Department of Internal Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Invest New Drugs. 2012 Feb;30(1):266-72. doi: 10.1007/s10637-010-9506-3. Epub 2010 Aug 10.
This study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of TTI-237, a novel anti-tubulin drug, administered weekly in patients with refractory solid tumors.
Using an accelerated dose escalation design, patients with refractory solid tumors were enrolled in this study and treated with TTI-237 intravenously on days 1, 8 and 15 of a 28-day cycle. The starting dose was 4.5 mg/m(2). Pharmacokinetic studies were performed in patients at all dose levels.
Twenty-eight patients were enrolled and treated with TTI-237 at dose of 4.5, 9, 15, 22.5 and 31.5 mg/m(2). One dose-limiting toxicity neutropenia fever was observed at 31.5 mg/m(2), and all seven patients developed grade 3 or 4 neutropenia at that dose level. TTI-237 dosage was de-escalated to 22.5 and 18 mg/m(2). Six patients were treated at the 18 mg/m(2) dose level without dose-limiting toxicity prior to trial termination. The mean terminal-phase elimination half-life (t(1/2)) for TTI-237 was 25-29 h, and the mean area under the concentration time curve at 31.5 mg/m(2) was 2,768 ng•h/mL.
A protocol defined maximum tolerated dose was not determined because of early termination of the TTI-237 trial by the sponsor. 18 mg/m(2) may be a tolerable dose of TTI-237.
本研究旨在确定每周给药的新型抗微管药物 TTI-237 在难治性实体瘤患者中的最大耐受剂量、剂量限制性毒性和药代动力学特征。
采用加速剂量递增设计，入组难治性实体瘤患者，每 28 天周期的第 1、8 和 15 天静脉注射 TTI-237。起始剂量为 4.5mg/m2。在所有剂量水平的患者中进行药代动力学研究。
28 例患者接受了 TTI-237 治疗，剂量分别为 4.5、9、15、22.5 和 31.5mg/m2。在 31.5mg/m2 时观察到 1 例剂量限制性毒性中性粒细胞减少发热，该剂量水平的所有 7 例患者均发生 3 或 4 级中性粒细胞减少。TTI-237 剂量下调至 22.5 和 18mg/m2。在试验终止前，6 例患者在 18mg/m2 剂量水平下未发生剂量限制性毒性。TTI-237 的平均终末相消除半衰期（t1/2）为 25-29h，31.5mg/m2 时的平均浓度时间曲线下面积为 2768ng•h/mL。
由于研究发起者提前终止了 TTI-237 试验，因此未确定方案定义的最大耐受剂量。18mg/m2 可能是 TTI-237 的可耐受剂量。
