Background: PQR309 is a novel, orally bioavailable, balanced pan-PI3K, mTORC1 and mTORC2 inhibitor. Methods: An accelerated 3+3 DE, open label Phase 1 trial of continuous once daily (OD) PQR309 to evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD) in pts with advanced solid tumours was performed. Pts had no standard therapeutic options. An expansion cohort at maximum tolerated dose (MTD) is planned. The starting dose of PQR309 was 10mg OD. The dose limiting toxicity (DLT) period was the first cycle of treatment, 21 days (d). Paired tumour biopsies (PTB) were collected. Results: 25 pts (18F:7M) were enrolled as of January 2015 and treated at 11 doses ranging from 10-150mg. Common adverse events (AE) ( ≥ 30% pts) included fatigue, hyperglycaemia, nausea, diarrhea, constipation, rash, anorexia and vomiting. Grade (G) 3/4 drug-related AE were seen in 11 and 3 pts respectively. The most common drug-related AE ≥ G3 was hyperglycaemia observed in 7 pts. DLT occurred in 2/6 pts at 100mg OD associated with sequential AE G2-4; one patient (pt) with > 14d interruption in PQR309 due to G2-4 rash, hyperbilirubinaemia, suicide attempt and one pt with dose reduction to 80 mg due to G2-3 fatigue, diarrhea, transaminitis, both during cycle 1. Preliminary PK shows fast absorption (T_max 1-2h), dose proportionality for C_max and AUC and an estimated T_1/2 of around 20 hours, consistent with PQR309 in vivo models. Preliminary PD analysis of 16 phosphoproteins (PP) involved in PI3K/mTOR/MAPK signalling in PTB shows marked decrease of p-Akt, pS6 and p4EPB from 40mg OD with moderate inhibition of p-Erk. A partial response (PR) in a pt with metastatic thymus cancer (ca) and RICTOR gene amplification, 24% disease volume reduction in a pt with sinonasal ca and PIK3CA E545K mutation and stable disease for over 16 weeks in a pt with clear cell Bartholin’s gland ca have been observed. Conclusions: The MTD and recommended phase-2 dose of PQR309 is 80mg OD. PD shows PI3K pathway PP downregulation in PTB and PK is dose-proportional. Clinical activity including a PR has been observed in pts with known PI3K pathway dysregulation. Recruitment in the 80mg and planned expansion cohort is ongoing. Clinical trial information: NCT01940133