Abstract CT014: A large phase I study of TAS-114 in combination with S-1 in patients with advanced solid tumors
Authors: Fasolo Angelica , Aoyama Takekazu , Stathis Anastasios , Sessa Christiana , Hollebecque Antoine , Soria Jean Charles , Sobrero Alberto , Laethem Jean-Luc Van , Yoshisue Kunihiro , Gianni Lucca 
Published: August 2018

Abstract
Background: Deoxyuridine triphosphatase (dUTPase) is the key gatekeeper enzyme that inhibits 5-fluorouracil (5-FU) misincorporation into DNA in tumor cells, and its overexpression is associated with resistance to 5-FU-based chemotherapy.1 TAS-114 is an oral dUTPase inhibitor and has shown favorable safety and preliminary efficacy in combination with S-1 in patients (pts) with advanced solid tumors.2 This Phase I study further evaluated TAS-114/S-1 combination therapy in advanced solid tumors (NCT02454062).
Methods: Pts (≥18 years) with histologically or cytologically confirmed advanced solid tumors, ECOG performance status of 0 or 1, and who failed all standard therapies were enrolled. Primary objectives were safety and the maximum tolerated dose (MTD) of TAS-114 combined with S-1. Secondary objectives were pharmacokinetics (PK) and antitumor activity. In the dose-escalation phase, pts received an increasing dose of twice-daily (BID) TAS-114 (5 mg/m2 [dose level 1] to 240 mg/m2 [level 12]) + BID S-1 25 mg/m2 (levels 1-4), 30 mg/m2 (levels 5-11), or 36 mg/m2 (level 12) for 14 days with 7 days' rest in a 21-day cycle; the expansion cohort received the MTD. PK analyses were performed on day 1 (cycle 1) in both phases and following a single dose of S-1, 7-10 days before day 1 of treatment with TAS-114/S-1, in the expansion phase.
Results: 99 pts were enrolled: 53.5% were male, median age was 59.4 years (36-78), and 81.8% were Caucasian. Most common cancer types were colorectal (n=43; 43.4%) and pancreatic (n=16; 16.2%), and 45 pts (45.5%) had ≥4 prior lines of anticancer therapy. In the dose-escalation phase (n=37), 3 pts had dose-limiting toxicities (1 in dose level 7 and 2 in level 12) and the MTD was determined to be TAS-114 240 mg/m2 + S-1 30 mg/m2 BID (dose level 11). PK analysis did not show any significant correlation between the plasma concentrations of TAS-114 and S-1 or its metabolites. In the expansion phase (n=62), grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 47 pts (75.8%) and treatment related in 38 (61.3%). Overall, the most common grade ≥3 TEAEs were anemia (17.2%), rash (10.1%), asthenia (8.1%), neutropenia, and increased blood bilirubin (each 5.1%). Ten pts died during the study (none treatment related). PK interaction analysis in the expansion phase indicated similar exposure of 5-FU with S-1 alone and with TAS-114. Five pts had a partial response (1 each with breast, colorectal, and pancreatic cancer; 2 with non-small-cell lung cancer), 51 (51.5%) had stable disease (30 [68.4%] in the expansion cohort), and the objective response rate was 5.1% (8.1% in the expansion cohort).
Conclusions: TAS-114 combined with S-1 demonstrated an acceptable safety profile and preliminary efficacy in heavily pretreated pts with advanced solid tumors. 1. Ladner RD et al. Cancer Res 2000; 60: 3493-3503. 2. Aoyama T et al. Eur J Cancer 2016; 69: S117-S118.
Citation Format: Angelica Fasolo, Takekazu Aoyama, Anastasios Stathis, Christiana Sessa, Antoine Hollebecque, Jean Charles Soria, Alberto Sobrero, Jean-Luc Van Laethem, Kunihiro Yoshisue, Lucca Gianni. A large phase I study of TAS-114 in combination with S-1 in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT014.