James Jehana, Murry Daryl J, Treston Anthony M, Storniolo Anna Maria, Sledge George W, Sidor Carolyn, Miller Kathy D
Department of Medicine, Indiana University, Indianapolis, IN, USA.
Invest New Drugs. 2007 Feb;25(1):41-8. doi: 10.1007/s10637-006-9008-5. Epub 2006 Sep 13.
We report the first phase I trials of 2-methoxyestradiol (2ME2, Panzem Capsules, EntreMed, Rockville, MD), alone and in combination with docetaxel, in patients with metastatic breast cancer (MBC).
In Trial 001, 2ME2 monotherapy was administered orally once (200-1000 mg/d, cohorts 1-5) or twice daily (200-800 mg/q12h, cohorts 6-9) for 28 days followed by a 14-day observation period, continuously thereafter. In Trial 002, docetaxel 35 mg/m(2) was administered weekly for four of six weeks for a maximum six cycles; 2ME2 (200-1000 mg/d) was given orally once daily for 28 days followed by a 13-day observation period in cycle one, continuously thereafter. In both trials, responding or stable patients continued 2ME2 until progression.
Trial 001 enrolled 31 patients; there were no objective responses. Trial 002 enrolled 15 patients; ORR was 20% including one CR. There were no Grade IV toxicities; MTD was not reached in either study. When combined with docetaxel, three patients had significant transaminase elevations that returned to normal with continued treatment (in two of three patients). There was significant inter-patient variability and extensive metabolism to 2-methoxyestrone (2ME1). Steady-state AUC and trough concentrations of 2ME2 increased linearly up to 400-600 mg/d; doses above 400-600 mg/d did not increase 2ME2 levels. The target trough concentration (3-25 ng/mL) was not attained. Combined administration did not alter docetaxel or 2ME2 pharmacokinetics.
2ME2, alone or in combination with docetaxel, was well tolerated in patients with MBC but systemic exposure remained below the expected therapeutic range.
我们报告了2-甲氧基雌二醇（2ME2，Panzem胶囊，EntreMed公司，马里兰州罗克维尔）单药及联合多西他赛用于转移性乳腺癌（MBC）患者的首个I期试验。
在试验001中，2ME2单药治疗采用口服给药，每日一次（200 - 1000 mg/d，第1 - 5组）或每日两次（200 - 800 mg/每12小时，第6 - 9组），持续28天，随后为14天观察期，此后持续给药。在试验002中，多西他赛35 mg/m²每周给药一次，共六周中的四周，最多六个周期；2ME2（200 - 1000 mg/d）口服每日一次，持续28天，在第一个周期随后为13天观察期，此后持续给药。在两项试验中，有反应或病情稳定的患者持续使用2ME2直至病情进展。
试验001纳入31例患者；未观察到客观缓解。试验002纳入15例患者；客观缓解率为20%，包括1例完全缓解。未出现IV级毒性反应；两项研究均未达到最大耐受剂量。与多西他赛联合使用时，3例患者出现显著转氨酶升高，其中2例患者在继续治疗后恢复正常。患者间存在显著变异性，且2ME2大量代谢为2-甲氧基雌酮（2ME1）。2ME2的稳态曲线下面积（AUC）和谷浓度在剂量增至400 - 600 mg/d时呈线性增加；剂量高于400 - 600 mg/d时，2ME2水平未进一步升高。未达到目标谷浓度（3 - 25 ng/mL）。联合给药未改变多西他赛或2ME2的药代动力学。
2ME2单药或联合多西他赛用于MBC患者耐受性良好，但全身暴露仍低于预期治疗范围。
