Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors
Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors
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DOI：
10.1007/s10637-008-9142-3
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发表时间：
2008-10-01
影响因子：
3.4
通讯作者：
Abbruzzese, James L.
中科院分区：
文献类型：
--
作者：
Overman, Michael J.;Varadhachary, Gauri;Abbruzzese, James L.
本研究旨在确定 TAS-102 的安全性和最佳剂量，TAS-102 是 α-三氟胸苷 (FTD) 和胸苷磷酸化酶抑制剂的新型口服组合，在实体瘤患者中的安全性和最佳剂量。符合资格标准的患者接受两种不同 TAS-102 方案之一的治疗：每 4 周第 1-5 和 8-12 天每天一次（时间表 A）或每 3 周第 1-5 天（时间表 B）。主要目标是确定最大耐受剂量、剂量限制毒性 (DLT) 和推荐的 II 期剂量。在疗程 1 和疗程 2 期间进行药代动力学分析。63 名患者总共接受了 172 个疗程，两个疗程的中位疗程数均为 2。在疗程 A 中观察到 3 名患者的 DLT，分别为 70 mg/m(2)/天 (1) 和 110 mg/m(2)/天 (2)；方案 B 中的 5 名患者分别为 120 mg/m(2)/天 (1)、170 mg/m(2)/天 (2)、180 mg/m(2)/天 (2)。 8 例中的 7 例中，粒细胞减少症是 DLT。最常见的毒性是恶心、疲劳、粒细胞减少、贫血、腹泻和腹痛。 12 名患者（6 名按计划 A 进行，6 名按计划 B 进行）接受推荐的 II 期剂量治疗，具有良好的耐受性。在这个经过大量预处理的 5-FU 难治性人群中，没有观察到客观反应。 FTD的药代动力学参数为T-max为0.53至3.15小时，t(1/2)为1.46至4.20小时，分布容积为0.0526至0.483 1/kg，清除率为0.0194至0.197 1/h/kg。 TAS-102 的推荐 II 期剂量为方案 A 中的 100 mg/m(2)/天和方案 B 中的 160 mg/m(2)/天。TAS-102 的未来开发应侧重于多种每日给药方案。
This study was designed to determine the safety and optimal dosing of TAS-102, a novel oral combination of alpha alpha alpha-trifluorothymidine (FTD) and an inhibitor of thymidine phoshorylase, in patients with solid tumors. Patients who met the eligibility criteria were treated with one of two different TAS-102 regimens: once per day on either days 1-5 and 8-12 every 4 weeks (schedule A) or days 1-5 every 3 weeks (schedule B). The primary objectives were the determination of the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose. Pharmacokinetic analysis was conducted during courses 1 and 2. Sixty-three patients received a total of 172 courses of therapy with the median number of courses delivered on both schedules being 2. DLTs were observed in three patients on schedule A, 70 mg/m(2)/day (1) and 110 mg/m(2)/day (2); and in five patients on schedule B, 120 mg/m(2)/day (1), 170 mg/m(2)/day (2), 180 mg/m(2)/day (2). Granulocytopenia was the DLT in seven of the eight cases. The most frequent toxicities were nausea, fatigue, granulocytopenia, anemia, diarrhea, and abdominal pain. Twelve patients, 6 on schedule A and 6 on schedule B, were treated at the recommended phase II dose, with good tolerance. No objective responses were seen in this heavily pretreated, 5-FU-refractory population. The pharmacokinetic parameters of FTD are a T-max of 0.53 to 3.15 h, t(1/2) of 1.46 to 4.20 h, volume of distribution of 0.0526 to 0.483 1/kg, and clearance of 0.0194 to 0.197 1/h/kg. The recommended phase II doses for TAS-102 are 100 mg/m(2)/day on schedule A and 160 mg/m(2)/day on schedule B. Future development of TAS-102 should focus upon multiple daily dosing schedules.