Background: SAR260301 (SAR) is a potent (IC₅₀ 52 nM) PI3Kb inhibitor selectively inhibiting the PI3K pathway in PTEN-null models. This phase I Sanofi sponsored study was initiated to evaluate SAR maximum tolerated dose (MTD), overall safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity in patients with advanced solid tumors. Methods: Patients (pts) with locally advanced/metastatic solid tumors, ECOG PS ≤ 1, and adequate organ function were eligible. PTEN was evaluated in archival tissue by IHC. SAR was orally administered fasted in 28-day cycles. Dose escalation used an overdose control Bayesian strategy. Serial PK sampling was performed on Days 1 and 28 of Cycle (C) 1, and at C2 for food effect evaluation (n = 6). Platelet phospho-AKT (pAKT) was assessed at pre- and post-SAR for PD by MesoScale Discovery. Physiologically based PK modelling (PBPK) was used for exposure predictions. Results: 21 pts were treated at 6 dose levels from 100 mg QD to 800 mg BID. The MTD was not reached. Two DLTs were observed: Gr 3 pneumonitis (400 mg BID) and Gr 3 increase in GGT (600 mg BID). No other Gr ≥ 3 related AE was reported. The most frequent related AEs ( ≥ 3 pts): nausea (3), vomiting (3), and diarrhea (3). SAR absorption was rapid (t_max 0.5-1.5h) and showed a biphasic elimination profile with a rapid decrease in concentration after C_max. No significant accumulation or deviation from dose proportionality was observed. C_max and AUC_tau decreased respectively by 56% and 22% with food. Maximal inhibition of pAKT/tAKT in platelets correlated with exposure at steady state; C_max thresholds for 60% & 80% inhibition were respectively ~ 7 & ~11 µM. Concentrations > 7 µM were reached in 3 pts but for no longer than 2h out of 24h. The PBPK model predicted that doses > 1.2g BID would be needed to reach concentrations sufficient to maintain PD effect between doses. No objective response were documented in this study (3 of 21 pts had PTEN-null disease). Conclusions: SAR has an acceptable safety profile at pharmacologically active doses. However, the rapid clearance of SAR does not allow for sustained pathway inhibition that is required for anti-tumor activity in preclinical models. Clinical trial information: NCT01673737