Background: PQR is an oral pan-PI3K, mTORC1/mTORC2 inhibitor in clinical development. Methods: A Phase I trial of PQR to evaluate safety, PK and PD in pts with advanced solid tumors was performed, using the standard “3+3” design. Pts with ECOG PS of 0-1 were treated with escalating doses of PQR administered on a once daily continuous dosing schedule (qd). The dose limiting toxicity (DLT) period was the first 21 days of treatment. PK samples were obtained at predefined time points. Blood samples for the evaluation of glucose, insulin and c-peptide as PD markers were obtained at multiple time points. Results: 16 pts (11F:5M) were enrolled as of November 30 2015 and treated at 3 doses of PQR (80, 100 and 120 mg) qd. Median duration of therapy was 50 days (range 7 – 255). Adverse events (AEs) in ≥ 50% pts included fatigue, hyperglycemia, rash, nausea, vomiting, diarrhea and weight loss. Drug related grade 3 AEs seen in more than 1 pt were fatigue, hyperglycemia, rash and elevated transaminases. DLT’s were grade 3 fatique in 3 pts at 120mg and 1 pt at 100mg qd. However, dose interruptions at the 100mg dose indicated that this was not a tolerable dose. Thus the recommended phase II dose (RP2D) and MTD is 80 mg qd. PK analysis shows fast absorption (T_max 1-2h), dose proportionality, an accumulation ratio of about 3.6 and an estimated T_1/2 of 51 hours. Blood PD analysis demonstrated concentration dependent elevations in glucose, insulin and c-peptide within 2 hours after the administration of PQR. One pt with progressing mesothelioma had stable disease (SD) for 8.5 months. One pt each with leiomyosarcoma and ovarian cancer had SD for 3 months. Conclusions: Consistent with an earlier study, the MTD and RP2D of PQR is 80mg qd. Concentration dependent hyperglycemia has been confirmed as a mechanism-based toxicity and will be investigated as a PD marker. The concomittant increase in serum insulin suggests that insulin should not be the initial therapy to manage drug-induced hyperglycemia. Glucose transport inhibitors may be the treatment of choice in management of hyperglycemia. Recruitment in the 80mg qd expansion cohort with a focus on tumors with PI3 kinase pathway aberrations is ongoing. Clinical trial information: NCT02483858