Hanauske A-R, Lahn M, Musib L C, Weigang-Köhler K, Yilmaz E, Graefe T, Kuenen B, Thornton D, McNealy P, Giaccone G
I. Medical Department, General Hospital, St Georg, Hamburg, Germany.
Early Phase Clinical Oncology Development, Eli Lilly and Company, Indianapolis, IN, USA.
Ann Oncol. 2009 Sep;20(9):1565-1575. doi: 10.1093/annonc/mdp049. Epub 2009 Jun 1.
This phase Ib study evaluated the safety, pharmacokinetics, and activity of enzastaurin either 500 mg once daily (QD) or 250 mg twice daily (b.i.d.) in combination with pemetrexed.
Pemetrexed 500 mg/m(2) with folic acid and vitamin B(12) was given on day 1 every 21 days with enzastaurin 500 mg orally QD starting on day 5 of cycle 1 after a loading dose of 400 mg thrice daily on day 4. To evaluate whether a b.i.d. regimen results in higher enzastaurin exposures, the study was amended. After amendment, in cycle 1, patients received 500 mg enzastaurin QD on days 1-15 without initial loading dose and 250 mg b.i.d. on days 16-30; in subsequent cycles, patients received pemetrexed on day 1 every 21 days with enzastaurin b.i.d.
Sixty-eight patients (42 preamendment and 26 postamendment) were assessed. Pemetrexed toxicity and pharmacokinetics did not appear to be altered by enzastaurin. Enzastaurin average steady-state plasma concentration (C(av,ss)) decreased by approximately 25% in the presence of pemetrexed. Enzastaurin C(av,ss) were approximately 40% higher in the b.i.d. versus QD regimen. Three patients (4.4%) with thyroid cancer of follicular/papillary type had partial response as defined by RECIST.
Pemetrexed plus enzastaurin is well tolerated with preliminary evidence of anticancer activity, particularly in thyroid cancer.
本Ib期研究评估了每日一次500毫克（QD）或每日两次250毫克（b.i.d.）的恩杂鲁胺与培美曲塞联合使用时的安全性、药代动力学和活性。
每21天的第1天给予培美曲塞500毫克/平方米，并补充叶酸和维生素B12，在第1周期的第5天开始口服恩杂鲁胺，剂量为每日一次500毫克，第4天给予负荷剂量每日三次400毫克。为评估每日两次给药方案是否会导致恩杂鲁胺有更高的暴露量，对研究进行了修正。修正后，在第1周期，患者在第1 - 15天接受每日一次500毫克恩杂鲁胺，无初始负荷剂量，在第16 - 30天接受每日两次250毫克；在随后的周期中，患者每21天的第1天接受培美曲塞，同时接受恩杂鲁胺每日两次给药。
评估了68例患者（42例修正前和26例修正后）。培美曲塞的毒性和药代动力学似乎未因恩杂鲁胺而改变。在有培美曲塞存在的情况下，恩杂鲁胺的平均稳态血浆浓度（C(av,ss)）下降了约25%。每日两次给药方案的恩杂鲁胺C(av,ss)比每日一次给药方案高约40%。3例（4.4%）滤泡状/乳头状甲状腺癌患者出现了根据实体瘤疗效评价标准（RECIST）定义的部分缓解。
培美曲塞加恩杂鲁胺耐受性良好，有初步的抗癌活性证据，尤其是在甲状腺癌中。
