PURPOSE: This first-in-human dose-escalation trial evaluated the safety, 
tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), 
pharmacokinetics, pharmacodynamics, and preliminary clinical activity of 
pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I 
phosphatidylinositol-3-kinases (PI3K).
PATIENTS AND METHODS: Sixty patients with solid tumors received pictilisib at 14 
dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 
days and later, using continuous dosing for selected dose levels. 
Pharmacodynamic studies incorporated (18)F-FDG-PET, and assessment of 
phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and 
tumor tissue.
RESULTS: Pictilisib was well tolerated. The most common toxicities were grade 
1-2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash 
(450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile 
was dose-proportional and supported once-daily dosing. Levels of phosphorylated 
serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and 
in tumor at pictilisib doses associated with AUC >20 h·μmol/L. Significant 
increase in plasma insulin and glucose levels, and >25% decrease in (18)F-FDG 
uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A 
patient with V600E BRAF-mutant melanoma and another with platinum-refractory 
epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification 
demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively.
CONCLUSION: Pictilisib was safely administered with a dose-proportional 
pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 
mg and signs of antitumor activity. The recommended phase II dose was continuous 
dosing at 330 mg once-daily.