title: Phase 1 study of cardiac safety of TAS-102 in patients with advanced solid tumors.
abstract: TAS-102 is a novel oral agent combining the antineoplastic thymidine-based nucleoside analogue, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil (molar ratio 1:0.5). TAS-102 has shown good activity in refractory metastatic colorectal cancer with acceptable safety. No QT prolongation was seen in clinical studies. This study aimed to investigate TAS-102 cardiac safety for regulatory requirements.
  
  
  
  This was a phase 1, non-randomized study in adults with advanced solid tumors. Intensive QT assessments were conducted at baseline, placebo, and following single and multiple doses of TAS-102 during a 28-day cycle.
  
  
  
  Following single- and multiple-dose administration (N = 30), the upper bounds of the one-sided 95 % confidence intervals for the difference between TAS-102 and placebo in time-matched baseline-subtracted 12-lead Holter QT intervals did not exceed 20 ms at any prespecified time point. One patient had a change from baseline in QTcI interval ≥60 ms, and one patient had a QTcI interval >500 ms following multiple-dose TAS-102 administration. No patient had an uncorrected QT, QTcF, or QTcB interval >500 ms. Based on the exposure-response analysis between TAS-102 plasma concentrations and the placebo-adjusted QTc intervals, none of the upper bounds of the one-sided 95 % prediction intervals exceeded 20 ms. There were no significant morphological changes for T or U waves. No cardiovascular AEs were reported in cycle 1. Across all cycles, no patient experienced an AE of ventricular tachycardia, ventricular fibrillation, syncope, or seizure.
  
  
  
  There was no clinically relevant relationship between TAS-102 plasma concentrations and QTc interval; TAS-102 had no clinically relevant effects on cardiac repolarization.
  
  
  
  ClinicalTrials.gov study number: NCT01867879.
authors.affiliation: GI Oncology Research, Drug Development Unit, Sarah Cannon Research Institute, 250 25th Avenue N, Suite 100, Nashville, TN, 37203, USA. jbendell@tnonc.com.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.affiliation: Florida Cancer Specialists, 600 N Cattlemen Rd, Suite 200, Sarasota, FL, 34232, USA.
authors.forename: Manish R
authors.initials: MR
authors.lastname: Patel
authors.affiliation: Taiho Oncology Inc, 101 Carnegie Center, Suite 101, Princeton, NJ, 08540, USA.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Taiho Oncology Inc, 101 Carnegie Center, Suite 101, Princeton, NJ, 08540, USA.
authors.forename: Jabed
authors.initials: J
authors.lastname: Seraj
authors.affiliation: Taiho Oncology Inc, 101 Carnegie Center, Suite 101, Princeton, NJ, 08540, USA.
authors.forename: Racquel
authors.initials: R
authors.lastname: Weaver
authors.affiliation: Sarah Cannon Research Institute UK, 93 Harley Street, London, W1G 6AD, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lemech
authors.affiliation: Medpace, 5375 Medpace Way, Cincinnati, OH, 45227, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Todaro
authors.affiliation: Peggy and Charles Stephenson Cancer Center, Science Center, 800 NE 10th Street, Suite 2500, Oklahoma City, OK, 73104, USA.
authors.forename: Shubham
authors.initials: S
authors.lastname: Pant
authors.affiliation: Sarah Cannon Research Institute UK, 93 Harley Street, London, W1G 6AD, UK.
authors.forename: Hendrik-Tobias
authors.initials: HT
authors.lastname: Arkenau
mesh_terms: D000284:Administration, Oral; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D066126:Cardiotoxicity; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004562:Electrocardiography; D015716:Electrocardiography, Ambulatory; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011759:Pyrrolidines; D013941:Thymine; D014271:Trifluridine / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D014498:Uracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use
chemical_list: D004338:Drug Combinations; D011759:Pyrrolidines; C000613803:trifluridine tipiracil drug combination; D014498:Uracil; D013941:Thymine; D014271:Trifluridine
keywords: 5-Fluorouracil; Cardiac; QT interval; TAS-102; Tipiracil; Trifluridine