity were observed.