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本帖最后由 bkcui 于 2011-10-6 20:03 编辑
写在前面：很多朋友对于新药寄予很大希望，即使是理论上的东西，其实怀有同样希望的还有药物研发机构，对于一个非常可信的结果的期望，我认为是共同的。但是期望不是现实，失败也是尝试过程中不可避免的。因此对于一些2期临床研究的结果，我看到很多，但是大部分我不敢发出来，唯恐给大家带来过多憧憬，给大家带来误导而致太多的失望。selumetinib这个药物是一个RAS下游的基因MEK的抑制剂，有一定潜力。但是很多肿瘤的研究都失败了，包括肝癌。但是胆管癌却似乎有非常显著的疗效。，顺便说的是，这个通路也是索拉菲尼的靶点。先将研究结果贴上来，顺带翻译部分，不很通达。以帮助了解大概意思。
研究目标：selumetinib治疗不能切除胆道癌,包括肝内外胆管癌及胆囊癌。Selumetinib是MEK1/2抑制剂，是RAS/RAF/ERK通路的小分子抑制剂,它在包括细胞增殖、凋亡和代谢功能等方面起着核心作用的调节作用。本研究目标旨在以RECIST标准确定总反应率,包括评价的毒副作用,无进展生存,总体生存期,评估和KRAS突变,其测量pERK和pAKT相关的通路激活情况。
结果：对于selumetinib给药的起始剂量及时间,口服药物100毫克,每日两次， 连续28天为周期。两个层次的减量计划(50毫克,每日两次,50毫克每日一次)。2009年1月至2007年12月共有29名患者入组。3个病人显示PR,客观有效率为12%。总的来说,17例(68%)显示稳定的疾病（SD）。大部分的病人(52%)显示肿瘤体积缩小靶。疾病无进展生存期为3.7个月(95%可信区间:3.5 - -4.9),平均生存9.8个月(95%可信区间:5.97-未获得)。最常见的毒性有皮疹(9 0%),口干(54%)和恶心(51%)。虽然大多数毒性是1或2级,最常见的不良反应是腹泻,恶心和疲劳,特别是,4级毒性反应为4%。所有的有不良反应才能是可逆的。
评论：这样的实验效果应该来说是非常不错的，我们知道胆管癌的靶向治疗单药很难达到10%的OR, 即使是已经上市的药物，另外的报道显示病人平均体重增加9磅，说明毒性反应小，病人体重增加，整个状态好转的表现。我认为是非常有前景的药物。
Methods & results
This study was a Phase II study of selumetinib monotherapy in patients with unresectable biliary tract cancer, including intra- or extra-hepatic cholangiocarcinoma and gallbladder cancer . Selumetinib is an inhibitor of MEK1/2 targeting the RAS/RAF/MEK/extracellular signal-related kinase (ERK) pathway, which plays a central role in the regulation of c ellular processes, including proliferation, apoptosis and metabolism. The primary objective of this study was to determine the overall reponse rate, as defned by the Response Evaluation Criteria In Solid Tumors, and the secondary objectives include evaluation of toxicity, overall survival, progression-free survival, assessment of BRAF and KRAS mutations, and measurement of phosphorylated (p) ERK and pAKT as indicators of activation of the relevant pathways.
With regard to the starting dose and dosing schedule of selumetinib, the drug was administere d orally at 10 0 mg twice daily in 28-day cycles without interruption. Two levels of dose reductions were planned (50 mg twice daily and 50 mg once daily), with patients taken off the study in the case of a need for any additional dose reductions. A total of 29 patients were enrolled between December 2007 and January 2009. Three patients showed a confrmed partial response, representing a response rate of 12%. In total, 17 patients (68 %) showed stable disease. The majority of patients (52%) showed a decrease in the size of the target lesion. The median progression free survival was 3.7 months (95% CI: 3.5 –4.9) and the median overall survival was 9.8 months (95% CI: 5.97–not available). The most common toxicities were rash (9 0%), xerostomia (54%) and nausea (51%). Although most toxicities were grade 1 or 2, the most common grade 3/4 toxicities were diarrhea, nausea
and fatigue; in particular, grade 4 fatigue was observed in 4% of the patients. All toxicities were manage able and reversible.
Analyses of biologic markers revealed no BR AF V60 0E mutations. Two patients with short-lived stable disease had KRA S
mutations. Absence of pERK staining was associate d with lack of response and positive immunostaining for pERK was associated with improved overall survival.
http://www.expert-reviews.com/doi/pdf/10.1586/egh.11.58
http://www.sciencedaily.com/releases/2011/04/110425173832.htm
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