Japanese phase I study of GC33, a humanized antibody against glypican-3 for advanced hepatocellular carcinoma.
Japanese phase I study of GC33, a humanized antibody against glypican-3 for advanced hepatocellular carcinoma.
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DOI：
10.1111/cas.12368
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发表时间：
2014-04
期刊：
影响因子：
5.7
通讯作者：
Furuse J
中科院分区：
文献类型：
--
作者：
Ikeda M;Ohkawa S;Okusaka T;Mitsunaga S;Kobayashi S;Morizane C;Suzuki I;Yamamoto S;Furuse J
GC33是一种人源化的抗人GPC3的单抗。在美国进行的第一项人类研究中，GC33耐受性良好，并在晚期肝细胞癌患者中显示出初步的抗肿瘤活性。本研究旨在评估GC33在日本晚期肝细胞癌患者中的安全性、耐受性和药代动力学特征。研究设计为常规的3+3剂量递增设计，以确定静脉注射GC33的最大耐受量。每周5、10或20毫克/公斤。采用免疫组织化学方法检测肿瘤活检组织中GPC3的表达。13名患者参加了三个剂量水平的研究，没有患者观察到最高计划剂量20毫克/公斤以下的任何剂量限制性毒性。最常见的不良事件是淋巴细胞计数下降，自然杀伤细胞计数下降，C反应蛋白升高，以及发热。在两个或更多的患者中观察到了3级不良事件(血压升高、淋巴细胞计数下降和血小板计数下降)。AUCinf从5 mg/kg剂量组到20 mg/kg剂量组呈剂量比例增加。GC33的低谷浓度在第四至第六次剂量后趋于稳定。13名患者中有7名病情稳定，另外6名患者病情进展。此外，有3例患者的病情长期稳定在5个月以上。总而言之，日本晚期肝细胞癌患者每周给予GC33 20 mg/kg的耐受性良好。
GC33 is a humanized mAb against human glypican-3 (GPC3). In the first-in-human study carried out in the USA, GC33 was well tolerated and showed preliminary antitumor activity in patients with advanced hepatocellular carcinoma. This study aimed to assess the safety, tolerability, and pharmacokinetic characteristics of GC33 in Japanese patients with advanced hepatocellular carcinoma. The study design was a conventional 3 + 3 dose-escalation design to determine the maximum tolerated dose of GC33 given i.v. at 5, 10, or 20 mg/kg weekly. Immunohistochemistry was carried out on tumor biopsies to evaluate GPC3 expression. Thirteen patients were enrolled across the three dose levels, and no patients observed any dose-limiting toxicity up to the highest planned dose of 20 mg/kg. The most common adverse events were decreased lymphocyte count, decreased natural killer cell count, increased C-reactive protein, and pyrexia. Grade 3 adverse events (increased blood pressure, decreased lymphocyte count, and decreased platelet count) were observed in two or more patients. The AUCinf showed a dose-proportional increase from the 5 mg/kg dose group to the 20 mg/kg dose group. The trough concentrations of GC33 appeared to reach a steady state after the fourth to the sixth dose. Seven of the 13 patients showed stable disease, the other six showed progressive disease. Furthermore, three patients showed long-term stable disease of more than 5 months. In conclusion, GC33 given at up to 20 mg/kg weekly was well tolerated in Japanese patients with advanced hepatocellular carcinoma.
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影响因子：
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作者：
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