SAR-125844(SAR-125844) - 药物靶点：c-Met_专利_临床

概要

基本信息

药物类型

小分子化药

别名

SAR 125844、SAR125844

靶点

c-Met

作用方式

抑制剂

作用机制

c-Met抑制剂(肝细胞生长因子受体抑制剂)

治疗领域

肿瘤呼吸系统疾病

在研适应症-

非在研适应症

晚期非小细胞肺癌晚期恶性实体瘤

原研机构

Sanofi

在研机构-

非在研机构

Sanofi

权益机构-

最高研发阶段无进展临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C25H23FN8O2S2

InChIKeyODIUNTQOXRXOIV-UHFFFAOYSA-N

CAS号1116743-46-4

关联

3

项与 SAR-125844 相关的临床试验

NCT02435121

/ Completed临床2期

Phase II, Open Label, Single Arm Study Assessing the Clinical Benefit of SAR125844, Administered as Single Agent by Weekly Intravenous (IV) Infusion, for the Treatment of Patients With Advanced Pretreated Non-Small Cell Lung Cancer (NSCLC) Harboring MET Gene Amplification

Primary Objective:
To determine objective response rate (ORR).
Secondary Objectives:
To assess duration of response (DR), progression free survival (PFS) and overall survival (OS).
To evaluate global safety profile. To determine pharmacokinetic profile. To assess clinical utility of fluorescence in situ hybridization (FISH) assay in selection of patients with mesenchymal-epithelial hybridization (MET) gene amplification.
To assess lung cancer symptoms, health-related quality of life and treatment satisfaction.

开始日期2015-11-01

申办/合作机构

Sanofi

NCT01657214

/ Completed临床1期

Phase I, Dose Escalation Study of Safety, Pharmacokinetic and Pharmacodynamic of SAR125844 Administered Weekly as Intravenous Infusion in Asian Adult Patients With Advanced Malignant Solid Tumors

Primary Objective:
In the dose escalation: to determine the maximum tolerated dose (MTD) of SAR125844.
In the expansion cohort: to evaluate the preliminary anti-tumoral effect of SAR125844 in patients with measurable and MET gene amplification (including gastric cancer patients).
Secondary Objectives:
To characterize and confirm the global safety profile of SAR125844 including cumulative toxicities.
To assess preliminary antitumor activity of SAR125844. To explore the pharmacodynamic effects (PDy) of SAR125844. To evaluate the pharmacokinetic profile of SAR125844. To explore the relationship of MET gene amplification status with antitumor effects.
To evaluate other pharmacodynamic biomarkers.

开始日期2012-09-01

申办/合作机构

Sanofi

NCT01391533

/ Completed临床1期

Dose Escalation, Safety, Pharmacokinetic and Pharmacodynamic, First in Man Study, of SAR125844 Single Agent Administered as Slow Intravenous Infusion in Adult Patients With Advanced Malignant Solid Tumors

Primary Objectives:
To determine the maximum tolerated dose (MTD) of SAR125844. To confirm safety profile of SAR125844 when administered as single agent at the MTD.
To evaluate the preliminary anti-tumoral effect of SAR125844 in patients with MET-gene amplified solid tumors (including sub-group of MET-amplified non-small cell lung cancer [NSCLC] patients) and in patients with Phospho-MET positive tumors without MET-gene amplification.
Secondary Objectives:
To characterize the global safety profile including cumulative toxicities. To evaluate the pharmacokinetic profile of SAR125844 in the proposed dosing schedule(s).
To assess preliminary antitumor activity in patients with measurable/evaluable disease, according to RECIST 1.1 criteria.
To explore the pharmacodynamic effects (PD) of SAR125844. To explore MET gene amplification status in Circulating Tumoral Cells (CTCs) and on tumor biopsies collected during the study, in the escalation part only.
To evaluate other pharmacodynamic biomarkers and help selection of patients who could benefit from SAR125844.
To explore MET-gene amplification status in circulating DNA.

开始日期2011-07-01

申办/合作机构

Sanofi

100 项与 SAR-125844 相关的临床结果

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100 项与 SAR-125844 相关的转化医学

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100 项与 SAR-125844 相关的专利（医药）

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7

项与 SAR-125844 相关的文献（医药）

2021-06-21·Chemical research in toxicology3区 · 医学

Reactive Metabolites from Thiazole-Containing Drugs: Quantum Chemical Insights into Biotransformation and Toxicity

3区 · 医学

Article

作者: Jaladanki, Chaitanya K. ; Khatun, Samima ; Gohlke, Holger ; Bharatam, Prasad V.

Drugs containing thiazole and aminothiazole groups are known to generate reactive metabolites (RMs) catalyzed by cytochrome P450s (CYPs). These RMs can covalently modify essential cellular macromolecules and lead to toxicity and induce idiosyncratic adverse drug reactions. Molecular docking and quantum chemical hybrid DFT study were carried out to explore the molecular mechanisms involved in the biotransformation of thiazole (TZ) and aminothiazole (ATZ) groups leading to RM epoxide, S-oxide, N-oxide, and oxaziridine. The energy barrier required for the epoxidation is 13.63 kcal/mol, that is lower than that of S-oxidation, N-oxidation, and oxaziridine formation (14.56, 17.90, and 20.20, kcal/mol respectively). The presence of the amino group in ATZ further facilitates all the metabolic pathways, for example, the barrier for the epoxidation reaction is reduced by ∼2.5 kcal/mol. Some of the RMs/their isomers are highly electrophilic and tend to form covalent bonds with nucleophilic amino acids, finally leading to the formation of metabolic intermediate complexes (MICs). The energy profiles of these competitive pathways have also been explored.

2018-11-08·Journal of medicinal chemistry1区 · 医学

Where Do Recent Small Molecule Clinical Development Candidates Come From?

1区 · 医学

Review

作者: Boström, Jonas ; Brown, Dean G.

An analysis of 66 published clinical candidates from Journal of Medicinal Chemistry has been conducted to shed light on which lead generation strategies are most frequently employed in identifying drug candidates. The most frequent lead generation strategy (producing a drug candidate) was based on starting points derived from previously known compounds (43%) followed by random high throughput screening (29%). The remainder of approaches included focused screening, structure-based drug design (SBDD), fragment-based lead generation (FBLG), and DNA-encoded library screening (DEL). An analysis of physicochemical properties on the hit-to-clinical pairs shows an average increase in molecular weight (ΔMW = +85) but no change in lipophilicity (ΔclogP = -0.2), although exceptions are noted. The majority (>50%) of clinical candidates were found to be structurally very different from their starting point and were more complex. Finally, several reports of noncovalent scaffolds modified by a covalent warhead using SBDD approaches are discussed.

2017-12-01·European journal of cancer (Oxford, England : 1990)1区 · 医学

A first-in-human phase I study of SAR125844, a selective MET tyrosine kinase inhibitor, in patients with advanced solid tumours with MET amplification

1区 · 医学

Article

作者: Harnois, Marzia ; Dotti, Katia ; Hollebecque, Antoine ; Isambert, Nicolas ; Azaro, Analia ; Moreno, Victor ; Angevin, Eric ; Gomez, Corinne ; Hervieu, Alice ; Salvagni, Stefania ; Spitaleri, Gianluca ; Assadourian, Sylvie ; De Marinis, Filippo ; Rodon, Jordi ; Rihawi, Karim

PURPOSE:

Dysregulated MET signalling is implicated in oncogenesis. The safety and preliminary efficacy of a highly selective MET kinase inhibitor (SAR125844) was investigated in patients with advanced solid tumours and MET dysregulation.

METHODS:

This was a phase I dose-escalation (3 + 3 design [50-740 mg/m²]) and dose-expansion study. In the dose escalation, patients had high total MET (t-MET) expression by immunohistochemistry (IHC) or MET amplification by fluorescence in situ hybridisation. In the dose expansion, patients had MET amplification (including a subset of patients with non-small cell lung cancer [NSCLC]) or phosphorylated-MET (p-MET) expression (IHC). Objectives were determination of maximum tolerated dose (MTD) of once-weekly intravenous SAR125844 based on dose-limiting toxicities; safety and pharmacokinetic profile; preliminary efficacy of SAR125844 MTD in the expansion cohort.

RESULTS:

In total, 72 patients were enrolled: dose escalation, N = 33; dose expansion, N = 39; 570 mg/m² was established as the MTD. Most frequent treatment-emergent adverse events (AEs) were asthenia/fatigue (58.3%), nausea (31.9%), and abdominal pain, constipation, and dyspnea (27.8% for each); 58.3% of patients reported grade 3 AEs (19.4% were treatment related). Of the 29 evaluable patients with MET amplification treated at 570 mg/m², five achieved a partial response, including four of 22 with NSCLC; 17 patients had stable disease. No response was observed in patients with high p-MET solid tumours. There was no correlation between tumour response and t-MET status or MET gene copy number.

CONCLUSION:

The MTD of once-weekly SAR125844 was 570 mg/m²; SAR125844 was well tolerated, with significant antitumour activity in patients with MET-amplified NSCLC.

CLINICAL TRIAL REGISTRATION NUMBER:

NCT01391533.

100 项与 SAR-125844 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15382

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
晚期非小细胞肺癌	临床2期	比利时	Sanofi	2015-11-01
晚期恶性实体瘤	临床1期	美国	Sanofi	2011-07-01
晚期恶性实体瘤	临床1期	法国	Sanofi	2011-07-01
晚期恶性实体瘤	临床1期	意大利	Sanofi	2011-07-01
晚期恶性实体瘤	临床1期	西班牙	Sanofi	2011-07-01

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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


NCT01391533 (Pubmed \| Eur J Cancer Care (Engl) \| Eur J Cancer) 人工标引	临床1期	晚期恶性实体瘤 MET Amplification	72	SAR125844	膚鬱鑰醖製鹽鏇網鏇觸(製構範製繭齋選壓鬱夢) = 遞夢醖廠衊淵觸蓋鑰壓憲鏇範鏇夢選鑰鏇選艱 (廠鹹窪簾獵鑰鹽獵範糧 ) 更多	积极	2017-12-01
NCT01657214 (SARMETA, Pubmed) 人工标引	临床1期	c-Met阳性胃癌 \| 实体瘤 MET-amplified	38	SAR125844 (dose escalation)	積壓築夢廠壓獵選淵顧(願壓蓋艱淵鏇簾網構膚) = 繭夢壓製齋醖艱顧鏇積夢窪簾膚觸蓋醖憲簾淵 (範糧範壓選獵顧願窪鹹 ) 更多	积极	2017-06-16
NCT01657214 (SARMETA, Pubmed) 人工标引	临床1期	c-Met阳性胃癌 \| 实体瘤 MET-amplified	38	SAR125844 (Dose expansion)	衊齋簾醖衊鏇繭廠廠鑰(選獵網淵醖遞餘鹹網鏇) = 齋範窪齋窪糧壓憲餘餘鹽鑰壓鬱繭淵鹹艱願衊 (膚鏇繭餘夢繭襯築鏇壓 ) 更多	积极	2017-06-16