Background: TAS-114 is a first-in-class oral deoxyuridine triphosphatase inhibitor, which acts as a modulator of the pyrimidine nucleotide metabolic pathway. We are conducting a first combination phase 1 dose escalation and expansion study of TAS-114 and S-1 to investigate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PK), pharmacogenomics and preliminary antitumor efficacy in pts with advanced solid tumors refractory to standard therapy. Methods: TAS-114 was administrated orally BID for 14 days followed by 7 days rest at the starting dosage of 5 mg/m² with the fixed dosage of S-1 (30 mg/m²). Dose-limiting toxicity (DLT) was evaluated during the 1st cycle in dose escalation cohort (DEC), using a 3 + 3 design. Expansion cohort (EC) is conducted in parallel with DEC at the dosage which was confirmed tolerable in DEC. Results: As of 25 September 2014, 56 pts were enrolled with 36 pts in the DEC and 20 pts in the EC. In DEC, dosage of TAS-114 was escalated up to 240 mg/m² with a MTD not yet reached. In EC, TAS-114 was administrated at the dosage of 120 and 160 mg/m² with the fixed dosage of S-1 (30 mg/m²). Currently, we are planning the dose escalation of TAS-114 with Japanese approved fixed dose of S-1 (36 mg/m²). A recommended phase 2 dose is expected to be reached soon. Two pts at the dosage of 10 and 240 mg/m² developed DLTs, including grade 2 platelet count decreased and grade 3 aspartate aminotransferase increased. The most common treatment related adverse events were white blood cell decreased, anemia and rash. TAS-114 exposures tend to increase dose-dependently with large inter-individual variability. Preliminary antitumor efficacy was observed with acceptable safety in pts with NSCLC, gastric cancer and pancreatic neuroendocrine tumor. Especially, partial responses were confirmed in 2 of efficacy evaluable 6 pts with NSCLC. Further safety, PK and efficacy data will be presented. Conclusions: The combination therapy of TAS-114 and S-1 was well tolerated in pts with severe treated advanced solid tumors, resulting in the promising antitumor efficacy. Further safety and efficacy of this combination therapy will be investigated in this phase 1 and subsequent phase 2 study. Clinical trial information: NCT01610479 Clinical trial information: NCT01610479