Department of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan.
Clin Cancer Res. 2011 Apr 15;17(8):2528-37. doi: 10.1158/1078-0432.CCR-10-2638. Epub 2011 Mar 3.
E7080, an oral multitargeted receptor tyrosine kinase inhibitor, has antiangiogenic and antitumor activity. This Phase I study investigated maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy in patients with advanced solid tumors.
In this sequential, dose-escalation, open-label study E7080 was administered orally twice daily in a 2-week-on/1-week-off cycle. Plasma angiogenic proteins, circulating endothelial cells (CEC) and circulating progenitor cells (CEP) were measured for biomarker analysis.
Twenty-seven patients (median age 53 years, performance status 0/1) were enrolled. E7080 was escalated from 0.5 to 1, 2, 4, 6, 9, 13, 16, and 20 mg bid by conventional 3-patient cohorts. During cycle 1, no grade 3/4 toxicity was observed up to 13 mg bid. DLTs included grade 3 AST/ALT increase in 1 patient at 16 mg bid and grade 3 platelet count decrease in 2 patients at 20 mg bid. The MTD of 13 mg bid was determined. After repeated doses, C(max) and area under the plasma concentration-time curve increased in a dose-dependent manner. After 14 days' treatment, c-kit(+) CEPs and CECs significantly decreased in cycle 1, but c-kit(-) CEPs and CECs did not. Change from baseline in c-kit(+) CEC ratio in cycle 1 and baseline SDF1α, c-kit(+) CEPs and c-kit(+) CEP ratio significantly correlated with the E7080 therapeutic effect.
E7080 has manageable toxicity up to 13 mg bid when administered in a 2-week-on/1-week-off cycle and shows preliminary activity for durable disease control. Biomarker analysis suggested antiangiogenic activity correlated with antitumor activity in patients with a wide range of solid tumors.
E7080 是一种口服多靶点受体酪氨酸激酶抑制剂，具有抗血管生成和抗肿瘤活性。本Ⅰ期研究旨在评估晚期实体瘤患者的最大耐受剂量（MTD）、剂量限制性毒性（DLT）、药代动力学（PK）、药效学（PD）和疗效。
本研究为序贯、剂量递增、开放标签研究，E7080 口服，2 周给药/1 周停药，2 次/天。检测血浆血管生成蛋白、循环内皮细胞（CEC）和循环祖细胞（CEP），进行生物标志物分析。
共 27 例患者（中位年龄 53 岁，体能状态 0/1）入组。E7080 起始剂量 0.5 mg bid，每 3 例患者递增 1 个剂量水平，依次递增至 1、2、4、6、9、13、16 和 20 mg bid。第 1 周期未观察到 3/4 级毒性。16 mg bid 和 20 mg bid 时各有 1 例患者出现 3 级 AST/ALT 升高和 2 例患者出现 3 级血小板计数下降，确定 13 mg bid 为 MTD。重复给药后，Cmax 和 AUC 呈剂量依赖性增加。第 1 周期治疗 14 天后，c-kit(+) CEC 和 CEP 显著减少，但 c-kit(-) CEP 和 CEC 无明显变化。第 1 周期 c-kit(+) CEC 比值较基线的改变和基线 SDF1α、c-kit(+) CEP 和 c-kit(+) CEP 比值与 E7080 疗效显著相关。
E7080 以 2 周给药/1 周停药方案，13 mg bid 剂量时毒性可耐受，且对多种实体瘤有持久的疾病控制作用。生物标志物分析表明，抗血管生成活性与患者抗肿瘤活性相关，对广泛的实体瘤患者有效。
