Background: The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is dysregulated in many malignant diseases. LY3023414 (LY) is an oral ATP competitive inhibitor of the class I PI3K isoforms, mTOR and DNA-PK. Based on preclinical results, we investigated LY in patients with advanced solid tumors. Methods: In this 3+3 dose escalation phase I study, patients with solid tumors refractory to standard therapies received LY once daily (QD) or twice daily (BID). The primary objective was to determine a recommended phase II dose (RPTD). Additional objectives were to assess LY dosing safety, pharmacokinetic/pharmacodynamic (PK/PD) profiles, drug-drug interaction with midazolam, and to document anecdotal antitumor activity. Results: As of September 2014, 47 pts have received LY either QD (at 20, 40, 80, 150, 225, 325, 450 mg) or BID (at 150, 200, 250 mg). Dose-limiting toxicities (DLTs) have been observed for LY QD only at 450 mg and consisted of grade [G] 4 thrombocytopenia, G4 hypotension, G3 hyperkalemia in 3/3 patients treated. For BID dosing, DLTs were observed in 3/4 patients at 250 mg (G4 hypophosphatemia, G3 fatigue, G3 mucositis) and in 1/15 patients at 200 mg (G2 nausea). Common treatment-related adverse events (all grades) included nausea (38%), fatigue (31%), vomiting (27%), and diarrhea (17%). PK analyses showed a dose-proportional increase in LY exposures (AUC) at tolerated dose levels with a half-life of 1.9 hours and a body clearance of 85 L/hr. Midazolam PK data indicated that LY is a weak inhibitor of CYP3A4. Biomarker assessment demonstrated dose-related target inhibition in peripheral mononuclear cells at LY doses ≥ 150 mg. Durable partial response according to RECIST was observed in an endometrial cancer patient harboring PIK3R1 and PTEN mutations and 22 additional patients (47%) had stable disease as their best response. Conclusions: LY appears to be safe when administered as single agent up to 325 mg QD or 200 mg BID. The RPTD of single-agent LY is 200 mg BID based on safety, tolerability, and PK/PD data. LY is currently studied in tumor-specific expansion cohorts for mesothelioma, breast cancer, indolent Non-Hodgkin Lymphoma and squamous NSCLC. Clinical trial information: NCT01655225