Phase I pharmacokinetic and pharmacodynamic study of recombinant human endostatin in patients with advanced solid tumors
Phase I pharmacokinetic and pharmacodynamic study of recombinant human endostatin in patients with advanced solid tumors
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DOI：
10.1200/jco.2003.12.120
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发表时间：
2003-01-15
影响因子：
45.3
通讯作者：
Wilding, G
中科院分区：
文献类型：
--
作者：
Thomas, JP;Arzoomanian, RZ;Wilding, G
目的：内皮抑素是第一个进入临床试验的内源性血管生成抑制剂。内皮抑素的实验室研究表明，广泛的抗肿瘤活性加上非常低的毒性。重组人内皮抑素的I期试验的目的是评估毒性和探索生物学有效性在难治性实体瘤患者。患者和方法：内皮抑素被管理作为1小时静脉输注，每天给予28天的周期。探索了30 mg/m2的起始剂量，随后剂量递增至60、100、150、225和300 mg/m2。对所有21例患者进行血清药代动力学评估。采用Western blot和质谱法评价内皮抑素代谢。内源性促血管生成生长因子的循环水平进行了检查。动态计算机断层扫描（CT），磁共振成像，超声和正电子发射tomography.Results：内皮抑素给予这个时间表基本上是免费的显着药物相关的毒性肿瘤和肿瘤血供成像。观察到2次一过性1级皮疹发作。未观察到临床反应。内皮抑素药代动力学与剂量呈线性关系，在临床前模型中达到的血清浓度与抗肿瘤活性相关。尽管有几例患者在入组研究时血管内皮生长因子水平持续下降，但未观察到对循环促血管生成生长因子的聚集效应。少数患者在动态CT扫描中表现出微血管密度下降的变化，尽管总体而言，内皮抑素对肿瘤血管系统的影响并不一致。结论：内皮抑素每日1小时静脉输注耐受性良好，剂量高达300 mg/m2时无剂量限制性毒性。(C)2003年，美国临床肿瘤学会。
Purpose: Endostatin is the first endogenous angiogenesis inhibitor to enter clinical trials. Laboratory investigations with endostatin have indicated broad antitumor activity coupled with remarkably low toxicity. A phase I trial of recombinant human endostatin was designed to evaluate toxicity and explore biologic effectiveness in patients with refractory solid tumors.Patients and Methods: Endostatin was administered as a 1-hour intravenous infusion given daily for a 28-day cycle. A starting dose of 30 mg/m(2) was explored with subsequent dose escalations of 60, 100, 150, 225, and 300 mg/m(2). Assessment of serum pharmacokinetics was performed on all 21 patients. Western blot assay and mass spectroscopy were employed to evaluate endostatin metabolism. Circulating levels of endogenous proangiogenic growth factors were examined. Tumor and tumor blood supply were imaged by dynamic computed tomography (CT), magnetic resonance imaging, ultrasound, and positron emission tomography.Results: Endostatin given on this schedule was essentially free of significant drug-related toxicity. Two transient episodes of grade 1 rash were observed. No clinical responses were observed. Endostatin pharmacokinetics were linear with dose, and serum concentrations were achieved that are associated with antitumor activity in preclinical models. No aggregate effect on circulating proangiogenic growth factors were seen, although several patients exhibited persistent declines in vascular endothelial growth factor levels while enrolled in the study. A few patients demonstrated changes in their dynamic CT scans suggestive of a decline in microvessel density, although overall, no consistent effect of endostatin on tumor vasculature was seen.Conclusion: Endostatin given daily as a 1-hour intravenous infusion was well tolerated without dose-limiting toxicity at doses up to 300 mg/m(2). (C) 2003 by American Society of Clinical Oncology.