In patients (pts) with heavily pretreated metastatic colorectal cancer (mCRC), TAS-102 -a combination of trifluridine and tipiracil- plus bevacizumab (bev) combination therapy has shown a promising activity with manageable safety. In previously reported this combination therapy, TAS-102 have been given every 4 weeks (35mg/m2 given orally twice daily on day 1-5 and 8-12 in a 28-day cycle) and bev have been administered every 2 weeks. The aim of this study was to assess the activity and safety of biweekly TAS-102 (given orally twice daily on day 1-5 every 2 weeks) with bev combination for pts with mCRC.
Inclusion criteria were ≥ 20 years; histologically confirmed unresectable metastatic colorectal adenocarcinoma; refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF, and anti-EGFR therapy (for tumors with wild-type RAS); ECOG performance status 0 or 1; evaluable lesion according to the RECIST version 1.1. Using a dose de-escalation design in phase Ib part and we determined the recommended phase II dose (RP2D).
From October 2017 to January 2018, totally 46 pts were enrolled, and six were enrolled in phase Ib part. The patient characteristics of phase Ib part were as follows: median age, 74 (range, 68-82); male, 50%; ECOG PS 0/ 1, 3/ 3 (50/ 50%); right-sided primary/ left-, 2/ 4 (33/ 67%); median prior chemotherapy regimen, 3 (range, 2-4). Of the six pts, grade 3 or higher relevant toxicities during the DLT evaluation period were anemia (n = 1) and anorexia (n = 1). Common grade 3 or higher relevant toxicities through the treatment period were anemia (n = 2), anorexia (n = 2), nausea (n = 2), leucopenia (n = 1) and proteinuria (n = 1). No DLT and no treatment related death was observed. Best overall response was were stable disease in 4 pts (67%), and progressive disease in 2 pts (33%).
Biweekly TAS-102 with bev combination for pts with mCRC showed a promising antitumor activity with acceptable toxicity. The RP2D was determined to as biweekly TAS-102 (35mg/m2 given orally twice daily on day 1-5 every 2 weeks) with bev (5mg/kg, every 2 weeks).
Clinical trial identification
Legal entity responsible for the study
T. Kato: Chugai Pharmaceutical CO., Ltd, Takeda Pharmaceutical Company Limited, Eli Lilly and Company, Bayer Yakuhin, Ltd., Sanofi S.A., Yakult Honsha Company, Limited. K. Oba: Consultant fee: Takeda Pharmaceutical Co. Inc., Ono Pharma Icn., Asahi-Kasei Pharma Inc.; Honoraria: Eisai Co.Inc., Chugai Pharmaceutical Co. Inc., Daiichi-Sankyo Co. Inc. K. Muro: Grants: Ono, MSD, Daiichi Sankyo, Kyowa Hakko Kirin, Shionogi, Pfizer, Gilead Sciences, Merck Serono; Personal fees: Chugai, Taiho, Takeda, Bayer, Eli Lilly, personal fees from outside the submitted work. Y. Komatsu, A. Tsuji, Y. Kakeji: Honoraria: Taiho, Chugai, Takeda, Eli Lilly. T. Yoshino: Grants/research suppots: MSD, Sanofi, Sumitomo Dainippon, Chugai, GlaxoSmithKline, Nippon Boehringer Ingelheim; Honoraria or consultation fees: Sanofi, Chugai, Eli Lilly, Merck Serono. K. Yamazaki: Honoraria: Chugai, Taiho. M. Kotaka: Honoraria: Chugai, Yakult, Takeda, Eli Lilly. E. Oki: Honoraria: Taiho, Chugai, Takeda, Merck Serono, Eli Lilly. S. Junichi: Consultant fee: Takeda. Honoraria: Chugai, Tsumura, Nihon Kayaku. All other authors have declared no conflicts of interest.