Background: The PI3K-PTEN-AKT signaling pathway is deregulated in a wide variety of cancers. GDC-0941 is a potent inhibitor of class I PI3K and demonstrates broad activity in preclinical xenograft models. Methods: A 2-stage phase I study of GDC-0941 was initiated (GDC4254g). Stage 1 utilized a 3+3 escalation design in patients (pts) with advanced solid tumors. Stage 2 is an expansion phase including pts with multiple myeloma, PIK3CA mutant (mt) tumors, and tumors evaluable by magnetic resonance imaging (MRI) methods. A single dose of GDC-0941 was administered followed by a 1-week washout and then QD dosing on a 21/28- or 28/28-day dose schedule. Objectives include: safety, pharmacokinetics, pharmacodynamic (PD) endpoints in tumor and platelet rich plasma (PRP); evaluating the use of imaging modalities (FDG-PET and functional MRI studies); and examining any relationship of PIK3CA mt status and PTEN expression and clinical activity. Results: Stage 1 has been completed with 42 pts enrolled in 11 cohorts (15-450 mg QD, 21/28-day schedule). Drug-related adverse events (AEs) reported in ≥ 10% of pts were nausea, diarrhea, fatigue, vomiting, dysgeusia, and decreased appetite. The MTD was exceeded at 450 mg with DLT of Grade (Gr) 3 maculopapular rash in 2 pts. Other drug-related AEs ≥ Gr 3 have been Gr 3 fatigue at 450 mg, Gr 3 neutropenia at 330 mg, and Gr 4 hyperglycemia at 130 mg. GDC-0941 displays dose-proportional PK. Decreased levels of pAKT in PRP correlated with GDC-0941 plasma concentrations. Signs of clinical activity include a partial response by RECIST in a pt with melanoma (V600E RAF mt) treated at 330 mg on-study for > 9 mo; a small bowel GIST (cKIT exon 9 mt) pt treated at 450 mg with 49% decrease by FDG-PET on-study for >7 mo; and an ovarian cancer (PTEN negative) pt treated at 100 mg with 30% decrease by FDG-PET, 56% decrease in pS6 staining in paired biopsies, and 80% decrease in CA-125 who was on study for ~5 months. Conclusions: GDC-0941 is generally well tolerated below 450 mg QD with signs of anti-tumor activity. Decreases in the PD markers pAKT and pS6 are consistent with downstream modulation of the PI3K pathway. The potential phase II dose is under evaluation.