National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Cancer Chemother Pharmacol. 2013 Jan;71(1):227-35. doi: 10.1007/s00280-012-2000-1. Epub 2012 Nov 3.
To evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of trebananib (AMG 386)--a first-in-class angiopoietin-1/2 antagonist peptide-Fc fusion protein--in Japanese patients, we conducted a phase 1, dose escalation study.
Eligible patients were men or women, aged between 20 and 74 years, who had histologically or cytologically confirmed advanced solid tumors refractory to standard treatment. Trebananib (3, 10, and 30 mg/kg) was administered intravenously over 60 min in weekly cycles.
From June 2009 to April 2010, a total of 18 patients (6 for each dose cohort) were enrolled into the study. Trebananib was tolerated at all dose levels. No dose-limiting toxicities were observed. The most common adverse events were peripheral edema, constipation, fatigue, and pyrexia. Exposure to trebananib appeared to increase according to the dose administered. Serum clearance appeared to be similar across the dose range with the mean terminal-phase half-life ranging from 93.9 to 95.9 h. No neutralizing antibodies were detected. Tumor response was assessed in 18 patients. Of these, one patient with colon cancer in the 3-mg/kg cohort and one with bladder cancer in the 30-mg/kg cohort had partial responses as their best responses. These 2 patients were on treatment at the time of data cutoff (January 17, 2012).
Trebananib was tolerated and showed acceptable safety profile in Japanese patients with advanced solid tumors. The pharmacokinetic profiles were similar to those in the previous studies in the United States. Trebananib also showed evidence of durable antitumor activity in some patients.
评估替拉那尼（AMG 386）——一种新型的血管生成素-1/2 拮抗剂肽-Fc 融合蛋白——在日本患者中的安全性、耐受性、药代动力学和抗肿瘤活性。我们进行了一项 1 期、剂量递增研究。
符合条件的患者为男性或女性，年龄在 20 至 74 岁之间，患有组织学或细胞学证实的晚期实体瘤，对标准治疗无反应。替拉那尼（3、10 和 30mg/kg）以 60 分钟静脉输注，每周一次。
从 2009 年 6 月至 2010 年 4 月，共有 18 名患者（每个剂量组 6 名）入组该研究。替拉那尼在所有剂量水平下均耐受良好。未观察到剂量限制性毒性。最常见的不良反应为外周水肿、便秘、疲劳和发热。替拉那尼的暴露量似乎与给药剂量成正比。血清清除率在剂量范围内似乎相似，平均终末相半衰期范围为 93.9 至 95.9 小时。未检测到中和抗体。对 18 名患者进行了肿瘤反应评估。其中，1 名结肠癌患者（3mg/kg 组）和 1 名膀胱癌患者（30mg/kg 组）的最佳反应为部分缓解。这 2 名患者在数据截止日期（2012 年 1 月 17 日）时仍在接受治疗。
替拉那尼在日本晚期实体瘤患者中具有可耐受的安全性，且安全性特征与之前在美国的研究相似。药代动力学特征与之前在美国的研究相似。替拉那尼在一些患者中也显示出持久的抗肿瘤活性。
