Phase I clinical trial of recombinant human endostatin administered as a short intravenous infusion repeated daily
Phase I clinical trial of recombinant human endostatin administered as a short intravenous infusion repeated daily
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DOI：
10.1200/jco.2002.02.082
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发表时间：
2002-09-15
影响因子：
45.3
通讯作者：
Kufe, DW
中科院分区：
文献类型：
--
作者：
Eder, JP;Supko, JG;Kufe, DW
目的：进行一项I期临床试验，重组人血管内皮抑制素（rhEndostatin; RheumMed，Rockville，MD）作为每日20分钟静脉（IV）注射给药在成人难治性实体瘤Patients and Methods：每日剂量从15增加到240 mg/m2（3例患者的队列中的100%的因素）。在不存在剂量限制性毒性的情况下，继续不间断治疗，直至肿瘤负荷较基线增加超过50%。相关研究包括动态增强磁共振成像肿瘤血流，尿血管内皮生长因子和碱性成纤维细胞生长因子水平，rhEndostatin血清药代动力学，并监测循环抗体rhEndostatin.Results：有没有显着的治疗相关的毒副作用15例患者接受共50个月的周期rhEndostatin。1例胰腺神经内分泌肿瘤患者有轻微缓解，2例患者显示疾病稳定。rhEndostatin药代动力学的线性通过第一次给药的曲线下面积和稳态时的峰值血清浓度的剂量成比例增加来指示。在接受240 mg/m2/d的患者中，rhEndostatin的每日全身暴露量比临床前研究中提供的治疗最佳剂量低约50%。结论：rhEndostatin以高达240 mg/m2的剂量每日20分钟静脉注射给药，未显示出明显的毒性。在3例患者中观察到临床获益的证据。由于与重复短时间IV输注方案相关的血清峰浓度和谷浓度之间的高度变异性，每日血清药物水平仅短暂超过体外抗血管生成作用所需的浓度。(C)2002年，美国临床肿瘤学会。
Purpose: To perform a phase I trial of recombinant human endostatin (rhEndostatin; EntreMed, Rockville, MD) given as a daily 20-minute intravenous (IV) injection in adult patients with refractory solid tumors.Patients and Methods: The daily dose was increased from 15 to 240 mg/m(2) by a factor of 100% in cohorts of three patients. In the absence of dose-limiting toxicity, uninterrupted treatment was continued until the tumor burden increased by more than 50% from baseline. Correlative studies included dynamic contrast-enhanced magnetic resonance imaging of tumor blood flow, urinary vascular endothelial growth factor and basic fibroblast growth factor levels, rhEndostatin serum pharmacokinetics, and monitoring of circulating antibodies to rhEndostatin.Results: There were no notable treatment related toxicities among 15 patients receiving a total of 50 monthly cycles of rhEndostatin. One patient with a pancreatic neuroendocrine tumor had a minor response and two patients showed disease stabilization. Linearity in the pharmacokinetics of rhEndostatin was indicated by dose-proportionate increases in the area under the curve for the first dose and the peak serum concentration at steady state. Daily systemic exposure to rhEndostatin in patients receiving 240 mg/m(2)/d was approximately 50% lower than that provided by the therapeutically optimal dose in preclinical studies.Conclusion: rhEndostatin administered as a 20-minute daily IV injection at doses up to 240 mg/m(2) showed no significant toxicities. Evidence of clinical benefit was observed in three patients. Due to high variability between the peak and trough serum concentrations associated with the repeated short IV infusion schedule, daily serum drug levels only briefly exceeded concentrations necessary for in vitro antiangiogenic effects. (C) 2002 by American Society of Clinical Oncology.