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Phase 1 study of cardiac safety of TAS-102 in patients with advanced solid tumors

Bendell, JC; Patel, MR; Yoshida, K; Seraj, J; Weaver, R; Lemech, C; Todaro, TG; ... Arkenau, H-T; + view all (2016) Phase 1 study of cardiac safety of TAS-102 in patients with advanced solid tumors. Cancer Chemother Pharmacol , 77 (6) pp. 1275-1283. 10.1007/s00280-016-3031-9. Green open access

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Abstract

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: There was no clinically relevant relationship between TAS-102 plasma concentrations and QTc interval; TAS-102 had no clinically relevant effects on cardiac repolarization.

Type: Article
Title: Phase 1 study of cardiac safety of TAS-102 in patients with advanced solid tumors
Open access status: An open access version is available from UCL Discovery
DOI: 10.1007/s00280-016-3031-9
Publisher version: http://dx.doi.org/10.1007/s00280-016-3031-9
Language: English
Additional information: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Keywords: Science & Technology, Life Sciences & Biomedicine, Oncology, Pharmacology & Pharmacy, 5-Fluorouracil, Cardiac, QT interval, TAS-102, Tipiracil, Trifluridine, Metastatic Colorectal-Cancer, Trial
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/10050827
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