(Merestinib) - 药物靶点：AXL x NTRK x ROS1 x TYRO3 x Tie-2 x c-Met_在研适应症：晚期胆管癌，晚期癌症_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Merestinib (USAN/INN)

靶点

AXL x NTRK x ROS1 x TYRO3 x Tie-2 x c-Met

作用机制

AXL抑制剂(AXL受体酪氨酸激酶抑制剂)、NTRK抑制剂(神经酪氨酸激酶受体抑制剂)、ROS1抑制剂(原癌基因酪氨酸蛋白激酶ROS抑制剂)

+ [3]

治疗领域

肿瘤消化系统疾病其他疾病

在研适应症

晚期胆管癌晚期癌症

非在研适应症

腺癌成人急性髓性白血病骨转移癌+ [10]

原研机构

Eli Lilly & Co.

在研机构

Eli Lilly & Co.

非在研机构-

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)无进展

特殊审评特殊审批 (中国)、孤儿药 (美国)

结构

分子式C30H22F2N6O3

InChIKeyQHADVLVFMKEIIP-UHFFFAOYSA-N

CAS号1206799-15-6

关联

12

项与 Merestinib 相关的临床试验

NCT03292536 / Terminated临床1期IIT

An Exploratory Phase 1B Study to Assess the Effects of Merestinib on Bone Metastases in Subjects With Breast Cancer

This is an open label, pharmacodynamics, intrapatient dose escalation phase 1B study.

开始日期2018-01-11

申办/合作机构

University of Utah

[+1]

NCT03125239 / Completed临床1期IIT

A Phase 1 Study of Merestinib in Combination With LY2874455 in Relapsed or Refractory Acute Myeloid Leukemia

This research study is studying a combination of two targeted therapies as a possible treatment for acute myeloid leukemia (AML) that has relapsed after initial treatment or did not fully respond.
The name of the study interventions involved in this study are:
Merestinib
LY2874455

开始日期2017-08-10

申办/合作机构

Dana-Farber Cancer Institute, Inc.

[+1]

NCT03027284 / Completed临床1期

A Phase I Study of Merestinib Monotherapy or in Combination With Other Anti-Cancer Agents in Japanese Patients With Advanced and/or Metastatic Cancer

The main purpose of this study is to evaluate tolerability of merestinib monotherapy or in combination with other anti-cancer agents in Japanese participants with advanced and/or metastatic cancer.

开始日期2017-02-03

申办/合作机构

Eli Lilly & Co.

100 项与 Merestinib 相关的临床结果

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100 项与 Merestinib 相关的转化医学

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100 项与 Merestinib 相关的专利（医药）

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22

项与 Merestinib 相关的文献（医药）

2023-03-01·Clinical Cancer Research

Targeting MET and FGFR in Relapsed or Refractory Acute Myeloid Leukemia: Preclinical and Clinical Findings, and Signal Transduction Correlates

Article

作者: Look, A. Thomas ; DeAngelo, Daniel J. ; Tošić, Isidora ; Garcia, Jacqueline S. ; Galinsky, Ilene ; Wadleigh, Martha ; Neuberg, Donna ; Luskin, Marlise R. ; Stone, Richard M. ; Pozdnyakova, Olga ; Chen, Evan C. ; Leonard, Rebecca ; O'Day, Kelsey ; Fell, Geoffrey G. ; Gandler, Helen ; Frank, David A. ; Fiore, Ashlee ; Winer, Eric S. ; de Jonge, Adrienne

AbstractPurpose:Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and require new therapies. In AML, autocrine production of hepatocyte growth factor (HGF) drives MET signaling that promotes myeloblast growth and survival, making MET an attractive therapeutic target. MET inhibition exhibits activity in AML preclinical studies, but HGF upregulation by the FGFR pathway is a common mechanism of resistance.Patients and Methods:We performed preclinical studies followed by a Phase I trial to investigate the safety and biological activity of the MET inhibitor merestinib in combination with the FGFR inhibitor LY2874455 for patients with R/R AML. Study Cohort 1 underwent a safety lead-in to determine a tolerable dose of single-agent merestinib. In Cohort 2, dose-escalation of merestinib and LY2874455 was performed following a 3+3 design. Correlative studies were conducted.Results:The primary dose-limiting toxicity (DLT) observed for merestinib alone or with LY2874455 was reversible grade 3 transaminase elevation, occurring in 2 of 16 patients. Eight patients had stable disease and one achieved complete remission (CR) without measurable residual disease. Although the MTD of combination therapy could not be determined due to drug supply discontinuation, single-agent merestinib administered at 80 mg daily was safe and biologically active. Correlative studies showed therapeutic plasma levels of merestinib, on-target attenuation of MET signaling in leukemic blood, and increased HGF expression in bone marrow aspirate samples of refractory disease.Conclusions:We provide prospective, preliminary evidence that MET and FGFR are biologically active and safely targetable pathways in AML.

2022-12-01·Journal of Hematology & Oncology

Foretinib can overcome common on-target resistance mutations after capmatinib/tepotinib treatment in NSCLCs with MET exon 14 skipping mutation

Article

作者: Fujino, Toshio ; Shimoji, Masaki ; Hamada, Akira ; Ohara, Shuta ; Suda, Kenichi ; Soh, Junichi ; Takemoto, Toshiki ; Chiba, Masato ; Koga, Takamasa ; Mitsudomi, Tetsuya

AbstractBackgroundCapmatinib and tepotinib are guideline-recommended front-line treatments for non-small-cell lung cancer (NSCLC) patients with MET exon 14 skipping mutations (METex14). However, the emergence of acquired resistance to capmatinib/tepotinib is almost inevitable partially due to D1228X or Y1230X secondary mutations of the MET. In this study, we explored agents that are active against both D1228X and Y1230X MET to propose an ideal sequential treatment after capmatinib/tepotinib treatment failure in NSCLC patients with METex14.MethodsThe inhibitory effects of 300 drugs, including 33 MET-TKIs, were screened in Ba/F3 cells carrying METex14 plus MET D1228A/Y secondary mutations. The screen revealed four-candidate type II MET-TKIs (altiratinib, CEP-40783, foretinib and sitravatinib). Therefore, we performed further growth inhibitory assays using these four MET-TKIs plus cabozantinib and merestinib in Ba/F3 cells carrying MET D1228A/E/G/H/N/V/Y or Y1230C/D/H/N/S secondary mutations. We also performed analyses using Hs746t cell models carrying METex14 (with mutant allele amplification) with/without D1228X or Y1230X in vitro and in vivo to confirm the findings. Furthermore, molecular dynamics (MD) simulations were carried out to examine differences in binding between type II MET-TKIs.ResultsAll 6 type II MET-TKIs were active against Y1230X secondary mutations. However, among these 6 agents, only foretinib showed potent activity against D1228X secondary mutations of the MET in the Ba/F3 cell and Hs746t in vitro model and Hs746t in vivo model, and CEP-40783 and altiratinib demonstrated some activity. MD analysis suggested that the long tail of foretinib plays an important role in binding D1228X MET through interaction with a residue at the solvent front (G1163). Tertiary G1163X mutations, together with L1195F/I and F1200I/L, occurred as acquired resistance mechanisms to the second-line treatment foretinib in Ba/F3 cell models.ConclusionsThe type II MET-TKI foretinib may be an appropriate second-line treatment for NSCLCs carrying METex14 after campatinib/tepotinib treatment failure by secondary mutations at residue D1228 or Y1230.

2022-09-09·BioMed Research International

Comparison of Different First-Line Systemic Therapies in Advanced Biliary Tract Cancer Based on Updated Random Controlled Trials: A Systematic Review and Network Meta-Analysis

Review

作者: Yi, Fengming ; Xu, Haoqian ; Feng, Long ; Wang, Ying

Background and Aim. The prognosis of advanced biliary tract cancer (BTC) is relatively poor, with limited survival. Currently, the first-line standard of care treatment is gemcitabine plus cisplatin, whereas numerous trials are trying to explore new regimens and prolong the life span of these patients. Herein, we aim to compare the effectiveness of different treatments and conclude more promising regimens for patients with advanced BTC. Methods. We searched PubMed, Web of Science, and Cochrane Library for abstracts and full-text articles published from database inception through May 2022. All the random controlled trials (RCTs) were assessed and collected as eligible studies. The primary outcome was overall survival (OS). The second outcome was progression-free survival (PFS). Results. Seventeen studies, including 3632 patients, were selected from 1361 records. In the network meta-analysis for OS, gemcitabine + cisplatin (GemCis) + cediranib (HR, 0.11; 95% CI, 0.00-2.88), GemCis+durvalumab (HR, 0.27; 95% CI, 0.06-1.29), and GemCis + merestinib (HR, 0.37; 95% CI, 0.03-4.36) showed the trend of OS benefit over standard treatment (GemCis), although there was no significant difference. GemCis, GemOxa, and gemcitabine+S1 (GemS1) did not differ when comparing OS. In the network meta-analysis for PFS, GemCis+merestinib (HR, 0.67; 95% CI, 0.54-0.83) and GemCis+durvalumab (HR, 0.22; 95% CI, 0.08-0.62) showed PFS benefit over standard treatment (GemCis) with a significant difference. GemCis, GemOxa, and GemS1 did not differ when comparing PFS. Conclusion. GemCis+durvalumab might be the most promising regimen for advanced BTC when considering OS and PFS. GemOxa and GemS1 could be alternative options for advanced BTC patients with nontolerance to GemCis.

100 项与 Merestinib 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11763	-	-	DB12381

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
胆道肿瘤	临床3期	意大利	Eli Lilly & Co.	2016-03-31
晚期胆管癌	临床2期	美国	Eli Lilly & Co.	2016-05-19
晚期胆管癌	临床2期	阿根廷	Eli Lilly & Co.	2016-05-19
晚期胆管癌	临床2期	捷克	Eli Lilly & Co.	2016-05-19
晚期胆管癌	临床2期	-	Eli Lilly & Co.	2016-05-19
晚期胆管癌	临床2期	墨西哥	Eli Lilly & Co.	2016-05-19
晚期胆管癌	临床2期	奥地利	Eli Lilly & Co.	2016-05-19
晚期胆管癌	临床2期	英国	Eli Lilly & Co.	2016-05-19
晚期胆管癌	临床2期	韩国	Eli Lilly & Co.	2016-05-19
晚期胆管癌	临床2期	德国	Eli Lilly & Co.	2016-05-19

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临床结果

适应症

分期

评价

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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


NCT02791334 (AACR2017)	临床1期	肿瘤	-	Merestinib + anti-PD-L1 Ab	(網艱憲鏇餘築餘遞膚壓) = 衊衊醖襯餘餘餘願襯艱選鹹衊觸糧築獵餘顧鏇 (鏇醖鏇壓憲顧鹹廠願製 )	积极	2017-07-01
				anti-PD-L1 Ab	(網艱憲鏇餘築餘遞膚壓) = 糧淵鹽選鹹鹹醖觸鹽窪選鹹衊觸糧築獵餘顧鏇 (鏇醖鏇壓憲顧鹹廠願製 )
NCT02920996 (CTgov)	临床2期	非小细胞肺癌	12	Merestinib (NSCLC (Met Exon 14 Mutation))	(鏇醖蓋簾顧網獵築蓋鏇) = 壓蓋簾餘製鏇願獵範網鬱積糧製築窪願蓋蓋鹽 (製構製鏇繭築製憲窪鏇, 鏇獵餘繭衊艱蓋壓齋蓋 ~ 齋膚鹽憲鹹餘鹽蓋網製) 更多	-	2024-04-11
				Merestinib (Solid Tumor (NTRK1,2,3 Rearrangement))	範蓋獵鹽鬱壓簾簾艱選(蓋夢鑰廠艱築窪積壓築) = 繭積製積願鏇構襯鹽繭繭築築齋廠窪鹹衊襯鹽 (鬱襯膚襯鹽廠醖鑰鏇鹽, 鏇鑰製築網鏇鹹鏇製觸 ~ 齋淵夢壓鬱獵壓網觸網) 更多
NCT03027284 (Pubmed) 人工标引	临床1期	肿瘤转移	18	merestinib (Part A)	(鹽壓蓋餘鹹糧廠鹽衊觸) = 鏇遞獵鹽膚艱憲願繭齋遞築壓壓鬱選憲鑰餘鏇 (鑰製選齋繭鑰艱襯膚構 ) 更多	积极	2021-10-01
				Cisplatin+gemcitabine+merestinib (Part B)	(餘醖積願網襯鏇遞艱遞) = 淵顧糧衊蓋鑰艱餘衊積簾鬱襯蓋選壓鹹繭夢膚 (製構蓋簾齋糧鑰積蓋壓 ) 更多
NCT02745769 (AACR2017)	临床1期	套细胞淋巴瘤 \| 结直肠癌 \| 晚期癌症	23	Merestinib (LY2801653)	(顧鏇衊窪蓋繭艱鹹膚壓) = 築蓋選製鏇觸膚獵網鑰鹹夢糧觸積觸鹽淵獵鹹 (鏇製膚鏇鏇鬱壓鹹窪網 )	-	2017-07-01
				DC101	(顧鏇衊窪蓋繭艱鹹膚壓) = 夢襯膚願獵製艱構齋壓鹹夢糧觸積觸鹽淵獵鹹 (鏇製膚鏇鏇鬱壓鹹窪網 )
AACR2014	N/A	肺癌 MET receptor tyrosine kinase \| RON tyrosine kinase receptor	-	LY2801653	顧遞築獵窪顧蓋淵鑰繭(遞鏇齋糧醖襯憲糧糧壓) = 醖製選鏇選選觸選餘繭鏇衊簾遞廠獵簾廠觸廠 (獵鏇蓋襯簾範夢夢窪糧 )	积极	2014-10-01
NCT02745769 (Pubmed \| Oncologist) 人工标引	临床1期	转移性结直肠癌	23	merestinib+ramucirumab	(窪鑰蓋築夢鏇築構壓範) = proteinuria of 7 phase Ia patients 衊遞遞選鏇遞製積製簾 (窪艱襯壓鏇製餘選醖遞 ) 更多	积极	2020-11-01
NCT01285037 (AACR2016)	临床1期	肿瘤 \| 晚期癌症	190	Merestinib	遞衊鏇積膚餘衊築醖築(廠鏇鏇淵餘鑰選窪製蓋) = 醖鑰獵鹹繭糧鏇壓製簾壓築蓋顧繭鏇衊壓顧襯 (蓋廠鹹觸顧廠廠夢製憲 ) 更多	积极	2016-07-15
				Crizotinib	遞衊鏇積膚餘衊築醖築(廠鏇鏇淵餘鑰選窪製蓋) = 鏇構鏇齋簾積鹹網壓遞壓築蓋顧繭鏇衊壓顧襯 (蓋廠鹹觸顧廠廠夢製憲 ) 更多
NCT02711553 (CTgov)	临床2期	晚期癌症 \| 晚期胆管癌	309	Gemcitabine+cisplatin+Ramucirumab (8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine)	(鹹範顧廠餘鏇夢積膚襯) = 積鏇獵遞艱膚憲齋構顧網鏇願鹽遞夢築齋鑰淵 (觸鬱積鬱鑰鹹築窪範築, 製鑰顧觸構鏇顧糧膚鏇 ~ 積範簾淵顧製製鹹積獵) 更多	-	2021-02-26
				Gemcitabine+cisplatin+Merestinib (80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine)	(鹹範顧廠餘鏇夢積膚襯) = 蓋獵築簾齋襯夢蓋蓋憲網鏇願鹽遞夢築齋鑰淵 (觸鬱積鬱鑰鹹築窪範築, 衊鬱構淵觸淵醖廠糧淵 ~ 蓋製廠觸襯襯鑰積簾範) 更多