纳妥单抗依司他托克斯单药用于晚期癌症患者以及多西他赛用于晚期非小细胞肺癌患者的I期剂量递增、药代动力学和药效学研究。
Phase I dose escalation, pharmacokinetic and pharmacodynamic study of naptumomab estafenatox alone in patients with advanced cancer and with docetaxel in patients with advanced non-small-cell lung cancer.
作者信息
Borghaei Hossein, Alpaugh Katherine, Hedlund Gunnar, Forsberg Göran, Langer Corey, Rogatko Andre, Hawkins Robert, Dueland Svein, Lassen Ulrik, Cohen Roger B
机构信息
DO, Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, USA.
出版信息
J Clin Oncol. 2009 Sep 1;27(25):4116-23. doi: 10.1200/JCO.2008.20.2515. Epub 2009 Jul 27.
PURPOSE
Two phase I studies were conducted of ABR-217620 alone or in combination with docetaxel. This is a recombinant fusion protein consisting of a mutated variant of the superantigen staphylococcal enterotoxin E (SEA/E-120) linked to fragment antigen binding moiety of a monoclonal antibody recognizing the tumor-associated antigen 5T4.
PATIENTS AND METHODS
Patients with non-small-cell lung cancer (NSCLC), pancreatic cancer (PC), and renal cell cancer (RCC) received 5 daily boluses of ABR-217620 (3-month cycles) in escalating doses to determine the maximum-tolerated dose (MTD; ABR-217620 dose escalation monotherapy [MONO] study). Doses were selected based on individual patient anti-SEA/E-120 titers pretreatment. Patients with NSCLC received 4 daily, escalating doses of ABR-217620 followed by docetaxel in 21-day cycles (ABR-217620 dose escalation combination with docetaxel [COMBO] study).
RESULTS
Thirty-nine patients were enrolled in the MONO study and 13 were enrolled in the COMBO study. The monotherapy MTD was 26 microg/kg (NSCLC and PC) and 15 microg/kg (RCC). Dose-limiting toxicities (DLTs) in the MONO study were fever, hypotension, acute liver toxicity, and vascular leak syndrome. In the COMBO study, the MTD was 22 microg/kg (neutropenic sepsis). Adverse events included grade 1 to 2 fever, hypotension, nausea, and chills. Treatment caused a systemic increase of inflammatory cytokines and selective expansion of SEA/E-120 reactive T-cells. Tumor biopsies demonstrated T-cell infiltration after therapy. Fourteen patients (36%) had stable disease (SD) on day 56 of the MONO study. Two patients (15%) in the COMBO study had partial responses, one in a patient with progressive disease on prior docetaxel, and five patients (38%) had SD on day 56.
CONCLUSION
ABR-217620 was well tolerated with evidence of immunological activity and antitumor activity.
目的
开展了两项关于ABR-217620单独使用或与多西他赛联合使用的I期研究。这是一种重组融合蛋白，由超抗原葡萄球菌肠毒素E（SEA/E-120）的突变变体与识别肿瘤相关抗原5T4的单克隆抗体的片段抗原结合部分相连组成。
患者与方法
非小细胞肺癌（NSCLC）、胰腺癌（PC）和肾细胞癌（RCC）患者接受5次每日静脉推注ABR-217620（每3个月为一个周期），剂量逐步递增，以确定最大耐受剂量（MTD；ABR-217620剂量递增单药治疗[MONO]研究）。剂量根据患者治疗前抗SEA/E-120滴度进行选择。NSCLC患者接受4次每日递增剂量的ABR-217620，随后每21天周期接受多西他赛治疗（ABR-217620剂量递增联合多西他赛[COMBO]研究）。
结果
39例患者参加了MONO研究，13例患者参加了COMBO研究。单药治疗的MTD为26μg/kg（NSCLC和PC）和15μg/kg（RCC）。MONO研究中的剂量限制性毒性（DLT）为发热、低血压、急性肝毒性和血管渗漏综合征。在COMBO研究中，MTD为22μg/kg（中性粒细胞减少性脓毒症）。不良事件包括1至2级发热、低血压、恶心和寒战。治疗导致炎症细胞因子全身性增加以及SEA/E-120反应性T细胞选择性扩增。肿瘤活检显示治疗后有T细胞浸润。在MONO研究的第56天，14例患者（36%）病情稳定（SD）。COMBO研究中有2例患者（15%）出现部分缓解，其中1例是之前接受多西他赛治疗病情进展的患者，5例患者（38%）在第56天病情稳定。
结论
ABR-217620耐受性良好，有免疫活性和抗肿瘤活性的证据。
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