Background: TAS-116 is an oral non-ansamycin, non-purine, and non-resorcinol highly selective inhibitor of HSP90α/β. The objective of this FIH study was to determine the MTD and investigate the safety, tolerability, PK, PD (HSP70 protein levels in PBMCs), and antitumor activity of TAS-116. Methods: The study is being conducted in Japan and the UK. Patients with advanced solid tumors received escalating doses of TAS-116 once daily (QD) with an accelerated titration design. After the MTD was determined, safety and tolerability of 5 days on / 2 days off per week administration (QDx5) at the MTD in QD was explored. In parallel, the MTD with every other day administration (QOD) was evaluated by using a 3 + 3 design. Results: As of 20 September 2016, 52 patients were enrolled. TAS-116 was evaluated at doses of 4.8 to 150.5 mg/m²/day in the QD schedule and doses of 107.5 to 295.0 mg/m²/day in the QOD schedule. The MTD was 107.5 mg/m²/day with QD and 210.7 mg/m²/day with QOD. QDx5 at the MTD in QD using a flat dose of 160 mg was evaluated. The most common adverse events in all regimens were gastrointestinal disorders and increased creatinine. DLTs were observed in 4 patients in QD (night blindness, visual disorder, AST/ ALT/gamma-GTP elevations, and anorexia) and in 2 patients in QOD (platelet count decreased, febrile neutropenia, pneumonia, respiratory failure, and septic shock). Reversible eye disorders were observed in all schedules, but those observed in QDx5 were limited to grade 1. The PK level demonstrated dose proportionality without unexpected accumulation under repeated administration. Dose-related HSP70 induction of PBMCs was observed. As of 20 September 2016, three confirmed durable PRs by RECIST were observed (239 days in GIST and 173 days in NSCLC with QD; 293 + days in NSCLC with QOD). PR and SD ≥ 12 weeks were observed in 15 out of 47 patients. Conclusions: TAS-116 had an acceptable safety profile under all schedules, especially QDx5. Preliminary antitumor activity was demonstrated with evidence of target engagement. Dose expansion at the MTD in this phase 1 study and the phase 2 study in patients with GIST are ongoing. Parts of this study will be expanded to the US with an amended study protocol. Clinical trial information: NCT02965885