凯泰酮胺(HQP8361) - 药物靶点：c-Met_在研适应症：肿瘤_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

c-Met

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

在研适应症

非在研适应症

原研机构

在研机构

非在研机构

Merck Sharp & Dohme Corp.

广州顺健生物医药科技有限公司

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)临床1期

特殊审评特殊审批 (中国)

登录后查看时间轴

结构

分子式C25H21N5O3S

InChIKeyVMJFTOSOFDEKTM-UHFFFAOYSA-N

CAS号1001917-37-8

关联

2

项与凯泰酮胺相关的临床试验

CTR20160141 / Completed临床1期

HQP8361治疗晚期实体瘤患者剂量递增的Ⅰ期临床试验

主要目的：评价HQP8361的安全性、耐受性，包括剂量限制性毒性（DLT），最大耐受剂量（MTD），和Ⅱ期临床推荐剂量（RP2D）。次要目的：评估HQP8361体内的药代动力学特征。探索HQP8361的药效动力学特征（PK-PD）。初步评估HQP8361在晚期实体肿瘤患者中的疗效。基于药效动力学特征和疗效资料确定II期试验给药方案以及敏感瘤种。

开始日期2016-04-21

申办/合作机构

广州顺健生物医药科技有限公司

NCT00559182 / Completed临床1期

A Phase I Dose Escalation Study of MK-8033 in Patients With Advanced Solid Tumors

This is a first-in-human trial to establish the safety, tolerability, Recommended Phase II Dose (RP2D), pharmacodynamic, and clinical activity of MK-8033.
Parts A and B of the study will determine the maximum tolerated dose (MTD) and RP2D. Part C of the study will be a single panel crossover study to determine the effect of omeprazole, a gastric pH modifier, on the pharmacokinetics of MK-8033.

开始日期2007-12-05

申办/合作机构

Merck Sharp & Dohme Corp.

100 项与凯泰酮胺相关的临床结果

登录后查看更多信息

100 项与凯泰酮胺相关的转化医学

登录后查看更多信息

100 项与凯泰酮胺相关的专利（医药）

登录后查看更多信息

4

项与凯泰酮胺相关的文献（医药）

2020-01-01·American journal of cancer research

The novel MET inhibitor, HQP8361, possesses single agent activity and enhances therapeutic efficacy of AZD9291 (osimertinib) against AZD9291-resistant NSCLC cells with activated MET.

Article

作者: Chen, Zhen ; Sun, Shi-Yong ; Li, Yiting ; Yu, Danlei ; Sun, Keven Dy ; Owonikoko, Taofeek K ; Gu, Jiajia ; Ramalingam, Suresh S

HQP8361 (MK8033) is a novel and selective MET kinase inhibitor that has completed a phase I clinical trial. AZD9291 (osimertinib) represents the first-approved third generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) for the treatment of non-small cell lung cancer (NSCLC) with activating EGFR mutations and resistant T790M mutation, but faces the giant challenge of acquired resistance developed in patients in the clinic. The current study focuses on determining the activity and mechanism of action of HQP8361 as a single agent and in combination with AZD9291 against human NSCLC cells, particularly those with acquired resistance to AZD9291. The majority of human NSCLC cell lines tested had very low levels of MET and p-MET and were insensitive to HQP8361. However, AZD9291-resistant (AR) cell lines with high levels of MET and p-MET responded to HQP8361 single agent and particularly to the combination of HQP8361 and AZD9291. The HQP8361 and AZD9291 combination synergistically decreased the survival of these HCC827/AR cell lines with enhanced induction of apoptosis that involved alteration of Bim and Mcl-1 levels via modulating their degradation. Moreover, the combination also very effectively inhibited the growth of HCC827/AR xenografts in nude mice. These preclinical findings support the potential of HQP8361 in the treatment of NSCLCs with MET amplification or highly activated MET and, when combined with AZD9291, in overcoming acquired resistance to EGFR-TKIs due to MET amplification.

2018-10-01·Investigational New Drugs3区 · 医学

First-in-human phase I dose escalation study of MK-8033 in patients with advanced solid tumors

3区 · 医学

Article

作者: Keedy, Vicki L ; Lenz, Heinz-Josef ; Camacho, Luis H ; Berlin, Jordan D ; Whisenant, Jennifer G ; Saltz, Leonard

Background C-Met, which is frequently activated in multiple cancers, has been implicated in tumor formation, progression, metastasis, angiogenesis, and resistance to multiple therapies. MK-8033 is a small-molecule inhibitor of c-Met that binds preferentially to the activated conformation, and has demonstrated anti-tumor activity in preclinical models. This first-in-human trial was performed to establish the safety and maximum tolerated dose (MTD), as well as preliminary pharmacokinetics (PK) and clinical activity. Methods Forty-seven patients were enrolled in three parts. The primary objective of Parts A and B was safety, whereas Part C evaluated the effect of proton-pump inhibitors on MK-8033 absorption. Dose escalation used an accelerated continual reassessment method, and dose-limiting toxicities (DLTs) were any treatment-related, first course non-hematologic grade ≥ 3 toxicity (except alopecia or inadequately treated nausea/vomiting/diarrhea), grade 4 hematologic toxicity (except grade 3 neutropenic fever and thrombocytopenia), or toxicity where treatment is held >3 weeks. Results Forty-six patients were treated across nine dose levels, and the MTD was 750 mg twice daily. DLTs were fatigue, nausea, vomiting, transaminitis, and hypokalemia. Most frequent toxicities were fatigue (28.3%), nausea (21.7%), and alopecia (19.6%), predominately grade ≤ 2. One patient with endometriod adenocarcinoma achieved a partial response and eight had stable disease. Median progression-free survival (PFS) was 57 days. Strikingly, the PFS for the one responder was 846 days. PK results showed that proton-pump inhibitors have no effect on MK-8033 absorption. Conclusion MK-8033 was well tolerated with no significant toxicity issues, albeit with limited clinical activity. Unfortunately, the company decided to discontinue further clinical development of MK-8033.

2013-05-01·Oncology Reports3区 · 医学

A novel c-Met inhibitor, MK8033, synergizes with carboplatin plus paclitaxel to inhibit ovarian cancer cell growth

3区 · 医学

Article

作者: Patricia L. Judson ; Johnathan M. Lancaster ; Robert M. Wenham ; Yin Xiong ; Elona Bicaku ; Nadim Bou Zgheib ; Sachin M. Apte ; Entidhar Al Sawah ; Xiaomang Ba Stickles ; Alex S. Lopez ; Christopher L. Cubitt ; Douglas C. Marchion ; Anders Berglund ; Jesus Gonzalez-Bosquet

Elevated serum levels of hepatocyte growth factor (HGF) and high tumor expression of c-Met are both indicators of poor overall survival from ovarian cancer (OVCA). In the present study, we evaluated the role of the HGF signaling pathway in OVCA cell line chemoresistance and OVCA patient overall survival as well as the influence of HGF/c-Met signaling inhibition on the sensitivity of OVCA cells to combinational carboplatin plus paclitaxel therapy. The prevalence of the HGF receptor, c-Met, was determined by immunohistochemistry in primary OVCA samples (n=79) and OVCA cell lines (n=41). The influence of the c-Met-specific inhibitor MK8033 on OVCA cell sensitivity to combinations of carboplatin plus paclitaxel was examined in a subset of OVCA cells (n=8) by CellTiter-Blue cell viability assays. Correlation tests were used to identify genes associated with response to MK8033 and carboplatin plus paclitaxel. Identified genes were evaluated for influence on overall survival from OVCA using principal component analysis (PCA) modeling in an independent clinical OVCA dataset (n=218). Immunohistochemistry analysis indicated that 83% of OVCA cells and 92% of primary OVCA expressed the HGF receptor, c-Met. MK8033 exhibited significant anti-proliferative effects against a panel of human OVCA cell lines. Combination index values determined by the Chou-Talalay isobologram equation indicated synergistic activity in combinations of MK8033 and carboplatin plus paclitaxel. Pearson's correlation identified a 47-gene signature to be associated with MK8033-carboplatin plus paclitaxel response. PCA modeling indicated an association of this 47-gene response signature with overall survival from OVCA (P=0.013). These data indicate that HGF/c-Met pathway signaling may influence OVCA chemosensitivity and overall patient survival. Furthermore, HGF/c-Met inhibition by MK8033 represents a promising new therapeutic avenue to increase OVCA sensitivity to carboplatin plus paclitaxel.

100 项与凯泰酮胺相关的药物交易

登录后查看更多信息

研发状态

10 条进展最快的记录,

登录

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
晚期恶性实体瘤	临床2期	-	Merck Sharp & Dohme Corp.	2007-12-05
肿瘤	临床1期	中国	亞盛醫藥集團	2022-07-12
晚期癌症	临床前	-	Merck Sharp & Dohme Corp.	2007-12-05