Department of Internal Medicine, Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
Invest New Drugs. 2010 Oct;28(5):650-8. doi: 10.1007/s10637-009-9287-8. Epub 2009 Jul 8.
We conducted a phase I trial of the antiangiogenic agent 6-O-(4-dimethylaminoethoxy) cinnamoyl fumagillol hemioxalate (CKD-732). Our aims were to determine the maximum tolerated dose (MTD), pharmacokinetics (PK), and safety profiles as well as identify the biologically active dose (BAD) from ex vivo pharmacodynamics (PD) and biomarkers of CKD-732. Using a dose escalation schedule, 19 patients with refractory solid tumors were enrolled at dose levels of CKD-732 ranging from 1 to 15 mg/m(2) given twice weekly for 2 weeks followed by a 1-week rest. No treatment-related deaths occurred in this study. Confusion and insomnia were dose-limiting toxicities (DLTs), and MTD was 15 mg/m(2). The area under the concentration-time curve (AUC) and maximum concentration (Cmax) increased dose dependently with increasing doses. The BAD was 5 mg/m(2) according to ex vivo PD. A decrement in soluble vascular endothelial growth factor receptor-3 (sVEGF-3) level was correlated with a reduction in tumor size (r = 0.54, P = 0.045). The results from this study showed an MTD of 15 mg/m(2) and a BAD of 5 mg/m(2).
我们进行了抗血管生成剂 6-O-(4-二甲氨基乙氧基)肉桂酰呋拉茶碱半草酸盐（CKD-732）的 I 期临床试验。我们的目的是确定最大耐受剂量（MTD）、药代动力学（PK）和安全性特征，以及从体外药效学（PD）和 CKD-732 的生物标志物确定生物有效剂量（BAD）。采用剂量递增方案，19 名患有难治性实体瘤的患者在 CKD-732 剂量水平为 1 至 15 mg/m2，每周两次，持续 2 周，然后休息 1 周。在这项研究中没有发生与治疗相关的死亡。意识混乱和失眠是剂量限制性毒性（DLT），MTD 为 15 mg/m2。浓度-时间曲线下面积（AUC）和最大浓度（Cmax）随剂量增加呈剂量依赖性增加。根据体外 PD，BAD 为 5 mg/m2。可溶性血管内皮生长因子受体-3（sVEGF-3）水平的降低与肿瘤大小的减少相关（r = 0.54，P = 0.045）。这项研究的结果显示，MTD 为 15 mg/m2，BAD 为 5 mg/m2。
