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A Phase 1, Open‐Label, Randomized, Crossover Study Evaluating the Bioavailability of TAS‐102 (Trifluridine/Tipiracil) Tablets Relative to an Oral Solution Containing Equivalent Amounts of Trifluridine and Tipiracil

TAS‐102 (trifluridine/tipiracil) is composed of an antineoplastic thymidine‐based nucleoside analogue trifluridine (FTD), and a thymidine phosphorylase inhibitor, tipiracil (TPI), at a molar ratio of 1:0.5 (weight ratio, 1:0.471). A phase 1 study evaluated relative bioavailability of TAS‐102 tablets compared with an oral solution containing equivalent amounts of FTD and TPI. In an open‐label, 2‐sequence, 3‐period, crossover bioavailability study (part 1), patients 18 years or older with advanced solid tumors were randomized to receive TAS‐102 tablets (60 mg; 3 × 20‐mg tablets) on day 1 and TAS‐102 oral solution (60 mg) on days 8 and 15, or the opposite sequence. In an extension (part 2), all patients received TAS‐102 tablets. Of the 46 patients treated in the crossover study, 38 were evaluable in the crossover bioavailability pharmacokinetic population. For area under the concentration‐time curve (AUC)0‐∞ and AUC0‐last for FTD and TPI, and maximum plasma concentration (Cmax) for TPI, the 90% confidence intervals (CIs) of the geometric mean ratios were within the 0.80 to 1.25 boundary for demonstration of bioequivalence; for FTD Cmax, the lower limit of the 90%CI was 0.786. The most frequently reported treatment‐related grade 3 or 4 adverse events were neutropenia (7 patients) and decreased neutrophil count (3 patients). Although the lower limit of the 90%CI for the geometric mean ratio of FTD Cmax was slightly lower than 0.80, the bioavailability of the TAS‐102 tablet is considered clinically similar to that of a TAS‐102 oral solution. TAS‐102 was well tolerated in this population of patients with advanced solid tumors.