Background: BI 860585 is a potent, selective ATP-competitive mTOR serine/threonine kinase inhibitor which has shown preclinical activity against various cancer types. This Phase I trial (NCT01938846) aims to determine the maximum tolerated dose (MTD) of BI 860585 as a single agent or combined with exemestane or paclitaxel in patients (pts) with advanced solid tumors. Methods: This study used a 3+3 design in 3 treatment arms (all in 28-day cycles): single-agent BI 860585 (5–300 mg/day; Arm A), BI 860585 (40–220 mg/day) combined with fixed-dose exemestane (25 mg/day; Arm B), and BI 860585 (80–160 mg/day) combined with paclitaxel (60 or 80 mg/m²/week; Arm C). MTD is defined as the highest dose at which ≤ 1 out of 6 pts experience a dose-limiting toxicity (DLT) during cycle 1. Results: To date, 41 pts have been treated in Arm A, 24 in Arm B and 17 in Arm C. DLTs have been observed in (n DLTs/n evaluable): 4/36 pts, and 4/20 pts in Arm A and B, respectively. No DLT has occurred in 12 pts in Arm C. DLTs (all grade 3) were diarrhea, rash and alanine/aspartate aminotransferase increased in Arm A; and stomatitis and rash in Arm B. The MTD was determined as 220 mg/day in Arm A. The most frequent treatment-related adverse events (AEs) have been: hyperglycemia (54%), diarrhea (39%) and nausea (37%) in Arm A; hyperglycemia (38%), diarrhea and rash (both 33%) in Arm B; and hyperglycemia (53%) and fatigue (47%) in Arm C; the majority of AEs were Grade ≤ 2. No Grade 5 treatment-related AEs were observed. Preliminary best response data showed stable disease (SD) in Arm A (n = 18), SD (n = 6) and partial response (PR; n = 4) in Arm B, including a breast cancer pt pretreated with an mTORC1 inhibitor and exemestane, and SD (n = 8) and PR (n = 1) in Arm C. Disease control rates (PR+SD) were 44% in Arm A, 46% in Arm B and 59% in Arm C. Preliminary PK analysis showed linear PK with no food effect and no drug-drug interaction with exemestane or paclitaxel. Conclusions: MTD was determined as 220 mg/day for BI 860585 monotherapy. At MTD, AEs were mild-to-moderate and consistent with the mode of action of the compound. Early signs of efficacy were observed in varied tumor types with BI 860585 monotherapy and in combination. The study is ongoing. Clinical trial information: NCT01938846