阶段1剂量递增和扩张的研究binimetinib (MEK162),一个强有力的和选择性口服MEK1/2抑制剂。

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Bendell JC, Javle M, Bekaii-Saab TS,芬恩RS,温伯格咱,Laheru哒,Weekes CD,谭BR,汗GN, Zalupski毫米,小亲王,琼斯,帕帕多普洛斯KP, Tolcher啊,Chavira再保险公司Christy-Bittel杰,巴雷特E, Patnaik

阶段1剂量递增和扩张的研究binimetinib (MEK162),一个强有力的和选择性口服MEK1/2抑制剂。

Br J癌症。2017年2月28日,116 (5):575 - 583。doi: 10.1038 / bjc.2017.10。Epub 2017 2月2。

PubMed ID

28152546 (在PubMed

]

文摘

背景:Binimetinib (MEK162;- 438162)是一个强大的和选择性口服MEK 1/2抑制剂。这第一阶段的研究确定最大耐受剂量(MTD)、安全性、药代动力学和药效学资料,和初步的抗肿瘤活性binimetinib先进的固体肿瘤,患者与扩张胆道癌患者群或喀斯特——或者BRAF-mutant结肠直肠癌。方法:Binimetinib每天服用两次。扩张军团后,参赛者MTD确定后3 + 3剂量递增的设计。从等离子体药代动力学性质测定样品。肿瘤样本在RAS突变,英国皇家空军和其他相关的基因。药效学特性进行评估血清和皮肤活检样本。结果:九十三名患者接受binimetinib(剂量递增阶段,19个;扩张,74)。 The MTD was 60 mg twice daily, with dose-limiting adverse events (AEs) of dermatitis acneiform and chorioretinopathy. The dose for expansion patients was subsequently decreased to 45 mg twice daily because of the frequency of treatment-related ocular toxicity at the MTD. Common AEs across all dose levels included rash (81%), nausea (56%), vomiting (52%), diarrhoea (51%), peripheral oedema (46%), and fatigue (43%); most were grade 1/2. Dose-proportional increases in binimetinib exposure were observed and target inhibition was demonstrated in serum and skin punch biopsy samples. Three patients with biliary cancer had objective responses (one complete and two partial). CONCLUSIONS: Binimetinib demonstrated a manageable safety profile, target inhibition, and dose-proportional exposure. The 45 mg twice daily dose was identified as the recommended phase 2 dose. The three objective responses in biliary cancer patients are encouraging and support further evaluation in this population.

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药物

Binimetinib