title: Phase 1 study of oral TAS-102 in patients with refractory metastatic colorectal cancer.
abstract: OBJECTIVE
  To evaluate safety of TAS-102 administered twice daily (bid) on days 1-5 and 8-12 of a 4-week cycle, confirm feasibility of the Japanese recommended dose (RD), 35 mg/m(2), in Western patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapies, and describe preliminary antitumor activity.
  
  
  METHODS
  This open-label, dose-escalation phase 1 study was conducted at four US centers. Patients were enrolled into two sequential cohorts [30 (cohort 1) or 35 mg/m(2)/dose bid (cohort 2)]; dose-limiting toxicities (DLT) were evaluated during cycle 1 in dose-escalation cohorts. At RD, 15 additional patients were enrolled in an expansion cohort.
  
  
  RESULTS
  Patients (N = 27) with refractory mCRC received TAS-102; 74 % had received ≥4 prior regimens. DLT was not observed in three patients in cohort 1, and was in one out of nine patients in cohort 2 (grade 3 febrile neutropenia). Therefore, RD was identified as 35 mg/m(2) bid. At RD, fatigue (63 %), gastrointestinal disturbances and nausea (46 %), vomiting (46 %), and diarrhea (42 %) were common but rarely grade 3/4. Grade 3/4 nausea, vomiting, and diarrhea occurred at 4 % each. Grade 3/4 toxicity was predominantly hematologic [neutropenia (71 %), anemia (25 %)]; febrile neutropenia was observed in two patients. Stable disease lasting ≥6 weeks was achieved by 16 evaluable patients (70 %); median progression-free survival and overall survival were 5.3 and 7.5 months, respectively.
  
  
  CONCLUSIONS
  TAS-102 has an acceptable safety profile and preliminary evidence of disease stabilization in Western patients with refractory mCRC. Results from a randomized phase 3 study have shown survival benefit with disease stabilization evidence in this population.
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, 250 25th Avenue North, Suite 200, Nashville, TN, 37203, USA. jbendell@tnonc.com.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.affiliation: University of California, 2020 Santa Monica Blvd., Suite 600, Los Angeles, CA, 90404, USA.
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
authors.affiliation: Dana-Farber Cancer Institute, 450 Brookline Ave., Dana 1602, Boston, MA, 02215, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mayer
authors.affiliation: University of California, 2020 Santa Monica Blvd., Suite 600, Los Angeles, CA, 90404, USA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Goldman
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, 250 25th Avenue North, Suite 200, Nashville, TN, 37203, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: Taiho Oncology Inc., 212 Carnegie Center, Suite 201, Princeton, NJ, 08540, USA.
authors.forename: Fabio
authors.initials: F
authors.lastname: Benedetti
authors.affiliation: Taiho Pharmaceutical of Beijing Co., Ltd., 9F-9A3, Hanwei Plaza, 7th, Guanghua Rd., Chaoyang Dist., Beijing City, 100004, China.
authors.forename: Donghu
authors.initials: D
authors.lastname: Lin
authors.affiliation: Taiho Oncology Inc., 212 Carnegie Center, Suite 201, Princeton, NJ, 08540, USA.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Mizuguchi
authors.affiliation: Taiho Oncology Inc., 212 Carnegie Center, Suite 201, Princeton, NJ, 08540, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Zergebel
authors.affiliation: Sarah Cannon Research Institute/Florida Cancer Specialists, 600 N. Cattlemen Road, Suite 200, Sarasota, FL, 34232, USA.
authors.forename: Manish R
authors.initials: MR
authors.lastname: Patel
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000556:secondary*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005221:Fatigue / Q000139:chemically induced; D064147:Febrile Neutropenia / Q000139:chemically induced; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D016879:Salvage Therapy; D013941:Thymine; D016896:Treatment Outcome; D014271:Trifluridine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014498:Uracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D011759:Pyrrolidines; C000613803:trifluridine tipiracil drug combination; D014498:Uracil; D013941:Thymine; D014271:Trifluridine
keywords: Antimetabolite; Metastatic colorectal cancer; Phase 1 study; Recommended dose; Safety; TAS-102