Phase Ib safety and pharmacokinetic evaluation of daily and twice daily oral enzastaurin in combination with pemetrexed in advanced/metastatic cancer
Phase Ib safety and pharmacokinetic evaluation of daily and twice daily oral enzastaurin in combination with pemetrexed in advanced/metastatic cancer
复制标题
DOI：
10.1093/annonc/mdp049
复制
发表时间：
2009-09-01
影响因子：
50.5
通讯作者：
Giaccone, G.
中科院分区：
文献类型：
--
作者：
Hanauske, A. -R.;Lahn, M.;Giaccone, G.
患者和方法：培美曲塞500 mg/m2联合叶酸和维生素B-12于第1天给药，每21天1次，恩杂鲁肽500 mg口服，每日3次，于第4天负荷剂量400 mg后，从第1周期第5天开始，每日1次。为了评估b.i.d.治疗方案导致较高的恩扎鲁肽暴露，因此对研究进行了修订。修改后，在第1周期，患者在第1-15天接受500 mg恩扎鲁肽QD，无初始负荷剂量，250 mg b.i.d.第16-30天;在随后的周期中，患者在第1天接受培美曲塞治疗，每21天一次，恩扎鲁肽每日两次。结果：评估了68例患者（修订前42例，修订后26例）。恩扎妥林似乎没有改变培美曲塞的毒性和药代动力学。与培美曲塞联用时，Enzalutamide的平均稳态血药浓度（C-av、C-ss）降低了约25%。C-av、C-ss中的酶联免疫吸附试验相似，b.i.d.组高40%。对比QD方案。3例（4.4%）甲状腺癌的滤泡/乳头状型有部分反应定义的RECIST.Conclusions：培美曲塞加恩杂鲁肽是耐受性良好的抗癌活性的初步证据，特别是在甲状腺癌。
Patients and methods: 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.Results: 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,C-ss) decreased by similar to 25% in the presence of pemetrexed. Enzastaurin C-av,C-ss were similar to 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.Conclusions: Pemetrexed plus enzastaurin is well tolerated with preliminary evidence of anticancer activity, particularly in thyroid cancer.