Developmental Therapeutics Program, Division of Medical Oncology, University of Colorado, Aurora, CO 80045, USA.
Invest New Drugs. 2011 Apr;29(2):340-6. doi: 10.1007/s10637-009-9383-9. Epub 2010 Jan 19.
2-methoxyestradiol (2ME2) is an estradiol-17β metabolite with antiproliferative and antiangiogenic activities. ENMD-1198 is an analog of 2ME2 which was developed to decrease the metabolism and increase both the bioavailability and antitumor activities of the parent molecule. This first-in-human phase I study evaluated the tolerability, pharmacokinetics and preliminary evidence of activity of ENMD-1198 in advanced cancer patients.
Eligible patients received ENMD-1198 orally once daily in Part A (standard 3 + 3 dose escalation design), or in Part B (accelerated dose escalation design). Cycle 1 consisted of 28 days daily dosing followed by a 14-(Part A) or 7-(Part B) day observation period, then continuously in 28 day cycles thereafter.
A total of 29 patients were enrolled in 12 dose cohorts (5 to 550 mg/m²)/d). The most common drug-related toxicities were Grade 1/2 fatigue (55%), nausea and vomiting (37%), and constipation (34%). Two DLTs (Grade 4 neutropenia) occurred at 550 mg/m²/day, and 425 mg/m²/d was declared the maximum tolerated dose. ENMD-1198 was absorbed rapidly with a T(max) of 1-2 h. Exposure to ENMD-1198 (C(max) and AUC₀₋₂₄ hr increased linearly with dose. The mean terminal half-life was 15 h. A 3-fold accumulation was found after multiple doses. Five patients achieved stabilization of disease for at least 2 cycles, three of whom (with neuroendocrine carcinoma of pancreas, prostate cancer and ovarian cancer) demonstrated prolonged stabilization ranging from 8-24.5 cycles.
ENMD-1198 is well-tolerated with a pharmacokinetic exposure profile compatible with once daily dosing. The recommended phase II dose of ENMD-1198 is 425 mg/m²/d. Early evidence of prolonged disease stabilization in pre-treated patients suggests ENMD-1198 is worthy of additional investigation.
2-甲氧基雌二醇（2ME2）是一种具有抗增殖和抗血管生成活性的雌二醇 17β代谢物。ENMD-1198 是 2ME2 的类似物，其开发目的是降低母体分子的代谢率，同时提高其生物利用度和抗肿瘤活性。这项首次人体 I 期研究评估了在晚期癌症患者中 ENMD-1198 的耐受性、药代动力学和初步疗效。
符合条件的患者在 A 部分（标准的 3+3 剂量递增设计）或 B 部分（加速剂量递增设计）中口服 ENMD-1198 每日一次。第 1 周期为 28 天的每日给药，然后进行 14 天（A 部分）或 7 天（B 部分）的观察期，之后连续进行 28 天周期。
共招募了 29 名患者，分为 12 个剂量组（5 至 550mg/m²/d）。最常见的药物相关毒性是 1/2 级疲劳（55%）、恶心和呕吐（37%）以及便秘（34%）。2 例剂量限制性毒性（4 级中性粒细胞减少症）发生在 550mg/m²/d 时，425mg/m²/d 被宣布为最大耐受剂量。ENMD-1198 吸收迅速，Tmax 为 1-2 小时。ENMD-1198 的暴露量（Cmax 和 AUC₀₋₂₄hr）随剂量呈线性增加。平均终末半衰期为 15 小时。多次给药后发现有 3 倍的蓄积。5 名患者的疾病稳定至少 2 个周期，其中 3 名（患有胰腺神经内分泌癌、前列腺癌和卵巢癌）的稳定时间从 8 到 24.5 个周期延长。
ENMD-1198 耐受性良好，药代动力学暴露特征与每日一次给药一致。ENMD-1198 的推荐 II 期剂量为 425mg/m²/d。在预处理患者中早期出现的疾病稳定延长的证据表明，ENMD-1198 值得进一步研究。
