A phase I/II, first-in-human dose-escalation study of GSK2636771 in patients (pts) with PTEN-deficient advanced tumors.

2514^ Background: GSK2636771 is a potent, orally bioavailable and selective inhibitor of PI3Kβ (0.89 nM), with >900-fold selectivity over PI3Kα/PI3Kγ and >10-fold over PI3Kδ. It inhibits AKT phosphorylation and downstream signalling measured as decrease of PRAS40-, GSK3β-, and RPS6-phosphorylation in PTEN mutant cell lines. Methods: An ongoing phase-I/IIa FTIH, open label dose escalation study of GSK2636771, once daily (QD), is being conducted to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy in pts with advanced tumors deficient in PTEN. The study comprised 3 parts: starting-dose selection, 3+3 dose escalation and phase-2 expansion. Backfill cohorts with mandatory, paired biopsies were opened to evaluate PD. The DLT period was 28 days. Results: As of 01/2014, 53 pts (35 m: 18 f, mean 60 yrs) were enrolled into 7 dose escalation (25 -500 mg) and 4 PD cohorts (50-350 mg). In total 5 DLTs (3x hypophosphatemia/ 2x hypocalcemia G3) were observed in 3 pts at 500 mg, defining MTD. AE...