A phase I dose-escalation study of TAS-102 in patients (pts) with refractory metastatic colorectal cancer (mCRC).

3631 Background: TAS-102 is an oral combination of a novel antimetabolite 5-trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI) that prevents degradation of FTD. In preclinical studies, TAS-102 is effective against human colorectal tumors with innate and acquired resistance to 5FU. A Japanese randomized phase 2 study demonstrated a significant survival improvement of TAS-102 over placebo in refractory mCRC (HR=0.56 p=0.0011, EMCC2011). The present study was conducted to determine the MTD of TAS-102 in Western pts with refractory mCRC. Methods: Pts with mCRC who had received at least 2 lines of chemotherapy including a fluoropyrimidine, irinotecan and oxaliplatin were enrolled at an initial dose level of 30 mg/m 2 BID days 1- 5 and days 8-12 every 4wks using a standard 3+3 design. A second dose level of 35 mg/m 2 , which was the MTD for Japanese pts, was the maximal targeted dose in this study. Results: 12 pts received TAS-102 (30/35 mg/m 2 =3/9, M/F=7/5, Age 44-75, PS0/1=8/4). Pts received a median of 3 prior regimens for metastatic disease. No DLT was observed in the initial dose level (0/3) and one DLT (grade 3 febrile neutropenia) was observed at 35mg/m 2 (1/9). Other drug-related ≥ grade 3 toxicities observed in cycle 1 included neutropenia at 58% (7/12). To date, a median number of treatment cycles at the MTD has not been reached as 5 pts are still receiving therapy (range 1-3+ cycles). Conclusions: Western patients with refractory mCRC showed the same MTD as Japanese pts (35 mg/m 2 BID, days 1- 5 and days 8-12 every 4wks) and the safety profile was consistent between the populations. The trial has entered an expansion phase to assess further safety and preliminary efficacy. A phase 3 trial is being planned.