Gastrointestinal/Oncology Division, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Cancer Chemother Pharmacol. 2011 Sep;68(3):733-41. doi: 10.1007/s00280-010-1544-1. Epub 2010 Dec 16.
Conatumumab is a fully human monoclonal agonist antibody against human death receptor 5 (DR5). The primary objectives of this phase 1 study were to assess the safety, tolerability, and pharmacokinetics (PK) of conatumumab in Japanese patients with advanced solid tumors.
This is an open-label ascending dose study with a starting dose level of 3 mg/kg. Subsequent doses of 10 and 20 mg/kg were planned. Six patients were enrolled into 1 of 3 dose cohorts (3, 10, or 20 mg/kg) of conatumumab administered intravenously once every 2 weeks as a single agent. No conatumumab was administered on day 43 to allow the assessment of terminal PK parameters. The primary endpoints were the incidence of dose-limiting toxicities (DLTs) and assessment of PK parameters of conatumumab.
Eighteen patients received at least 1 dose of conatumumab. There were no DLTs observed as defined in the protocol. No patients had an adverse event leading to conatumumab discontinuation. Conatumumab demonstrated dose-linear kinetics. A best response of stable disease was reported in nine patients. Monocytes were found to express DR5 and showed a high degree of conatumumab receptor occupancy after treatment at all dose levels.
Conatumumab administered up to 20 mg/kg once every 2 weeks was well tolerated in Japanese patients with advanced solid tumors. Adverse events and PK in these patients were similar to those in the first in human (FIH) study.
康奈妥单抗是一种针对人死亡受体 5（DR5）的全人源单克隆激动性抗体。这项 I 期研究的主要目的是评估康奈妥单抗在晚期实体瘤日本患者中的安全性、耐受性和药代动力学（PK）。
这是一项开放标签递增剂量研究，起始剂量水平为 3mg/kg。计划后续剂量为 10mg/kg 和 20mg/kg。6 名患者入组了康奈妥单抗的 3 个剂量队列（3mg/kg、10mg/kg 或 20mg/kg）中的 1 个，每 2 周静脉输注 1 次作为单药治疗。第 43 天不给予康奈妥单抗，以评估终末 PK 参数。主要终点是剂量限制性毒性（DLT）的发生率和康奈妥单抗 PK 参数的评估。
18 名患者至少接受了 1 剂康奈妥单抗。根据方案定义，未观察到 DLT。没有患者因不良事件而停止使用康奈妥单抗。康奈妥单抗显示出剂量线性动力学。9 名患者报告了疾病稳定的最佳反应。在所有剂量水平下，治疗后发现单核细胞表达 DR5 并表现出高程度的康奈妥单抗受体占有率。
在晚期实体瘤的日本患者中，每 2 周静脉输注 20mg/kg 的康奈妥单抗耐受性良好。这些患者的不良反应和 PK 与首次人体（FIH）研究相似。
