Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Saif MW

PROVIDER: S-EPMC6533429 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Saif Muhammad Wasif MW Rosen Lee L Rudek Michelle A MA Sun Weijing W Shepard Dale R DR Becerra Carlos C Yamashita Fumiaki F Bebeau Paul P Winkler Robert R

British journal of clinical pharmacology 20190328 6

<h4>Aims</h4>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.<h4>Methods</h4>Patients aged ≥18 years with advanced solid tumou ...[more]

PMID: 30628113

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Project description:Purpose:Trifluridine/tipiracil (FTD/TPI) is approved in Japan, the United States (US), and Europe for metastatic colorectal cancer (mCRC) refractory to standard therapies. This Phase 1b open-label study focused on the pharmacokinetic (PK) and toxicity profiles of FTD/TPI in Chinese patients with solid tumors. Methods:Patients with definitive histologically or cytologically confirmed advanced/metastatic solid tumors refractory to standard treatments were enrolled. FTD/TPI (35 mg/m2) was administered orally twice daily for five consecutive days, followed by a 2-day recovery. Treatment was repeated for five consecutive days, followed by a 16-day recovery. The primary objective was to assess PK characteristics of FTD, 5-trifluoromethyl-2,4 (1H,3H)-pyrimidinedione (FTY; an inactive form of FTD), and TPI, calculated from plasma concentrations. Additionally, these PK values were compared with those from similar Phase 1 studies in patients from Japan and the US, using Tukey-Kramer's honestly significant difference (HSD) multiple comparison tests. Safety and preliminary efficacy of FTD/TPI were assessed. Results:Fifteen patients (12 males, three females) were enrolled, most with CRC (87%). Geometric mean analysis showed that maximum plasma concentration (Cmax) of FTD increased after multiple administration (from day 1 [3019.5 ng/mL] to day 12 [3693.1 ng/mL]), and the exposure (AUC0-t) increased 2.4-fold (day 1:7796.6 ng/mL•h; day 12:18,181.3 ng/mL•h). There was no meaningful change in the exposure to FTY and TPI throughout the study. HSD tests showed comparable PK for FTD, FTY, and TPI between Chinese and Japanese patients, and comparable exposure to FTD between Chinese and US patients. Eight patients (53.3%) experienced Grade 3 treatment-emergent adverse events, most frequently anemia and fatigue (13.3%, two events each). Median progression-free survival was 1.9 months. Conclusion:FTD/TPI had an acceptable safety and efficacy profile and PK characteristics were comparable between Chinese, Japanese, and US patients, suggesting that this treatment may be suitable for Chinese patients with refractory mCRC. Trial Registration:This trial was registered at clinicaltrials.gov as NCT02261532.

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Dataset Information

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

Aims

Methods

Results

Conclusions

Publications

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

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