MK-8353 的研发，一种口服 ERK1/2 抑制剂，用于治疗晚期实体瘤患者。
Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors.
机构信息
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
出版信息
JCI Insight. 2018 Feb 22;3(4). doi: 10.1172/jci.insight.92352.
BACKGROUND
Constitutive activation of ERK1/2 occurs in various cancers, and its reactivation is a well-described resistance mechanism to MAPK inhibitors. ERK inhibitors may overcome the limitations of MAPK inhibitor blockade. The dual mechanism inhibitor SCH772984 has shown promising preclinical activity across various BRAFV600/RAS-mutant cancer cell lines and human cancer xenografts.
METHODS
We have developed an orally bioavailable ERK inhibitor, MK-8353; conducted preclinical studies to demonstrate activity, pharmacodynamic endpoints, dosing, and schedule; completed a study in healthy volunteers (P07652); and subsequently performed a phase I clinical trial in patients with advanced solid tumors (MK-8353-001). In the P07652 study, MK-8353 was administered as a single dose in 10- to 400-mg dose cohorts, whereas in the MK-8353-001 study, MK-8353 was administered in 100- to 800-mg dose cohorts orally twice daily. Safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity were analyzed.
RESULTS
MK-8353 exhibited comparable potency with SCH772984 across various preclinical cancer models. Forty-eight patients were enrolled in the P07652 study, and twenty-six patients were enrolled in the MK-8353-001 study. Adverse events included diarrhea (44%), fatigue (40%), nausea (32%), and rash (28%). Dose-limiting toxicity was observed in the 400-mg and 800-mg dose cohorts. Sufficient exposure to MK-8353 was noted that correlated with biological activity in preclinical data. Three of fifteen patients evaluable for treatment response in the MK-8353-001 study had partial response, all with BRAFV600-mutant melanomas.
CONCLUSION
MK-8353 was well tolerated up to 400 mg twice daily and exhibited antitumor activity in patients with BRAFV600-mutant melanoma. However, antitumor activity was not particularly correlated with pharmacodynamic parameters.
TRIAL REGISTRATION
ClinicalTrials.gov NCT01358331.
FUNDING
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., and NIH (P01 CA168585 and R35 CA197633).
背景
ERK1/2 的组成性激活发生在各种癌症中，其重新激活是 MAPK 抑制剂耐药的一种已有描述的机制。ERK 抑制剂可能克服 MAPK 抑制剂阻断的局限性。双机制抑制剂 SCH772984 在各种 BRAFV600/RAS 突变型癌细胞系和人类癌症异种移植模型中显示出有前景的临床前活性。
方法
我们开发了一种口服生物可利用的 ERK 抑制剂 MK-8353；进行了临床前研究以证明其活性、药效终点、剂量和方案；在健康志愿者中完成了一项研究（P07652）；随后在晚期实体瘤患者中进行了一项 I 期临床试验（MK-8353-001）。在 P07652 研究中，MK-8353 以 10-400mg 剂量组的单剂量给药，而在 MK-8353-001 研究中，MK-8353 以 100-800mg 剂量组每天两次口服给药。分析了安全性、耐受性、药代动力学、药效学和抗肿瘤活性。
结果
MK-8353 在各种临床前癌症模型中与 SCH772984 具有相当的效力。48 名患者入组 P07652 研究，26 名患者入组 MK-8353-001 研究。不良事件包括腹泻（44%）、疲劳（40%）、恶心（32%）和皮疹（28%）。在 400mg 和 800mg 剂量组观察到剂量限制毒性。MK-8353 的暴露量足以与临床前数据中的生物学活性相关。在 MK-8353-001 研究中可评估治疗反应的 15 名患者中有 3 名部分缓解，均为 BRAFV600 突变黑色素瘤患者。
结论
MK-8353 以每天两次 400mg 的剂量耐受良好，并在 BRAFV600 突变黑色素瘤患者中显示出抗肿瘤活性。然而，抗肿瘤活性与药效学参数没有特别相关。
试验注册
ClinicalTrials.gov NCT01358331。
资金来源
默克公司的子公司默克夏普和多姆公司（Merck Sharp & Dohme Corp.， a subsidiary of Merck & Co. Inc.）和美国国立卫生研究院（P01 CA168585 和 R35 CA197633）。
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