PMID- 34097100 OWN - NLM STAT- MEDLINE DCOM- 20211117 LR - 20220325 IS - 1432-0843 (Electronic) IS - 0344-5704 (Linking) VI - 88 IP - 3 DP - 2021 Sep TI - 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. PG - 485-497 LID - 10.1007/s00280-021-04308-z [doi] AB - PURPOSE: 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. METHODS: 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/m(2) 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/m(2) twice daily. RESULTS: 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. CONCLUSION: FTD/TPI is safe and tolerable at the recommended 35 mg/m(2) dose in patients with mild/moderate RI and at the reduced 20 mg/m(2) dose in patients with severe RI. TRIAL REGISTRATION: NCT02301117, registration date: November 21, 2014. CI - (c) 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature. FAU - Saif, Muhammad Wasif AU - Saif MW AUID- ORCID: 0000-0001-8154-957X AD - Medical Oncology, Northwell Health Cancer Institute, 1111 Marcus Avenue, Suite 216, Lake Success, NY, 11042, USA. wsaif@northwell.edu. FAU - Becerra, Carlos R AU - Becerra CR AD - Texas Oncology, Baylor University Medical Center, Dallas, TX, USA. FAU - Fakih, Marwan G AU - Fakih MG AD - City of Hope Comprehensive Cancer Center, Duarte, CA, USA. FAU - Sun, Weijing AU - Sun W AD - Division of Oncology, University of Kansas Medical Center, Kansas City, KS, USA. FAU - Popovic, Lazar AU - Popovic L AD - Oncology Institute of Vojvodina, University of Novi Sad, Novi Sad, Serbia. FAU - Krishnamurthi, Smitha AU - Krishnamurthi S AD - Cleveland Clinic, Cleveland, OH, USA. FAU - George, Thomas J AU - George TJ AD - University of Florida Health Cancer Center, Gainesville, FL, USA. FAU - Rudek, Michelle A AU - Rudek MA AD - Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA. FAU - Shepard, Dale R AU - Shepard DR AD - Cleveland Clinic, Cleveland, OH, USA. FAU - Skopek, Jiri AU - Skopek J AD - Thomayer Hospital Prague and Department of Biophysics and Informatics, First Medical Faculty, Prague, Czech Republic. FAU - Sramek, Vladimir AU - Sramek V AD - Fakultni Nemocnice u Sv. Anny v Brne, Anesteziologicko Resustitacni Klinika, Brno, Czech Republic. FAU - Zaric, Bojan AU - Zaric B AD - Institute for Pulmonary Diseases of Vojvodina, University of Novi Sad, Novi Sad, Serbia. FAU - Yamamiya, Ikuo AU - Yamamiya I AD - Taiho Oncology, Inc., Princeton, NJ, USA. FAU - Benhadji, Karim A AU - Benhadji KA AD - Taiho Oncology, Inc., Princeton, NJ, USA. FAU - Hamada, Kensuke AU - Hamada K AD - Taiho Oncology, Inc., Princeton, NJ, USA. FAU - He, Yaohua AU - He Y AD - Taiho Oncology, Inc., Princeton, NJ, USA. FAU - Rosen, Lee AU - Rosen L AD - Division of Hematology-Oncology, University of California, Los Angeles, CA, USA. LA - eng SI - ClinicalTrials.gov/NCT02301117 PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210607 PL - Germany TA - Cancer Chemother Pharmacol JT - Cancer chemotherapy and pharmacology JID - 7806519 RN - 0 (Drug Combinations) RN - 0 (Pyrrolidines) RN - 0 (trifluridine tipiracil drug combination) RN - QR26YLT7LT (Thymine) RN - RMW9V5RW38 (Trifluridine) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Anemia/chemically induced/epidemiology MH - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse effects/pharmacokinetics MH - Area Under Curve MH - Cohort Studies MH - Drug Combinations MH - Female MH - Humans MH - Kidney Diseases/*physiopathology MH - Male MH - Middle Aged MH - Neoplasms/*drug therapy MH - Neutropenia/chemically induced/epidemiology MH - Pyrrolidines/*administration & dosage/adverse effects/pharmacokinetics MH - Severity of Illness Index MH - Thymine/*administration & dosage/adverse effects/pharmacokinetics MH - Trifluridine/*administration & dosage/adverse effects/pharmacokinetics OTO - NOTNLM OT - Pharmacokinetics OT - Renal impairment OT - Safety OT - TAS-102 OT - Trifluridine/tipiracil EDAT- 2021/06/08 06:00 MHDA- 2021/11/18 06:00 CRDT- 2021/06/07 12:29 PHST- 2021/01/29 00:00 [received] PHST- 2021/05/30 00:00 [accepted] PHST- 2021/06/08 06:00 [pubmed] PHST- 2021/11/18 06:00 [medline] PHST- 2021/06/07 12:29 [entrez] AID - 10.1007/s00280-021-04308-z [pii] AID - 10.1007/s00280-021-04308-z [doi] PST - ppublish SO - Cancer Chemother Pharmacol. 2021 Sep;88(3):485-497. doi: 10.1007/s00280-021-04308-z. Epub 2021 Jun 7.