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

• Published in: Cancer chemotherapy and pharmacology 2021-09, Vol.88 (3), p.485-497
• Main Authors: Saif, Muhammad Wasif, Becerra, Carlos R., Fakih, Marwan G., Sun, Weijing, Popovic, Lazar, Krishnamurthi, Smitha, George, Thomas J., Rudek, Michelle A., Shepard, Dale R., Skopek, Jiri, Sramek, Vladimir, Zaric, Bojan, Yamamiya, Ikuo, Benhadji, Karim A., Hamada, Kensuke, He, Yaohua, Rosen, Lee
• Format: Article
• Language: English
• Subjects: Adult; Adverse events; Aged; Aged, 80 and over; Anemia; Anemia - chemically induced; Anemia - epidemiology; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antiviral drugs; Area Under Curve; Cancer Research; Cohort Studies; Dosage; Drug Combinations; Female; Frontotemporal dementia; Humans; Impairment; Kidney Diseases - physiopathology; Male; Medicine; Medicine & Public Health; Middle Aged; NCT; NCT02301117; Neoplasms - drug therapy; Neutropenia; Neutropenia - chemically induced; Neutropenia - epidemiology; Oncology; Original Article; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Pyrrolidines - administration & dosage; Pyrrolidines - adverse effects; Pyrrolidines - pharmacokinetics; Renal function; Safety; Severity of Illness Index; Solid tumors; Thymine - administration & dosage; Thymine - adverse effects; Thymine - pharmacokinetics; Trifluridine - administration & dosage; Trifluridine - adverse effects; Trifluridine - pharmacokinetics; Tumors
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-021-04308-z

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.