Head and Neck/Head and Neck Medical Oncology and Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Clin Cancer Res. 2010 Dec 1;16(23):5883-91. doi: 10.1158/1078-0432.CCR-10-0631. Epub 2010 Oct 14.
To determine the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of conatumumab, an investigational, fully human monoclonal agonist antibody against human death receptor 5, in patients with advanced solid tumors.
In the dose-escalation phase, patients received escalating intravenous doses of conatumumab (0.3, 1, 3, 10, or 20 mg/kg, 3-9 per cohort) every 2 weeks. In the dose-expansion phase, 10 patients with colorectal cancer (CRC) and 7 with non-small cell lung cancer (NSCLC) received 20 mg/kg of conatumumab every 2 weeks.
Thirty-seven patients received 1 or more doses of conatumumab. Conatumumab seemed to be well tolerated; there were no dose-limiting toxicities. Of adverse events possibly related to treatment, only 3 patients (8%) had a grade 3 event (fatigue and/or elevated lipase), and no anticonatumumab antibodies were detected. An MTD was not reached. Conatumumab exhibited dose linear kinetics from 3 to 20 mg/kg, with a mean terminal half-life of 13 to 19 days. One patient with NSCLC (0.3 mg/kg) had a confirmed partial response (PR) at week 32 (38% reduction in tumor size), with further reduction (48%) by week 96; this patient remains on conatumumab after 4.2 years with a sustained PR. Fourteen patients had a best response of stable disease, 2 for 32 weeks or more. One patient with CRC (0.3 mg/kg) and stable disease for 24 weeks had a 24% reduction in tumor size by RECIST (Response Evaluation Criteria in Solid Tumors) and a 35% reduction in the sum of standardized uptake values of all lesions measured by [18F]fluorodeoxyglucose positron emission tomographic scan. Changes in tumor levels of activated caspase-3 did not appear to be associated with tumor response.
Conatumumab can be administered safely up to the target dose of 20 mg/kg every 2 weeks.
评估研究性全人源单克隆激动型抗体 conatumumab 治疗晚期实体瘤的安全性、耐受性、药代动力学和最大耐受剂量（MTD）。
在剂量递增阶段，患者每 2 周静脉注射递增剂量的 conatumumab（0.3、1、3、10 或 20mg/kg，每组 3-9 人）。在剂量扩展阶段，10 例结直肠癌（CRC）和 7 例非小细胞肺癌（NSCLC）患者每 2 周接受 20mg/kg 的 conatumumab。
37 例患者接受了 1 次或多次 conatumumab 治疗。conatumumab 耐受性良好，未观察到剂量限制毒性。与治疗相关的不良事件中，仅有 3 例（8%）出现 3 级事件（疲劳和/或脂肪酶升高），未检测到抗 conatumumab 抗体。未达到 MTD。conatumumab 在 3 至 20mg/kg 之间呈剂量线性动力学，平均终末半衰期为 13 至 19 天。1 例 NSCLC（0.3mg/kg）患者在第 32 周（肿瘤大小缩小 38%）时获得确认的部分缓解（PR），第 96 周时进一步缩小（48%）；该患者在 4.2 年后仍在接受 conatumumab 治疗，持续 PR。14 例患者的最佳反应为疾病稳定，其中 2 例持续 32 周以上。1 例 CRC（0.3mg/kg）患者疾病稳定 24 周，根据实体瘤反应评估标准（RECIST）肿瘤体积缩小 24%，所有病变标准化摄取值总和（SUV）减少 35%，该患者通过氟[18F]脱氧葡萄糖正电子发射断层扫描（FDG-PET）检查。肿瘤中激活的半胱天冬酶-3水平的变化似乎与肿瘤反应无关。
conatumumab 以每 2 周 20mg/kg 的目标剂量安全给药。
Zotero 插件