Phase I study of TAS-102 treatment in Japanese patients with advanced solid tumours
Phase I study of TAS-102 treatment in Japanese patients with advanced solid tumours
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DOI：
10.1038/bjc.2012.274
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发表时间：
2012-07-24
影响因子：
8.8
通讯作者：
Sasaki, T.
中科院分区：
文献类型：
--
作者：
Doi, T.;Ohtsu, A.;Sasaki, T.
背景：TAS-102由a，a，a-三氟胸苷（TFT）和胸苷磷酸化酶（TPI）抑制剂组成。我们在日本晚期实体瘤患者中进行了一项剂量递增I期研究，方法：TAS-102在标准化疗难治性实体瘤患者中每日两次给药，第1-5天和第8-12天，28天为一周期，以确定其最大耐受剂量（MTD）、剂量限制性毒性（DLT）和药代动力学（PK）。在第1周期评价MTD。结果：在21例接受TAS-102 30、40、50、60或70 mg m（-2）/天治疗的患者中评价了安全性和PK。在30和70 mg m-2剂量组的2例患者中观察到DLT，如4级白细胞减少、4级中性粒细胞减少和4级血小板减少。α，α，α-三氟胸苷和TPI暴露量呈剂量依赖性增加，中性粒细胞计数下降百分比与TFT暴露量显著相关。18例结直肠癌患者的疾病控制率为50.0%，中位无进展生存期为2.4个月。由于3级和4级中性粒细胞减少症的增加趋势，TAS-102的剂量不增加至70 mg m（-2）/天以上，70 mg m（-2）/天是II期研究的推荐剂量。结论：TAS-102 70 mg m（-2）/天在日本晚期实体瘤患者中耐受。II期研究正在结直肠癌患者中进行。英国癌症杂志（2012）107，429-434。doi：10.1038/bjc.2012.274 www.bjcancer.com在线发布2012年6月26日（C）2012英国癌症研究
BACKGROUND: TAS-102 consists of a, a, a-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). alpha,alpha,alpha-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. British Journal of Cancer (2012) 107, 429-434. doi: 10.1038/bjc.2012.274 www.bjcancer.com Published online 26 June 2012 (C) 2012 Cancer Research UK