Background: BYL719 is an oral small-molecule inhibitor of the p110α catalytic subunit of phosphatidylinositol 3-kinase(PI3K),which is encoded by the PIK3CA gene,one of the most commonly mutated genes in human cancers.BYL719 inhibits proliferation of PI3Kα-driven cancer cell lines in vitro and causes regression of PIK3CA-mutant tumor models in vivo.Methods: This Ph I study was performed in patients(pts)with advanced solid tumors carrying a somatic mutation of PIK3CA.Dose escalation used an adaptive Bayesian logistic regression model with overdose control.Following determination of the maximum tolerated dose(MTD),an expansion cohort was opened at the MTD to evaluate safety,pharmacokinetics(PK),and clinical activity in pts with PIK3CA-mutant advanced solid tumors,including estrogen receptor-positive(ER+)metastatic breast cancer(mBC).Results: During dose escalation 36 pts received doses up to 450 mg/d,where 4/9 pts had dose-limiting toxicities(DLTs).The MTD for once-daily dosing was declared as 400 mg/d.As of Nov 20 2012,DLTs were hyperglycemia,nausea,vomiting,and diarrhea.The most common BYL719-related adverse events(all grades,all cohorts,>25%)were hyperglycemia(49%),nausea(45%),diarrhea(40%),decreased appetite(38%),vomiting(30%),and fatigue(27%).39 pts are enrolled in the MTD dose-expansion cohort.Investigation of a twice-daily regimen is also ongoing.BYL719 has a favorable,approximately dose-proportional PK profile with a Tmax of 2h and a T1/2 of 11h at the MTD.Partial responses were seen in 7 pts(in ER+ breast [2],cervical,trichilemmal,endometrial,ovarian,and head &neck cancer [1 each]); 17 pts stayed on study for >24 weeks.For 67 pts(76%)treated at doses of ≥270 mg/d,the median progression-free survival(mPFS)was 3.6 months(mo; 95%CI: 3.5–5.5 mo).mPFS in 15 ER+ HER2– mBC pts treated at ≥270 mg/d was 5.5 mo(95%CI: 3–7 mo).Conclusions: BYL719 displays dose-proportional and predictable PK.The safety profile is favorable,with mostly manageable on-target toxicities.At doses of ≥270 mg/d,tumor regression and prolonged disease control were observed in heavily pretreated pts with various tumor types carrying a PIK3CA mutation.