Safety, tolerability, pharmacokinetics and immunogenicity of an antibody–drug conjugate (SHR-A1201) in patients with HER2-positive advanced breast cancer: an open, phase I dose-escalation study

耐受性 医学 药代动力学 不利影响 恶心 内科学 毒性 乳腺癌 药理学 转移性乳腺癌 胃肠病学 最大值 无症状的 癌症
作者
Yinjuan Li,Lu Qi,Yu Wang,Xia Zhao,Shuzhen Lv,Yu Feng,Chen Liu,Pu Li,Bingjun Xiong,Yihui Guo,Dapeng Lv,Yongbo Liu,Ting Mei,Keyu Yuan,Xiaoqiang Cheng,Yanping Li,Xinghe Wang
出处
期刊:Anti-Cancer Drugs [Ovid Technologies (Wolters Kluwer)]
卷期号:34 (6): 763-774 被引量:2
标识
DOI:10.1097/cad.0000000000001456
摘要

SHR-A1201 is an antibody–drug conjugate (ADC) that combines trastuzumab with DM1 (a chemotherapeutic agent) using a chemical connector. This phase I study investigated the safety, tolerability and pharmacokinetics of SHR-A1201 in patients with human epidermal growth factor receptor 2-positive advanced breast cancer. This phase I study enrolled patients in a traditional 3 + 3 dose-escalation design to receive a single dose of SHR-A1201 (1.2 mg/kg, 2.4 mg/kg, 3.6 mg/kg or 4.8 mg/kg). The observation period of dose-limiting toxicity (DLT) was 21 days. A total of 12 patients were enrolled and received SHR-A1201. Most treatment-emergent adverse events (TEAEs) were grade 1 or 2 in severity, with elevated aspartate aminotransferase (75%), thrombocytopenia (75%), and nausea (66.7%) being reported most frequently. The common grade 3 TEAEs were thrombocytopenia and decreased lymphocyte count, and there were no grade 4 or above TEAEs. There were no serious adverse events or drug-related deaths. One DLT occurred in one patient treated with SHR-A1201 4.8 mg/kg (asymptomatic grade 3 increased γ-glutamyltransferase). The maximum tolerated dose of SHR-A1201 was not lower than that of T-DM1 (3.6 mg/kg). A total of 8.3% (1/12) of patients had ADA-positive reactions 504 h after administration, but no differences were observed in the type, incidence, or severity of TEAEs between patients with and without ADA. SHR-A1201 exhibited the pharmacokinetics characteristics of typical ADCs. An encouraging antitumor effect was observed in the 4.8 mg/kg dose group. SHR-A1201 was well tolerated and safe in patients with advanced HER2-positive breast cancer. The pharmacokinetics parameters showed a linear trend, and the immunogenicity results met the clinical expectations.
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