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A phase I, open-label study evaluating the safety and pharmacokinetics of trifluridine/tipiracil in patients with advanced solid tumors and varying degrees of renal impairment



Trifluridine/tipiracil (FTD/TPI) is approved for advanced colorectal and gastric/gastroesophageal cancer; however, data in patients with renal impairment (RI) are limited. This phase I study evaluated FTD/TPI in patients with advanced solid tumors and varying degrees of RI to develop dosing guidance.


Patients were enrolled into normal renal function (CrCl ≥ 90 mL/min), mild RI (CrCl 60–89 mL/min), or moderate RI (CrCl 30–59 mL/min) cohorts and administered the recommended FTD/TPI dose (35 mg/m2 twice daily, days 1–5 and 8–12; 28-day cycle). Based on interim pharmacokinetics/safety data, patients with severe RI (CrCl 15–29 mL/min) were enrolled and received FTD/TPI 20 mg/m2 twice daily.


Forty-three patients (normal renal function [n = 12]; mild RI [n = 12]; moderate RI [n = 11]; severe RI [n = 8]) were enrolled and treated. At steady state, compared to values in patients with normal renal function, FTD area under the curve (AUC) was not significantly different in patients with RI, but TPI AUC was significantly higher and increased with RI severity. FTD/TPI safety profile was consistent with prior experience, but grade ≥ 3 adverse events (AEs) were more frequent in the RI cohorts (83.3% [mild], 90.9% [moderate], 75.0% [severe], and normal [50.0%]). Hematologic AEs (anemia and neutropenia) were more frequent with RI. Overall, seven patients discontinued because of unrelated, nonhematologic AEs.


FTD/TPI is safe and tolerable at the recommended 35 mg/m2 dose in patients with mild/moderate RI and at the reduced 20 mg/m2 dose in patients with severe RI.

Trial registration

NCT02301117, registration date: November 21, 2014.

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Availability of data and material

Data generated or analyzed during this study are on file with Taiho Oncology, Inc., and Taiho Pharmaceuticals Co., Ltd., and are not publicly available. Inquiries about data access should be sent to

Code availability

Phoenix WinNonlin® software (Version 7.0, Certara LP; Princeton, New Jersey, USA) or SAS® statistical software, version 9.3 or a later version.


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This study was sponsored by Taiho Oncology, Inc., and Taiho Pharmaceutical Co., Ltd. The authors acknowledge Dr. Kenichiro Yoshida for the study design and regression model analysis. Medical writing and editorial assistance were provided by Vasupradha Vethantham, PhD, and Jennifer Robertson, PhD, of Ashfield Healthcare Communications (Lyndhurst, NJ, USA) and funded by Taiho Oncology, Inc.


This study was funded by Taiho Oncology, Inc., and Taiho Pharmaceutical Co. Ltd.

Author information




M.W.S., L.R., I.Y., K.H., and Y.H. were involved in the study design. M.W.S., C.R.B., M.G.F., W.S., L.P., S.K., T.J.G., M.A.R., D.R.S., J.S., V.S., B.Z., and L.R. contributed to data collection. M.W.S., L.R., I.Y., K.A.B., K.H., and Y.H were involved in data analysis and/or interpretation. All authors meet the criteria for authorship as recommended by the International Committee of Medical Journal Editors. All authors take full responsibility for the scope, direction, content of, and editorial decisions relating to the manuscript, were involved at all stages of development, and have approved the submitted manuscript.

Corresponding author

Correspondence to Muhammad Wasif Saif.

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Conflict of interest

M.W.S. reports research funding from Incyte, Lexicon, NGM Bio, Nouscom, Tesaro, and Yivia. C.R.B. is part of the speaker bureau for Taiho Oncology Inc. M.G.F. received research grant funding (to institution) from Amgen, AstraZeneca, and Novartis; has served on the advisory board of Amgen, Array Biopharma, Bayer, and Pfizer; is part of the speakers bureau for Amgen and Guardant360, and reports honoraria from Amgen. M.A.R. received research funding from Taiho Oncology, Inc, during the conduct of the study and from Celgene Corporation and the National Cancer Institute, outside the submitted work. K.H., I.Y., K.A.B., and Y.H are employees of Taiho Oncology, Inc. K.A.B. is a former employee and a stockholder of Eli Lilly. L.R. received research funding from Taiho Oncology, Inc. W.S., L.P., S.K., T.J.G., D.R.S., J.S., V.S., and B.Z have no financial disclosures to report.

Ethics approval

This study was performed in line with the Declaration of Helsinki. Approval was granted from the review board or ethics committee of each institution.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

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Saif, M.W., Becerra, C.R., Fakih, M.G. et al. A phase I, open-label study evaluating the safety and pharmacokinetics of trifluridine/tipiracil in patients with advanced solid tumors and varying degrees of renal impairment. Cancer Chemother Pharmacol 88, 485–497 (2021).

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  • Trifluridine/tipiracil
  • TAS-102
  • Renal impairment
  • Safety
  • Pharmacokinetics