Pharmacokinetics, Safety, and Preliminary Efficacy of Oral Trifluridine/Tipiracil in Chinese Patients with Solid Tumors: A Phase 1b, Open-Label Study

Xicheng Wang, Jianfeng Zhou, Yan Li, Yuping Ge, Yanping Zhou, Chunmei Bai, Lin Shen, Xicheng Wang, Jianfeng Zhou, Yan Li, Yuping Ge, Yanping Zhou, Chunmei Bai, Lin Shen

Abstract

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.

Keywords: Chinese; colorectal cancer; pharmacokinetics; safety; trifluridine/tipiracil.

Conflict of interest statement

Xicheng Wang, Chunmei Bai, Jianfeng Zhou, Yan Li, Yuping Ge, and Yanping Zhou have no conflicts of interest to declare. Lin Shen acknowledges honoraria and speakers’ fees from Novartis, Pfizer, Roche, Sanofi, and Taiho; has served as a consultant for Novartis, Roche, and Taiho; and acknowledges research funding from Hengrui Medicine, Roche, and Taiho. The authors report no other conflicts of interest in this work.

© 2020 Wang et al.

Figures

Figure 1
Figure 1
Mean plasma concentration-time profiles of FTD (A), FTY (B), and TPI (C) on days 1 and 12. Abbreviations: C1D1, Cycle 1 day 1; C1D12, Cycle 1 day 12; FTD, trifluridine; FTY, inactive metabolite of FTD; hr, hour; TPI, tipiracil.
Figure 2
Figure 2
Box plots of Cmax (A, B) and AUC0-t (C, D) of FTD after administration of FTD/TPI on day 1 (C1D1) and day 12 (C1D12) of Cycle 1 by regions of China, Japan, and the US. Differences between regions were assessed by Tukey–Kramer’s HSD multiple comparison test. Data for Japan and the US used for the comparison are presented in Table 3. Upper horizontal line of box indicates 75th percentile; lower horizontal line of box, 25th percentile; horizontal bar within box, median; upper horizontal bar outside box, 90th percentile; lower horizontal bar outside box, 10th percentile; circles represent outliers. Abbreviations: AUC0-t, area under the plasma-concentration time curve from time 0 to time of last quantifiable concentration; C, cycle; Cmax, maximum plasma concentration; D, day; FTD, trifluridine; HSD, honestly significant difference; TPI, tipiracil.
Figure 3
Figure 3
Box plots of Cmax (A, B) and AUC0-t (C, D) of TPI after administration of FTD/TPI on day 1 (C1D1) and day 12 (C1D12) of cycle 1 by regions of China, Japan, and the US. Data for Japan and the US used for the comparison are presented in Table 3. Differences between regions were assessed by Tukey–Kramer’s honestly significant difference multiple comparison test. *p<0.05 compared with China. Upper horizontal line of box indicates 75th percentile; lower horizontal line of box, 25th percentile; horizontal bar within box, median; upper horizontal bar outside box, 90th percentile; lower horizontal bar outside box, 10th percentile; circles represent outliers. Abbreviations: AUC0-t, area under the plasma-concentration time curve from time 0 to time of last quantifiable concentration; C, cycle; Cmax, maximum plasma concentration; D, day; FTD, trifluridine; TPI, tipiracil; US, United States.
Figure 4
Figure 4
Progression-free survival (efficacy set). Estimation by Kaplan–Meier method. Abbreviations: FTD, trifluridine; TPI, tipiracil.

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Source: PubMed

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