First-in-Man Phase I Study of GC33, a Novel Recombinant Humanized Antibody Against Glypican-3, in Patients with Advanced Hepatocellular Carcinoma
First-in-Man Phase I Study of GC33, a Novel Recombinant Humanized Antibody Against Glypican-3, in Patients with Advanced Hepatocellular Carcinoma
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DOI：
10.1158/1078-0432.ccr-12-2616
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发表时间：
2013-02-15
影响因子：
11.5
通讯作者：
Philip, Philip A.
中科院分区：
文献类型：
--
作者：
Zhu, Andrew X.;Gold, Philip J.;Philip, Philip A.
目的：GC 33是一种新型的重组人源化单克隆抗体，可与人磷脂酰肌醇蛋白聚糖3（GPC 3）结合。GC 33的抗肿瘤活性在肝细胞癌（HCC）的临床前模型中显示。进行首次人体临床试验以评估GC 33在晚期HCC患者中的安全性、药代动力学特征和初步疗效。实验设计：患有可测量的、经组织学证实的晚期HCC的患者被纳入GC 33（2.5-20 mg/kg）每周静脉内给药的剂量递增研究。主要终点是确定GC 33的最大耐受剂量，以便进一步开发。在血清样品中测量药代动力学特征。对肿瘤活检进行免疫组织化学以评估GPC 3表达。每8周使用实体瘤疗效评价标准（Response Evaluation Criteria in Solid Tumors criterions.Results）评估一次肿瘤疗效。未达到最大耐受剂量，因为在最高计划剂量水平下未出现剂量限制性毒性（DLT）。所有级别的常见不良事件包括疲劳（50%）、便秘（35%）、头痛（35%）和低钠血症（35%）。不良事件的发生率似乎与剂量无关。在5 mg/kg或更高剂量下，稳态血清谷浓度超过目标浓度。GPC 3高表达组的中位进展时间（TTP）为26.0周，低表达组为7.1周（P = 0.033）。结论：本研究表明GC 33在晚期HCC中耐受性良好，并提供了初步证据，证明GPC 3在HCC中的表达可能与GC 33的临床益处相关，值得进行前瞻性评价。临床癌症研究; 19（4）; 920-8。(c)2012年AACR。
Purpose: GC33 is a novel recombinant fully humanized monoclonal antibody that binds to human glypican-3 (GPC3). The antitumor activity of GC33 was shown in preclinical models of hepatocellular carcinoma (HCC). This first-in-man clinical trial was conducted to evaluate the safety, pharmacokinetic characteristics, and preliminary efficacy of GC33 in patients with advanced HCC.Experimental Design: Patients with measurable, histologically proven, advanced HCC were enrolled to a dose-escalation study of GC33 (2.5-20 mg/kg) given intravenously weekly. The primary endpoint was to determine the maximum tolerated dose of GC33 for further development. Pharmacokinetic characteristics were measured in serum samples. Immunohistochemistry was conducted on tumor biopsies to evaluate GPC3 expression. Tumor response was assessed every 8 weeks using Response Evaluation Criteria in Solid Tumors criteria.Results: Twenty patients were enrolled and treated with GC33. A maximum tolerated dose was not reached as there were no dose-limiting toxicities (DLT) up to the highest planned dose level. Common adverse events with all grades included fatigue (50%), constipation (35%), headache (35%), and hyponatremia (35%). The incidence of adverse events seemed not to be dose dependent. Trough serum concentrations at steady state were in excess of target concentration at doses of 5 mg/kg or greater. Median time to progression (TTP) was 26.0 weeks in the GPC3 high expression group and 7.1 weeks in the low expression group (P = 0.033).Conclusion: This study shows that GC33 was well tolerated in advanced HCC and provides preliminary evidence that GPC3 expression in HCC may be associated with the clinical benefit to GC33 that warrants prospective evaluation. Clin Cancer Res; 19(4); 920-8. (c) 2012 AACR.