title: Phase I study of TAS-102 and irinotecan combination therapy in Japanese patients with advanced colorectal cancer.
abstract: BACKGROUND
  TAS-102 is a nucleoside antitumor agent consisting of trifluridine (FTD) and tipiracil hydrochloride (TPI). We investigated the recommended dose (RD) of TAS-102 plus irinotecan for metastatic colorectal cancer refractory to 5-fluorouracil (5-FU) and oxaliplatin.
  
  
  METHODS
  This study was used a escalated dose of TAS-102 (40-70 mg/m(2)/day, for 5 days a week with 2 days rest for 2 weeks, followed by a 14-day rest) with a fixed dose of irinotecan (150 mg/m(2) on Days 1 and 15 of a 28-day schedule). The primary endpoints were determination of RD and assessment of safety.
  
  
  RESULTS
  Ten patients were enrolled; 7 at the Level 1 (50 mg/m(2)/day) and 3 at the Level 2 (60 mg/m(2)/day). One patient at Level 1 was excluded from the analysis of dose-limiting toxicities (DLT) and efficacy. Five DLTs occurred in 3 patients; 1 patient at Level 1 (Grade 3 febrile neutropenia and Grade 4 neutropenia), and 2 patients at Level 2 (Grade 3 febrile neutropenia in two patients and Grade 4 neutropenia in one). Grade 3 or higher treatment-related adverse events were neutropenia (100 %), leukopenia (70 %), febrile neutropenia (30 %) and lymphopenia, anaemia (20 % each). 2 patients (22 %) achieved partial response with the duration of response were 112 and 799 days.
  
  
  CONCLUSIONS
  The RD was determined to be 50 mg/m(2)/day of TAS-102 combined with 150 mg/m(2) of irinotecan although further investigation to explore optimal regimen is warranted.
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. tdoi@east.ncc.go.jp.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Doi
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshino
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Fuse
authors.affiliation: Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi, Sunto-gun, Shizuoka, 411-8777, Japan.|National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 216-8511, Japan.
authors.forename: Narikazu
authors.initials: N
authors.lastname: Boku
authors.affiliation: Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi, Sunto-gun, Shizuoka, 411-8777, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yamazaki
authors.affiliation: Department of Gastroenterology, Kitasato University School of Medicine, 2-1-1 Asamizodai, Minami-ku, Sagamihara, Kanagawa, 252-0380, Japan.
authors.forename: Wasaburo
authors.initials: W
authors.lastname: Koizumi
authors.affiliation: Department of Internal Medicine, Showa University Yokohama Northern Hospital, 35-1 Chigasakityuo, Tsuzuki-ku, Yokohama, Kanagawa, 224-8503, Japan.|Showa University Koto Toyosu Hospital, 5-1-38 Toyosu, Koto-ku, Tokyo, 135-8577, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Department of Internal Medicine, Showa University Yokohama Northern Hospital, 35-1 Chigasakityuo, Tsuzuki-ku, Yokohama, Kanagawa, 224-8503, Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Takinishi
authors.affiliation: Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011110:Polymorphism, Genetic; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011759:Pyrrolidines; D013941:Thymine; D014271:Trifluridine / Q000493:pharmacokinetics / Q000627:therapeutic use; D014498:Uracil / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D004338:Drug Combinations; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D016283:Proto-Oncogene Proteins p21(ras); D011759:Pyrrolidines; D013941:Thymine; D014271:Trifluridine; D014498:Uracil; D000099148:UGT1A1 Enzyme; C117307:KRAS protein, human; C000613803:trifluridine tipiracil drug combination
keywords: Colorectal cancer; FTD; Irinotecan; Phase I combination study; TAS-102; TPI