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

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.

Trifluridine Induces p53-Dependent Sustained G2 Phase Arrest with Its Massive Misincorporation into DNA and Few DNA Strand Breaks

“…Intriguingly, in a xenograft model, TAS-102 exhibits similar antitumor activity on FU-resistant cells and their parental cell line (15). In addition, TAS-102 has been developed for use in the clinic (16)(17)(18)(19) and surprisingly, significantly improves overall survival of patients with metastatic colorectal cancer who were refractory or intolerant to fluoropyrimidine, irinotecan, or oxaliplatin in a placebo-controlled, double-blinded randomized phase II study (20). However, it is not fully understood how FTD exerts its cytotoxic effects on tumor cells that are resistant to chemotherapeutic drugs.…”

New Drug Combination in Colorectal Cancer Treatment: Trifluridine and Tipiracil

“…21,22 Buna göre, trifluridin+tipirasil (TAS-102) ile yapılan ilk 3 faz 1 çalışmasında günlük tek doz TAS-102 kullanılmış ve bu çalışmalarda trifluridin yarılanma ömrünün oldukça kısa (yaklaşık 2 saat) olduğu gözlenirken toksik etkiler de belirlenmiştir. 23,24 Daha sonra TAS-102 ile faz 1 çalışması, University of Texas MD Anderson Cancer Center'da 15 hastada oral olarak günlük 3 kez 60-80 mg/m 2 /gün dozda haftada 5 gün 2 hafta uygulanarak (her 4 haftada bir tekrarlanmış) yapıl-mıştır.…”

“…25 Japonya'da yapılan birbaşka faz 1 çalışmasında ise çoğunluğu kolerektal kanser olan 21 hastaya günde 2 kez 30-70 mg/m 2 /gün dozda TAS-102 uygulanmış ve maksimum tolere dedilen doz 70 mg/m 2 /gün olarak belirlenirken 11 hastanın durumunun stabil olduğu görülmüştür. 22 Tuğçe AVCI ve ark.…”

TAS-102: A Novel Antimetabolite for the 21st Century

“…No objective responses were seen but nine patients had prolonged stable disease and five patients had radiographic reductions in tumor burden that did not meet objective response criteria by the RECIST. A Phase I study in Japanese population further evaluated twice daily dosing of TAS-102 and established an MTD of 70 mg/m 2 per day when given twice a day on days 1-5 and 8-12 of a 28-day cycle [19]. Again, no objective responses were seen but stable disease was achieved in more than 50% of heavily pretreated patients.…”