Phase I clinical evaluation of ZD6126, a novel vascular-targeting agent, in patients with solid tumors
Phase I clinical evaluation of ZD6126, a novel vascular-targeting agent, in patients with solid tumors
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DOI：
10.1007/s10637-008-9112-9
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发表时间：
2008-04-01
影响因子：
3.4
通讯作者：
Wheeler, Catherine
中科院分区：
文献类型：
--
作者：
LoRusso, Patricia M.;Gadgeel, Shirish M.;Wheeler, Catherine
背景：ZD6126是一种新型的血管靶向剂，可以破坏内皮细胞微管蛋白细胞骨架，导致肿瘤血管的选择性闭塞和广泛的肿瘤坏死。这项I期临床研究旨在评价ZD6126的剂量和给药方案。方法对现有治疗方法无效的成人实体瘤患者给予ZD6126单次静脉滴注10min，每14~21d一次。根据第一个给药周期内不良事件(AEs)的发生率，进行随后的剂量递增。采集血样进行药代动力学分析，利用DCE-MRI技术观察ZD6126对肿瘤血管的影响。结果44例患者接受ZD6126治疗(21天疗程5~112 mg/m(2)，n=35；14天疗程40~80 mg/m(2)，n=9)。两组常见的不良反应相似，包括腹痛、恶心和呕吐，似乎与剂量有关。在为期21天的研究中，腹痛的发生率为112 mg/m(2)，防止了进一步的剂量增加。药代动力学研究证实，ZD6126能迅速降解为ZD6126苯酚。ZD6126苯酚重复给药或两种给药方案之间的药代动力学无差异。DCE-MRI评估证实了ZD6126的抗血管作用。结论ZD6126以80 mg/m(2)剂量每2~3周给药一次，耐受性良好，出现轻度但可控的胃肠道不良反应。在大约11%(5/44)的患者中，ZD6126与被归类为剂量限制毒性的心脏事件有关(1名患者无症状地降低左心室射血分数(LVEF)，2名患者肌钙蛋白浓度升高，1名患者患有心肌缺血，1名患者有心肌缺血的心电图体征)。
Background ZD6126 is a novel vascular-targeting agent that disrupts the endothelial tubulin cytoskeleton causing selective occlusion of tumor vasculature and extensive tumor necrosis. This Phase I clinical study was conducted to evaluate the dose and administration schedule of ZD6126. Methods Adult patients with solid tumors refractory to existing treatments received a 10-min, single-dose intravenous infusion of ZD6126 every 14 or 21 days. Subsequent dose escalation was performed, based on the incidence of adverse events (AEs) within the first cycle of drug administration. Blood samples were obtained for pharmacokinetic analysis, and the effects of ZD6126 on tumor vasculature were visualized using DCE-MRI technology. Results Forty-four patients received ZD6126 (5-112 mg/m(2) in the 21-day schedule, n=35; 40-80 mg/m(2) in the 14-day schedule, n=9). Common AEs were similar in both groups and included abdominal pain, nausea and vomiting, which appeared to be dose related. The incidence of abdominal pain at 112 mg/m(2) in the 21-day study prevented further dose escalation. Pharmacokinetic studies confirmed that ZD6126 is rapidly hydrolyzed to ZD6126 phenol. There was no difference in the pharmacokinetics of ZD6126 phenol upon repeat administration or between the two dosing regimens. DCE-MRI evaluation has demonstrated the antivascular effects of ZD6126. Conclusions This study identified that ZD6126 administered every 2 or 3 weeks at 80 mg/m(2) was well tolerated, with mild but manageable gastrointestinal AEs. In approximately 11% (5 out of 44) of patients, ZD6126 was associated with cardiac events categorized as dose limiting toxicities (one patient with asymptomatic decreased left ventricular ejection fraction (LVEF), two with increased troponin concentrations, one with myocardial ischemia, and one with ECG signs of myocardial ischemia).