Open-label study to evaluate trifluridine/tipiracil safety, tolerability and pharmacokinetics in patients with advanced solid tumours and hepatic impairment.

AIMS: Trifluridine/tipiracil (FTD/TPI) prolongs survival in refractory metastatic colorectal cancer, but limited data exist on its use in patients with hepatic impairment. This Phase I, open-label, nonrandomized study investigated the safety, tolerability and pharmacokinetics of FTD/TPI in patients with advanced solid tumours (except breast cancer) and varying degrees of hepatic impairment, to provide dosing recommendations. METHODS: Patients aged ≥18 years with advanced solid tumours and normal hepatic function, or mild, moderate or severe hepatic impairment according to National Cancer Institute criteria, were planned to be enrolled. Patients received FTD/TPI 35 mg/m2 orally twice daily on days 1-5 and 8-12 of each 28-day cycle. RESULTS: Twenty-four patients were enrolled to the normal hepatic function (n = 8) and mild (n = 10) and moderate (n = 6) hepatic impairment cohorts. Overall, 12 patients (50.0%) had at least 1 adverse event leading to study discontinuation. In the moderate hepatic impairment cohort, 5 of 6 patients experienced grade ≥ 3 elevation in bilirubin. No patients with severe hepatic impairment were enrolled. FTD area under the curve at steady state decreased by 18% and 22% in the mild and moderate cohorts, respectively; however, no clear change was observed in TPI area under the curve. CONCLUSIONS: FTD/TPI can be safely administered in patients with normal hepatic function and mild hepatic impairment, with no initial dose adjustment. FTD/TPI is not recommended for use in patients with moderate hepatic impairment because of findings of grade 3 or 4 increased blood bilirubin. Therefore, FTD/TPI is not recommended for patients with moderate or severe hepatic impairment.

Integrated safety summary for trifluridine/tipiracil (TAS-102).

Trifluridine/tipiracil, an oral treatment combining trifluridine (an antineoplastic thymidine-based nucleoside analog) and tipiracil hydrochloride (a thymidine phosphorylase inhibitor), led to significant improvement in overall survival in metastatic colorectal cancer (mCRC) patients refractory to standard therapy in the phase III RECOURSE trial. Here, we report an integrated summary of the safety of trifluridine/tipiracil. The main safety analysis includes integrated data from the RECOURSE and J003 studies (safety data group 2) of patients with refractory mCRC receiving trifluridine/tipiracil at the recommended starting dose: 35 mg/m twice daily for 5 days with 2 days' rest for 2 weeks, followed by a 14-day rest (one cycle). Integrated data from a larger group of mCRC patients receiving trifluridine/tipiracil at the recommended starting dose (group 1) and nonintegrated data on serious adverse events (SAEs) representing all clinical experience with trifluridine/tipiracil as of the data cutoff date (group 3) are also summarized. In group 2, myelosuppressive and all-grade gastrointestinal adverse events (AEs) were more frequent in trifluridine/tipiracil patients than in placebo patients. The trifluridine/tipiracil and placebo patients had similar frequencies of AEs leading to discontinuation (9.0 vs. 11.5%) and SAEs (27.7 vs. 29.2%); fatal AEs were more frequent in placebo patients than in trifluridine/tipiracil patients (9.3 vs. 2.8%). AEs leading to interruptions/delays/reductions were more frequent in trifluridine/tipiracil patients (56.3 vs. 12.7%). Trifluridine/tipiracil was generally well tolerated, but over 50% of patients required interruptions/delays/reductions. There was a low rate of discontinuations, SAEs, and fatal AEs. This analysis confirms the safety profile observed in RECOURSE.