Phase I study of recombinant human endostatin in patients with advanced solid tumors
Phase I study of recombinant human endostatin in patients with advanced solid tumors
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DOI：
10.1200/jco.2002.11.061
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发表时间：
2002-09-15
影响因子：
45.3
通讯作者：
Abbruzzese, JL
中科院分区：
文献类型：
--
作者：
Herbst, RS;Hess, KR;Abbruzzese, JL
目的：内皮抑素是XVIII胶原蛋白的20kd片段，是一种有效的血管生成抑制剂。我们在一项I期试验中评估了重组人内皮抑素（rh-Endo），该试验旨在评估实体肿瘤患者血管生成的安全性、药代动力学和血清标志物。患者和方法：26名患者参加了一项剂量发现试验，rh-Endo作为静脉注射，每天一次，每次20分钟。3例患者分别接受15、30、60、120、180和600 mg/m(2)/d的剂量水平治疗，7例患者接受300 mg/m(2)/d的剂量水平治疗。治疗包括至少两个28天的周期。评估包括无创成像、药代动力学和血清生物标志物。结果：25例患者接受rh-Endo治疗。治疗耐受性良好；没有剂量限制性毒性作用。频繁的中央静脉输注引起的菌血症是最常见的问题。rh-Endo的药代动力学处置是线性的，最好使用双室开放模型来描述。总体平均半衰期为10.7±4.1小时。在临床前模型中，300mg /m(2)的剂量在与活性相关的浓度-时间曲线下达到了一个面积。在两名患者中，有抗肿瘤活性的证据，但没有看到反应。血管生成活性的血清标志物没有提供对rh-Endo活性的深入了解。血清对rh-Endo和毕赤酵母均有抗体，但未见过敏反应。结论：rh-Endo安全性好，耐受性好。在临床前模型中，rh-Endo药代动力学曲线在与活性相关的浓度-时间曲线下达到了面积。观察到少量抗肿瘤活性的证据，并指示进一步研究。(C) 2002年由美国临床肿瘤学会出版。
Purpose: Endostatin, a 20-kd fragment of collagen XVIII, is a potent inhibitor of angiogenesis. We evaluated recombinant human endostatin (rh-Endo) in a phase I trial designed to assess safety, pharmacokinetics, and serum markers of angiogenesis in patients with solid tumors.Patients and Methods: Twenty-six patients were enrolled onto a dose-finding trial of rh-Endo administered as an intravenous bolus over a 20-minute period once daily. Three patients each were treated at dose levels of 15, 30, 60, 120, 180, and 600 mg/m(2)/d, and seven patients were treated at 300 mg/m(2)/d. Treatment consisted of a minimum of two 28-day cycles. Evaluations included noninvasive imaging, pharmacokinetics, and serum biomarkers.Results: Twenty-five patients were treated with rh-Endo. Treatment was well tolerated; there were no dose-limiting toxic effects. Bacteremia from frequent central line access was the most common problem. The pharmacokinetic disposition of rh-Endo was linear and best described using a two-compartmental open model. The overall mean half-life was 10.7 +/- 4.1 hours. A dose of 300 mg/m(2) achieved an area under the concentration-time curve associated with activity in preclinical models. In two patients, there was evidence of antitumor activity, but no responses were seen. Serum markers of angiogenic activity did not provide insight into rh-Endo's activity. Serum antibodies were observed against both rh-Endo and the Pichia pastoris vector, but no allergic reactions were observed.Conclusion: rh-Endo was safe and well tolerated. rh-Endo pharmacokinetic profiles achieved area under the concentration-time curves associated with activity in preclinical models. Evidence of minor antitumor activity was observed and further studies are indicated. (C) 2002 by American Society of Clinical Oncology.