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Clinical Trial
. 2012 Jul 24;107(3):429-34.
doi: 10.1038/bjc.2012.274. Epub 2012 Jun 26.

Phase I study of TAS-102 treatment in Japanese patients with advanced solid tumours

T Doi  1 , A Ohtsu, T Yoshino, N Boku, Y Onozawa, A Fukutomi, S Hironaka, W Koizumi, T Sasaki
Affiliations
Clinical Trial

Phase I study of TAS-102 treatment in Japanese patients with advanced solid tumours

T Doi et al. Br J Cancer. .

Abstract

Background: TAS-102 consists of α, α, α-trifluorothymidine (TFT) and an inhibitor of thymidine phosphorylase (TPI). We conducted a dose-escalation phase I study in Japanese patients with advanced solid tumours.

Methods: TAS-102 was administered twice daily on days 1-5 and days 8-12 in a 28-day cycle to patients with solid tumours refractory to standard chemotherapy, to determine its maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics (PKs). MTD was evaluated in cycle 1.

Results: Safety and PKs were evaluated in 21 patients treated with TAS-102 at 30, 40, 50, 60, or 70 mg m(-2) per day. DLTs, such as grade 4 leucopenia, grade 4 neutropenia, and grade 4 thrombocytopenia, were observed in two patients at doses of 30 and 70 mg m(-2). α, α, α-trifluorothymidine and TPI exposures increased dose dependently, and the percentage of decrease in neutrophil count and TFT exposure were significantly correlated. The disease control rate was 50.0% with a median progression-free survival of 2.4 months in 18 colorectal cancer patients. The dose of TAS-102 was not increased above 70 mg m(-2) per day because of the increased tendency for grade 3 and 4 neutropenia, and 70 mg m(-2) per day was the recommended dose for phase II studies.

Conclusions: TAS-102 at 70 mg m(-2) per day was tolerated in Japanese patients with advanced solid tumours. Phase II studies are ongoing in patients with colorectal cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Kaplan–Meier plots of the median progression-free survival (PFS) (A) and median overall survival (OS) (B) in all patients.
Figure 2
Figure 2
Relationship between pharmacokinetic parameters of trifluorothymidine (TFT; Cmax and AUCinf) and the percent change of the neutrophil count of patients treated with 30–70 mg m−2 per day of TAS-102 on day 12 in 1 course. (A) Relationship between TFT Cmax and the percent change of the neutrophil count. (B) Relationship between TFT AUCinf and the percent change of the neutrophil count. Each symbol denotes an individual value.
See this image and copyright information in PMC

References

    1. Ansfield FJ, Ramirez G (1971) Phase I and II studies of 2'-deoxy-5-(trifluoromethyl)-uridine (NSC-75520). Cancer Chemother Rep 55: 205–208 - PubMed
    1. Emura T, Nakagawa F, Fujioka A, Ohshimo H, Yokogawa T, Okabe H, Kitazato K (2004a) An optimal dosing schedule for a novel combination antimetabolite, TAS-102, based on its intracellular metabolism and its incorporation into DNA. Int J Mol Med 13: 249–255 - PubMed
    1. Emura T, Suzuki N, Yamaguchi M, Ohshimo H, Fukushima M (2004b) A novel combination antimetabolite, TAS-102, exhibits antitumor activity in FU-resistant human cancer cells through a mechanism involving FTD incorporation in DNA. Int J Oncol 25: 571–578 - PubMed
    1. Fujiwara Y, Heidelberger C (1970a) Fluorinated pyrimidines. XXXVII. The incorporation of 5-trifluoromethyl-2'-deoxyuridine into the deoxyribonucleic acid vaccinia virus. Mol Pharmacol 6: 281–291 - PubMed
    1. Fujiwara Y, Oki T, Heidelberger C (1970b) Fluorinated pyrimidines. XXXVII. Effect of 5-trifluoromethyl-2'-deoxyuridine on the synthesis of deoxyribonucleic acid of mammalian cells in culture. Mol Pharmacol 6: 273–280 - PubMed

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