Background: The PI3K/mTOR pathway has emerged as a potential target for anticancer therapy. Considerable evidence suggests that targeting a single isoform of PI3K (p110α) would have sufficient antitumor activity and improved therapeutic window. Further, PI3KCA mutations, gene encoding isoform p110α, are described in pancreatic adenocarcinoma (PAC). BYL719 is an oral class I α-specific PI3K inhibitor that showed preclinical anti-tumor activity. The first in human phase 1 trial of BYL719 defined the maximum tolerated dose (MTD) at 400mg QD. Methods: This was a phase I, single center study (standard 3+3 design). The primary objective was to determine the MTD of BYL719 in combination with gemcitabine (G) and nab-paclitaxel (nabP) as frontline therapy in locally advanced or metastatic PAC. BYL719 was given orally daily (Table). Patients (pts) were restaged q2 cycles. The study was closed prematurely due to slow accrual. Results: Fifteen pts were enrolled (median age was 58 years). Three pts each participated in cohorts 1 and 2. Nine pts were enrolled in cohort 3, but 4 were replaced (3 pts withdrew consent prior to evaluation and 1 missed > 10 days of treatment). One pt in cohort 3 had DLT related to grade 3 nausea and vomiting. A total of 19 grade 3 and 4 adverse events were records as probably or possibly associated with BYL719. The most common ones were hyperglycemia, anemia, and neutrophil count decreased. One pt developed Posterior reversible encephalopathy syndrome (PRES) during cycle 7. Although we could not completely exclude BYL719 as a cause, PRES was attributed to G. One pt had sudden death during cycle 4 that was attributed to progression. Only 8 pts were evaluable for response. Two had stable disease, 5 had partial responses and 1 had progression. The median progression-free survival and overall survival were 5.36 months (1.6 to 10 months) and 8.74 months (3.8 to 21.2 months) respectively. Conclusions: The combination of full doses of G + nabP and BYL719 can be safely administered up to BYL dose of 250 mg/day. Clinical trial information: NCT02155088