This is a multicenter, worldwide, open-label study of MK-8353 in combination with selumetinib in participants with histologically or cytologically confirmed diagnosis of advanced solid tumor. This study will evaluate the safety, tolerability, and exploratory efficacy of MK-8353 in combination with selumetinib.

开始日期2019-02-22

申办/合作机构

Merck Sharp & Dohme Corp.

NCT02972034 / Completed临床1期

A Phase Ib Study to Evaluate the Safety and Tolerability of MK-8353 in Combination With Pembrolizumab in Patients With Advanced Malignancies

This study will evaluate the safety, tolerability and preliminary efficacy of MK-8353 when administered in combination with pembrolizumab (MK-3475). There are two parts in this study: Part 1 will be dose escalation and confirmation, and Part 2 will be a cohort expansion. In Part 1, the recommended phase II dose (RP2D) of MK-8353 in combination with a fixed dose of pembrolizumab in participants with advanced malignancies will be identified and confirmed. Participants will be initially enrolled to receive MK-8353 at 350 mg twice a day (BID) in combination with pembrolizumab at a fixed dose of 200 mg on Day 1 of each 3-week cycle (Q3W) for up to 24 months of treatment. In Part 2, participants with advanced colorectal cancer (CRC) that is microsatellite stable (i.e., non-microsatellite instability-high/deficient mismatch repair [non-MSI-H/dMMR]) who received at least one and up to five prior lines of therapy will be enrolled at the RP2D in the expansion cohort to further evaluate safety and efficacy.
The protocol has been amended to lower the starting doses of MK-8353 in combination with pembrolizumab. In addition, 3 arms have been added: one in which MK-8353 will be administered continuously once a day (QD) in combination with pembrolizumab, one optional arm in which MK-8353 will be administered 1 week on/1 week off QD in combination with pembrolizumab and one optional arm in which participants undergo a MK-8353 QD run-in period prior to starting combination therapy with pembrolizumab.

开始日期2017-01-13

申办/合作机构

Merck Sharp & Dohme Corp.

NL-OMON37039 / SuspendedN/A

A Phase 1 Study to Evaluate the Safety, Tolerability and Efficacy of MK-8353 Combination Therapies in Subjects With Advanced Solid Tumors - MK8353-010

开始日期2012-12-03

申办/合作机构-

100 项与 MK-8353 相关的临床结果

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100 项与 MK-8353 相关的转化医学

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100 项与 MK-8353 相关的专利（医药）

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项与 MK-8353 相关的文献（医药）

2023-06-01·Investigational new drugs

Results of an open-label phase 1b study of the ERK inhibitor MK-8353 plus the MEK inhibitor selumetinib in patients with advanced or metastatic solid tumors.

Article

作者: Nayak, Tapan ; Renouf, Daniel J. ; Suttner, Leah H. ; Freshwater, Tomoko ; Webber, Andrea L. ; Stathis, Anastasios ; Wang, Judy S. ; Tolcher, Anthony W. ; Chen, Lin-Chi ; Siu, Lillian L.

AIM:

We evaluated MK-8353 (small molecule inhibitor of extracellular signal-regulated kinase 1/2) plus selumetinib (mitogen-activated extracellular signal-regulated kinase 1/2 inhibitor) in patients with advanced solid tumors.

METHODS:

This phase 1b, open-label, dose-escalation study (NCT03745989) enrolled adults with histologically/cytologically documented, locally advanced/metastatic solid tumors. MK-8353/selumetinib dose combinations were intended to be investigated in sequence: 50/25, 100/50, 150/75, 200/75, 200/100, and 250/100. Each agent was administered orally BID 4 days on/3 days off in repeating cycles every 21 days. Primary objectives were safety and tolerability and to establish preliminary recommended phase 2 doses for combination therapy.

RESULTS:

Thirty patients were enrolled. Median (range) age was 61.5 (26-78) years and 93% had received previous cancer therapy. Among 28 patients in the dose-limiting toxicities [DLT]-evaluable population, 8 experienced DLTs: 1/11 (9%) in the MK-8353/selumetinib 100/50-mg dose level experienced a grade 3 DLT (urticaria), and 7/14 (50%) in the 150/75-mg dose level experienced grade 2/3 DLTs (n = 2 each of blurred vision, retinal detachment, vomiting; n = 1 each of diarrhea, macular edema, nausea, retinopathy). The DLT rate in the latter dose level exceeded the prespecified target DLT rate (~30%). Twenty-six patients (87%) experienced treatment-related adverse events (grade 3, 30%; no grade 4/5), most commonly diarrhea (67%), nausea (37%), and acneiform dermatitis (33%). Three patients (10%) experienced treatment-related adverse events leading to treatment discontinuation. Best response was stable disease in 14 patients (n = 10 with MK-8353/selumetinib 150/75 mg).

CONCLUSION:

MK-8353/selumetinib 50/25 mg and 100/50 mg had acceptable safety and tolerability, whereas 150/75 mg was not tolerable. No responses were observed.

2023-03-29·Journal of experimental & clinical cancer research : CR

FBXW7 loss of function promotes esophageal squamous cell carcinoma progression via elevating MAP4 and ERK phosphorylation.

Article

作者: Wang, Changxing ; Shen, Jingyi ; Lu, Chenchen ; Guo, Yuqing ; Liu, Jing ; Wu, Meiying ; Ma, Sai ; Liang, Zhipan ; Gao, Yingyin ; Li, Yinyan ; Pan, Yunzhi ; Qian, Yulan

BACKGROUND:

Increasing evidence suggests that FBXW7 has a high frequency of mutations in esophageal squamous cell carcinoma (ESCC). However, the function of FBXW7, especially the mutations, is not clear. This study was designed to investigate the functional significance of FBXW7 loss of function and underlying mechanism in ESCC.

METHODS:

Immunofluorescence was applied to clarify the localization and main isoform of FBXW7 in ESCC cells. Sanger sequencing were performed to explore mutations of FBXW7 in ESCC tissues. Proliferation, colony, invasion and migration assays were performed to examine the functional roles of FBXW7 in ESCC cells in vitro and in vivo. Real-time RT-PCR, immunoblotting, GST-pulldown, LC-MS/MS and co-immunoprecipitation assay were used to explore the molecular mechanism underlying the actions of FBXW7 functional inactivation in ESCC cells. Immunohistochemical staining were used to explore the expression of FBXW7 and MAP4 in ESCC tissues.

RESULTS:

The main FBXW7 isoform in ESCC cells was the β transcript in the cytoplasm. Functional inactivation of FBXW7 led to activation of the MAPK signaling pathway and upregulation of the downstream MMP3 and VEGFA, which enhanced tumor proliferation cell invasion and migration. Among the five mutation forms screened, S327X (X means truncated mutation) had an effect similar to the FBXW7 deficiency and led to the inactivation of FBXW7 in ESCC cells. Three other point mutations, S382F, D400N and R425C, attenuated but did not eliminate FBXW7 function. The other truncating mutation, S598X, which was located outside of the WD40 domain, revealed a tiny attenuation of FBXW7 in ESCC cells. Notably, MAP4 was identified as a potential target of FBXW7. The threonine T521 of MAP4, which was phosphorylated by CHEK1, played a key role in the FBXW7-related degradation system. Immunohistochemical staining indicated that FBXW7 loss of function was associated with tumor stage and shorter survival of patients with ESCC. Univariate and multivariate Cox proportional hazards regression analyses showed that high FBXW7 and low MAP4 was an independent prognostic indicator and prospective longer survival. Moreover, a combination regimen that included MK-8353 to inhibit the phosphorylation of ERK and bevacizumab to inhibit VEGFA produced potent inhibitory effects on the growth of FBXW7 inactivation xenograft tumors in vivo.

CONCLUSIONS:

This study provided evidence that FBXW7 loss of function promoted ESCC via MAP4 overexpression and ERK phosphorylation, and this novel FBXW7/MAP4/ERK axis may be an efficient target for ESCC treatment.

2020-07-01·Pathology international4区 · 医学

S100A12 promotes inflammation and apoptosis in ischemia/reperfusion injury via ERK signaling in vitro study using PC12 cells

4区 · 医学

Article

作者: Chen, Zuoquan ; Shu, Zhongwen ; Zhang, Xiang ; Zhang, Quanbin ; Shen, Rui

S100A12 is a member of S100 calcium‐binding proteins with effect to promote inflammation in brain damage and stroke. However, the role of S100A12 in ischemia/reperfusion (I/R) remains to be clarified. This study aimed to explore the effect of S100A12 on I/R and discover the possible mechanism. Oxygen‐glucose deprivation and reperfusion (OGD/R) was used to induce I/R injury model in vitro. Knockdown or overexpression of S100A12 was utilized to explore the role of S100A12 in I/R‐induced inflammation and apoptosis. Results indicated that S100A12 expression was dramatically upregulated after OGD/R. Knockdown of S100A12 inhibited, while overexpression of S100A12 enhanced, the activation of ERK1/2 protein. OGD/R also triggered the occurrence of inflammation and oxidative stress, while these effects were blunted by S100A12 silencing and aggravated by S100A12 overexpression, and the presence of MAP kinase signaling system (ERK) inhibitor MK‐8353 counteracted the effect of S100A12 overexpression. Besides, S100A12 silencing abolished, while its overexpression restored, the OGD/R‐induced increased apoptosis rate and pro‐apoptotic proteins expression. Similarly, ERK inhibitor MK‐8353 reversed the effects of S100A12 overexpression. In conclusion, S100A12 promoted OGD/R‐induced inflammation, oxidative stress and apoptosis via activation of ERK signaling in vitro.

项与 MK-8353 相关的新闻（医药）

2022-11-02

·药渡Daily

德琪医药ATG-017获FDA批准I期临床，治疗晚期实体瘤！

2022年11月1日，德琪医药宣布，ERK1/2小分子抑制剂ATG-017的1期临床试验申请（IND）已获美国食品药品监督管理局（FDA）批准，用于治疗晚期实体瘤。随后，德琪医药将在美国启动1期ERASER研究的联合治疗部分，以评估ATG-017联合纳武利尤单抗用于治疗晚期实体瘤的安全性、药代动力学和初步疗效。来源：德琪医药官网该项由德琪医药与百时美施贵宝合作的旨在评估ATG-017联合纳武利尤单抗的临床合作是基于已有的临床前数据，其中部分数据已于2021年11月在第36届肿瘤免疫治疗学会（SITC）年会及会前环节中公布。数据显示，ERK1/2抑制剂（ATG-017）联合免疫检查点抑制剂（ICI，PD-L1单抗，阿特朱单抗）发挥了协同作用，在ICI耐药的小鼠体内模型中产生了更好的疗效，达到肿瘤由“冷”至“热”的转化。此外，据Clinicaltrails.gov网站信息显示，2020年3月12日德琪医药登记了一项临床研究（NCT04305249），这是一项开放、多中心I期研究（代号：ERASER），主要评估ATG-107单药治疗晚期实体瘤和恶性血液瘤患者的安全性、药代动力学和初步疗效。目前该单药治疗爬坡正在澳大利亚顺利开展，并将继续参与联合治疗部分的研究。除澳大利亚和美国外，德琪医药还计划在中国开展这项国际多中心研究。目前在药物临床试验登记与信息公示平台暂未检索到ATG-017的临床试验登记号。关于ERK1/2细胞外信号调节蛋白激酶1/2（ERK1/2）是一类丝氨酸/苏氨酸蛋白激酶，是MEK1/2唯一已知的底物，位于RAS-RAF-MEK-ERK（MAPK）通路的下游，其作用是作为RAS-MAPK信号转导级联通路的终端激酶。该级联通路调节细胞增殖等多种细胞进程。RAS-MAPK通路失调发于30%以上的癌症患者，最为常见的变化为多个肿瘤类型的RAS或BRAF基因突变。ERK抑制剂可同时靶向RAS和BRAF突变疾病。目前，已有多种靶向RAS、RAF和MEK的小分子抑制剂被批准用于癌症治疗，然后，长期治疗中产生的获得性耐药降低了这些药物的疗效。近年来，选择性抑制ERK1/2被认为是一种潜在的癌症治疗策略，它不仅可以有效阻断MAPK通路，还可以克服RAS、RAF和MEK上游突变引起的耐药性。ERK1/2的关键调控通路来源：Fu et al. J Med Chem. 2022, 65(20): 13561-13573关于ATG-017ATG-017（AZD0364，Tizaterkib）是一款作用于细胞外信号调节激酶1和2（ERK1/2）的可逆型、ATP竞争性的强效、选择性口服小分子抑制剂，是以阿斯利康已有的先导化合物7为基础，进行构效关系（SAR）优化后得到的激酶选择性更强、药代动力学性质更佳的ATG-107。ATG-107对ERK2的IC50值为0.6 nM，水溶性468 uM，在体外大鼠和人肝细胞中均较稳定，渗透性（Caco-2 Papp）为26.7*10-6 cm/s，是高渗化合物，大鼠和犬灌胃给药后的生物利用度分别为30%和100%，具有较好的药代动力学性质。据文献报道，基于临床前试验数据推测的人体清除率范围是0.5-6 ml/min/kg，预测人体首次给药剂量为20-110 mg，一天两次。根据此前研究报道，在多个体内异种移植瘤模型中，ATG-017展现了对ERK1/2依赖性信号生物标志物的剂量和时间依赖性调节，从而使得BRAF敏感型和KRAS突变敏感型异种移植瘤的肿瘤消退。此外，ATG-01与MEK1/2抑制剂selumetinib (AZD6244和ARRY142886)的联合给药可以更深入、更持久地抑制RAS/MAPK信号通路，这是单药治疗无法实现的。ATG-017和selumetinib联合给药也会在KRAS突变的异种移植瘤模型中出现显著的肿瘤消退。因此，ERK1/2抑制剂和MEK1/2抑制剂的联合给药是靶向KRAS突变肿瘤的一种可行的临床方法。体外研究中，ATG-017对MAPK信号通路的直接下游底物具有高细胞活性（如在BRAFV600E突变的A375细胞中，抑制phospho-p90RSK，IC50= 5.73 nM）。ATG-107浓度为1 uM时，在包含353种激酶的激酶库中对其中9种激酶（MEK1, COT, BRAF, MEK2, c-RAF, ERK7, CDK2, CDK5 and ARK5）的抑制作用大于50%。A: AZD0364（ATG-017）的结构式B: AZD0364（ATG-017）与ERK2的结合位点来源：Vikki Flemington. et al. Mol Cancer Ther. 2021, 20(2): 238-249.“RAS/MAPK通路是癌症发生的一个重要驱动因素。ATG-017靶向ERK1/2不仅能阻止肿瘤细胞的生长，还能与其他MAPK激酶抑制剂协同作用，更有效地阻断RAS-MAPK信号传导，同时克服患者对RAF及MEK抑制剂产生耐药。”德琪医药创始人、董事长兼首席执行官梅建明博士说，“我们认为ATG-017拥有强大的临床潜力和广阔的应用前景。不单是针对实体瘤与血液瘤的单药疗法，德琪团队也正深入挖掘ATG-017与公司其他在研产品的协同性，以期获得更好的抗癌效果。”权益合作ATG-017由阿斯利康公司发现及早期研究，德琪医药拥有开发、生产及商业化该产品的全球独家权益。2019年11月6日，德琪医药宣布与英国阿斯利康公司达成一项全球性的独家授权协议，推进创新药物ATG-017（AZD0364）在全球的临床开发，生产和商业化。阿斯利康公司在此次交易前已终止了全球范围内其他关于ATG-017的授权协议，包括与辅仁药业的授权协议。2021年12月13日，德琪医药宣布与百时美施贵宝公司达成了一项临床合作协议，将共同开展一项旨在评估ATG-017联合百时美施贵宝的PD-1检查点抑制剂欧狄沃®（纳武利尤单抗）用于治疗晚期实体瘤的安全性、药代动力学和初步疗效的开放性1/2期临床研究。根据该协议，德琪医药将负责该临床试验的开展，并提供资金支持。百时美施贵宝公司将提供联合疗法的剂量爬坡和剂量扩展研究中所需的欧狄沃®。竞争格局目前关于靶向ERK药物的研究尚处在早期临床阶段，全球范围内仅有BioMed Valley Discoveries公司的BVD-523、Merck公司的MK-8353与Genentech的GDC-0994披露临床数据。全球范围内到目前为止没尚无任何一款已获批上市的ERK1/2抑制剂。BVD-523BVD-523（Ulixertinib，VRT752271）是由BioMed Valley Discoveries公司研发的可逆型、ATP竞争性ERK1/2抑制剂，其对ERK1的Ki < 0. 3 nM，对ERK2的Ki = 0. 04 nM。2017年12月15日，Cancer Discov杂志公布了ERK1/2抑制剂BVD-523的I期临床试验（NCT01781429）数据。结果提示2期临床试验推荐剂量为600 mg BID给药，最常见治疗相关不良反应包括腹泻(48%)、疲劳(42%)、恶心(41%)和痤疮性皮炎(31%)。在部分患者中，BVD-523治疗确实获得了部分缓解或疾病稳定状态，且疗效似不受肿瘤类型的影响。BVD-523具有可接受的安全性和良好的药代动力学性质。MK-8353MK-8353是通过改善SCH772984的PK 而优化得到的（ERK1：IC50= 20 nM；ERK2：IC50 = 7 nM）。SCH772984是由Merck公司通过基于亲和力的质谱高通量平台筛选、鉴定并通过结构优化得到的ATP 竞争性的ERK1/2抑制剂。2018年2月22日，JCI Insight杂志公布了ERK1/2抑制剂MK-8353的I期临床试验（NCT01358331）数据。在所有剂量中MK-8353总体安全性和耐受性良好，并且未发生严重不良事件（SAE）。在400毫克和800毫克剂量组中观察到剂量限制性毒性。在可评价治疗缓解的15名晚期实体瘤患者中，3名患者具有部分缓解，他们全部患有BRAFV600突变型黑色素瘤。GDC-0994GDC-0994是由Genentech公司研发的口服的选择性ERK1/2抑制剂，其对ERK1和ERK2的IC50分别为6. 1和3. 1 nmol/L。2020年3月15日，CCR杂志公布了新型ERK1/2抑制剂GDC-0994的I期临床试验（NCT01875705）数据。47名跨癌种的难治性晚期实体瘤患者，接受了该药物治疗。20名患者在接受治疗前后，均进行PET-CT检测，从PET-CT上可以反应肿瘤的代谢活性，其中11名患者肿瘤代谢活性明显下降，其中就包括4名胰腺癌患者。而从普通CT上看，45名患者中有15人肿瘤控制稳定。最难能可贵的是：2名BRAF突变的难治性肠癌患者，接受该药物治疗后，肿瘤明显缩小，缩小幅度超过30%，给这种极端难治的晚期肠癌患者带来了新的希望。CC-90003CC-90003是不可逆的共价结合的选择性ERK1/2 抑制剂，主要用于治疗KRAS突变的肿瘤，2015年进入1期临床研究。但是由于在1期临床试验中，其最大耐受剂量（MTD）结果不令人满意，目前已经暂停了其临床试验（NCT02313012）。此外，据药渡数据的不完全统计，目前临床阶段上二十多款ERK1/2抑制剂药物正在推进中，进展最快的项目也仅处于2期阶段。国内进展最快的是海和医药的BPI-27336、和记黄埔的HMPL-295S1和捷思英达的JSI-1187，相关ERK1/2抑制剂所处临床阶段多为1期。德琪医药的ATG-017因拥有同类最佳的潜力，且该品种还与免疫检查点抑制剂和其它靶向 RAS/MAPK通路的抑制剂具有很高的联用潜力，有望在竞争中先拔头筹。参考来源各公司官网；Leilei Fu. et al. Targeting Extracellular Signal-Regulated Protein Kinase 1/2 (ERK1/2) in Cancer: An Update on Pharmacological Small-Molecule Inhibitors [J]. J Med Chem. 2022, 65(20): 13561-13573.Richard A. Ward. et al. Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC) [J]. J Med Chem. 2019 62(24):11004-11018.Vikki Flemington. et al. AZD0364 is a potent and selective ERK1/2 inhibitor which enhances anti-tumour activity in KRAS mutant tumour models when combined with the MEK inhibitorSelumetinib [J]. Mol Cancer Ther. 2021, 20(2): 238-249.Andrea Varga. et al. A First-in-Human Phase I Study to Evaluate the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors [J]. Clin Cancer Res. 2020, 26(6):1229-1236.

免疫疗法小分子药物抗体合作

100 项与 MK-8353 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
FGF19阳性实体瘤	临床1期	美国	Merck Sharp & Dohme Corp.	2019-02-22
FGF19阳性实体瘤	临床1期	加拿大	Merck Sharp & Dohme Corp.	2019-02-22
FGF19阳性实体瘤	临床1期	瑞士	Merck Sharp & Dohme Corp.	2019-02-22
实体瘤	临床1期	美国	Merck Sharp & Dohme Corp.	2019-02-22
实体瘤	临床1期	加拿大	Merck Sharp & Dohme Corp.	2019-02-22
实体瘤	临床1期	瑞士	Merck Sharp & Dohme Corp.	2019-02-22
结直肠癌	临床1期	美国	Merck Sharp & Dohme Corp.	2017-01-13
结直肠癌	临床1期	加拿大	Merck Sharp & Dohme Corp.	2017-01-13
晚期恶性实体瘤	临床1期	-	Merck Sharp & Dohme LLC	2011-11-04

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03745989 (MK-8353-014 \| 8353-014, CTgov)	临床1期	实体瘤	30	Selumetinib+MK-8353 (MK-8353 50 mg + Selumetinib 25 mg)	構壓選築膚鹽選網壓願(選廠醖廠顧鹽齋製願鏇) = 網積顧願窪齋獵鹽膚鏇鬱齋構築鏇襯糧願鏇構 (廠襯網網觸築製獵顧襯, 構鬱範淵醖簾壓膚積願 ~ 構襯壓膚憲窪膚願願鑰) 更多	-	2023-01-25
				Selumetinib+MK-8353 (MK-8353 100 mg + Selumetinib 50 mg)	構壓選築膚鹽選網壓願(選廠醖廠顧鹽齋製願鏇) = 鑰鏇憲憲獵鏇簾蓋獵繭鬱齋構築鏇襯糧願鏇構 (廠襯網網觸築製獵顧襯, 夢淵襯鹹齋繭襯憲構壓 ~ 膚艱鏇衊襯鏇餘鹽襯醖) 更多
NCT01358331 (MK-8353-001 \| P06203, CTgov)	临床1期	晚期恶性实体瘤	25	MK-8353 (MK-8353 100 mg Twice Daily (BID))	鏇鏇壓衊蓋願壓製築構(範淵廠網顧膚鬱願衊艱) = 壓獵遞遞網窪憲壓蓋獵範鏇網築積艱餘夢網顧 (鏇餘餘鬱鏇鬱構顧製製, 淵願願構築鏇觸顧鹽構 ~ 鹽壓簾憲壓鹹範衊襯窪) 更多	-	2020-04-02
				MK-8353 (MK-8353 200 mg BID)	鏇鏇壓衊蓋願壓製築構(範淵廠網顧膚鬱願衊艱) = 觸鑰鑰壓範淵網鏇鑰顧範鏇網築積艱餘夢網顧 (鏇餘餘鬱鏇鬱構顧製製, 鏇網遞襯餘網製鹽廠觸 ~ 觸繭顧選網積餘膚膚鏇) 更多
NCT01358331 (MK-8353-001 \| P06203, Pubmed \| JCI Insight) 人工标引	临床1期	HR阳性/HER2低表达实体瘤 BRAF V600 Mutation	26	MK-8353	艱憲餘觸醖鑰簾遞齋鹽(範構膚繭繭壓鹽窪壓簾) = 艱繭積鏇獵窪顧糧壓繭選鹽鹽選鏇積壓獵憲襯 (齋鏇遞衊遞構鑰願鏇餘 )	积极	2018-02-22