Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial
Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial
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DOI：
10.1016/s1470-2045(12)70270-x
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发表时间：
2012-08-01
期刊：
影响因子：
51.1
通讯作者：
Messersmith, Wells A.
中科院分区：
文献类型：
--
作者：
Infante, Jeffrey R.;Fecher, Leslie A.;Messersmith, Wells A.
背景抑制MEK可阻止细胞增殖并诱导细胞凋亡，因此，该酶是一个关键的抗癌靶点。曲美替尼是一种选择性的口服MEK1/MEK2抑制剂。我们的目标是确定曲美替尼的最大耐受量和推荐的第二阶段剂量，并评估其安全性、药代动力学、药效学和缓解率。方法我们对器官功能正常的晚期实体肿瘤患者进行了多中心第一阶段研究。这项研究分为三个部分：剂量递增以确定最大耐受剂量；确定推荐的第二阶段剂量；以及评估药效学变化。对间歇给药和连续给药方案进行了分析。采集血样和肿瘤活检标本以评估药代动力学和药效学的变化。用常见的毒性标准定义不良事件，用实体瘤的反应评估标准来衡量肿瘤反应。这项研究在ClinicalTrials.gov上注册，编号NCT00687622。我们招募了206名患者(中位年龄58.5岁，范围19-92岁)。剂量限制性毒性反应包括皮疹(n=2)、腹泻(n=1)和中心性浆液性视网膜病变(n=2)。与治疗相关的不良反应最常见的是皮疹或皮炎(n=165；80%)和腹泻(87；42%)，大部分为1级和2级。最大耐受量为3 mg/d，推荐的2期剂量为2 mg/d。曲美替尼的有效半衰期约为4天。在推荐的第二阶段剂量下，该药物的暴露情况显示患者之间的变异性很小，峰谷比很小，为1.81。此外，在整个给药间隔内，血浆中的平均浓度大于临床前的目标浓度。观察到路径抑制和临床活动，记录了21(10%)个客观反应。解释说，推荐的第二阶段剂量，每天一次，2 mg曲美替尼是可以耐受的，副作用可控。曲美替尼对预期靶点和临床活性的抑制使其作为单一疗法和联合疗法得到进一步发展。
Background Inhibition of MEK stops cell proliferation and induces apoptosis; therefore, this enzyme is a key anticancer target. Trametinib is a selective, orally administered MEK1/MEK2 inhibitor. We aimed to define the maximum tolerated dose and recommended phase 2 dose of trametinib and to assess its safety, pharmacokinetics, pharmacodynamics, and response rate in individuals with advanced solid tumours.Methods We undertook a multicentre phase 1 study in patients with advanced solid tumours and adequate organ function. The study was in three parts: dose escalation to define the maximum tolerated dose; identification of the recommended phase 2 dose; and assessment of pharmacodynamic changes. Intermittent and continuous dosing regimens were analysed. Blood samples and tumour biopsy specimens were taken to assess pharmacokinetic and pharmacodynamic changes. Adverse events were defined with common toxicity criteria, and tumour response was measured by Response Evaluation Criteria In Solid Tumors. This study is registered with ClinicalTrials.gov, number NCT00687622.Findings We enrolled 206 patients (median age 58.5 years, range 19-92). Dose-limiting toxic effects included rash (n=2), diarrhoea (n=1), and central serous retinopathy (n=2). The most common treatment-related adverse events were rash or dermatitis acneiform (n=165; 80%) and diarrhoea (87; 42%), most of which were grade 1 and 2. The maximum tolerated dose was 3 mg once daily and the recommended phase 2 dose was 2 mg a day. The effective half-life of trametinib was about 4 days. At the recommended phase 2 dose, the exposure profile of the drug showed low interpatient variability and a small peak: trough ratio of 1.81. Furthermore, mean concentrations in plasma were greater than the preclinical target concentration throughout the dosing interval. Pathway inhibition and clinical activity were seen, with 21 (10%) objective responses recorded.Interpretation The recommended phase 2 dose of 2 mg trametinib once a day is tolerable, with manageable side-effects. Trametinib's inhibition of the expected target and clinical activity warrants its further development as a monotherapy and in combination.