Abstract CT012: Phase I study of TAS-114 in combination with capecitabine in patients with advanced solid tumors
Authors: LoRusso Patricia M. , Miller Kathy D. , Shields Anthony F. , Chung Ki Y. , Yoshisue Kunihiro , Aoyama Takekazu , Lenz Heinz-Josef 
Published: August 2018

Abstract
Background: TAS-114 is a novel dual inhibitor of deoxyuridine triphosphatase and dihydropyrimidine dehydrogenase, and has shown favorable safety and preliminary efficacy in combination with S-1 or capecitabine in patients (pts) with advanced solid tumors.1,2 This Phase I study further evaluated the TAS-114/capecitabine combination in pts with advanced solid tumors (NCT02025803).
Methods: Pts (≥18 years) with histologically or cytologically confirmed advanced solid tumors treated with standard anticancer therapy and an ECOG performance status of 0 or 1 were enrolled. Primary objective was safety and maximum tolerated dose (MTD) of TAS-114 combined with capecitabine; secondary objectives were pharmacokinetics (PK) and antitumor activity. In the dose-escalation phase, pts received an increasing dose of TAS-114 twice daily (BID; 10 mg/m2 [dose level 1] to 360 mg/m2 [level 12]) + capecitabine 380 mg/m2 BID (levels 1 to 9, 11, and 12) or capecitabine 450 mg/m2 BID (TAS-114, 240 mg/m2) for 14 days followed by 7 days' rest (21-day treatment cycle); the expansion cohort received the MTD. PK analyses were performed on days 1 and 14 of cycle 1 in the dose-escalation phase.
Results: Of 104 pts, 68 (65.4%) were female, median age was 57 years (28-81), 49 (47.2%) were in the dose-escalation phase, and 55 (52.9%) were in the 2 expansion cohorts (mini [n=8] and MTD [n=47]). In the dose-escalation phase, the majority of pts had colorectal cancer (CRC; n=17; 16.3%) and breast cancer (BC; n=23; 22.1%). Dose-limiting toxicities were reported in 5 pts (1 each had grade 2 and 3 Palmar-plantar erythrodysesthesia, 2 had grade 2 rash, and 1 had grade 3 maculopapular rash). MTD was determined to be TAS-114 360 mg/m2 BID + capecitabine 380 mg/m2 BID (dose level 12). PK analysis on day 1 showed a significant correlation between TAS-114 dose and the Cmax (p=0.0013) and AUC0-last (p&lt;0.0001) of 5-fluorouracil (5-FU), with an average maximum 5-FU AUC0-last of 712 ng·h/mL achieved at the MTD. Of 8 pts in the mini expansion cohort, 6 had CRC and 2 had BC; in the MTD expansion cohort, 29 had CRC and 18 had BC. Grade ≥3 treatment-emergent adverse events were reported in 39 pts (72.2%) and 67 (72.2%) in the overall population, with anemia (19.2%), fatigue (7.7%), stomatitis (6.7%), and maculopapular rash (5.8%) as the most common. No treatment-related deaths occurred during the study. In the 2 expansion cohorts, 2 pts (3.6%) had partial response (PR) and 18 (32.7%) had stable disease (SD) for ≥6 weeks. In the dose-escalation cohort, 3 pts (6.1%) had PR and 24 (48.9%) had SD.
Conclusions: TAS-114 combined with capecitabine at 30% of its standard dose achieved an equivalently efficacious 5-FU exposure as the standard capecitabine dose alone, with acceptable safety and preliminary efficacy in pts with advanced solid tumors. 1. Aoyama T et al. Eur J Cancer 2016; 69: S117-8. 2. LoRusso P et al. Eur J Cancer 2016; 69: S119.
Citation Format: Patricia M. LoRusso, Kathy D. Miller, Anthony F. Shields, Ki Y. Chung, Kunihiro Yoshisue, Takekazu Aoyama, Heinz-Josef Lenz. Phase I study of TAS-114 in combination with capecitabine 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 CT012.