Background: BKM120 is a pan-PI3K inhibitor with demonstrated activity in advanced solid tumors. The primary aim of this study was to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of BKM120 + BEV. Secondary objectives included safety, efficacy, and biomarker discovery. Methods: This was a 3+3 dose escalation study of BKM120 (60-100 mg/day (d)) + BEV (10 mg/kg every 2 weeks). After the MTD was defined, 14 pts were accrued to the expansion cohort. Results: A total of 32 pts were accrued (5 treated at 60 mg/d, 19 at 80 mg/d (2 remain on therapy), 6 at 100 mg/d, and 2 never received therapy). The majority had clear cell histology (88%) and 50% had ≥2 prior lines of systemic therapy. The MTD of BKM120 was 80 mg/d. With the exception of 1 case of cognitive disturbance deemed related to both agents, all DLTs (Table 1) were attributed to BKM120. 28 pts discontinued therapy: 16 due to progression, 7 dueto toxicity, 1 due to death, and 4 due to other reasons. Toxicity leading to therapy discontinuation included rash/pruritis, transaminitis, elevated lipase/amylase, suicidal ideation, and cognitive disturbances. Of the 30 pts who received at least 1 dose, 13% had a partial response (PR) (95% CI 4%, 31%), 50% had stable disease (SD), and 20% had progressive disease (PD). Of the 19 pts treated at the MTD, 11% had a PR (95% CI 1%, 33%), 53% had SD, and 16% had PD. The median time-to-treatment failure (TTF), progression-free survival (heavy censoring) and overall survival were 4 (95% CI 2, 9), 9 (95% CI 2, 9), and 18 (95% CI 4, not reached) months (mos) for the total cohort and 4 (95% CI 2, 9), 6 (95% CI 2, 9), and 13 (95% CI 5, not reached) mos for pts treated at the MTD, respectively. Of the 9 pts evaluated, 2 had activating PI3K mutations. One achieved a PR (TTF 13 mos) and the other achieved SD with 16% tumor shrinkage (TTF 9 mos). Conclusions: BKM120 at 80 mg/d + BEV was a tolerable regimen with preliminary activity in VEGF-refractory mRCC. Clinical trial information: NCT01283048

*≥1 CTCAE grade level increase defined as DLT.