This phase I/II trial studies the side effects and best dose of molibresib when given together with chemotherapy (etoposide and cisplatin) and how well they work for the treatment of NUT cancer that has spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Molibresib may stop the growth of tumor cells by blocking some of the proteins needed for cell growth. Drugs used in chemotherapy, such as etoposide and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Adding molibresib to chemotherapy (etoposide and cisplatin), may work better in treating patients with NUT cancer compared to the usual approach.

开始日期2020-09-18

申办/合作机构

National Cancer Institute

NCT03925428 / Withdrawn临床1期IIT

Phase I Study of GSK525762C and Entinostat in Advanced and Refractory Solid Tumors and Lymphomas

This phase I trial studies the side effects and best dose of GSK525762C (molibresib besylate) and entinostat in treating patients with solid tumors or lymphomas that have spread to other parts of the body (advanced) or are not responding to treatment (refractory). GSK525762C and entinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. This study may help doctors find out if giving the combination of GSK525762C and entinostat is better or worse than the usual approach for treating solid tumors or lymphomas.

开始日期2020-09-18

申办/合作机构

National Cancer Institute

NCT02964507 / Terminated临床1期

A Phase I/II Dose Escalation and Expansion Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK525762 in Combination With Fulvestrant in Subjects With Hormone Receptor-positive/HER2-negative (HR+/HER2-) Advanced or Metastatic Breast Cancer

This is a combination Phase I and Phase II study, with an aim to evaluate the combination of GSK525762 and fulvestrant in women with HR+/HER2- advanced or metastatic breast cancer, who have disease that has progressed after prior treatment with at least one line of endocrine therapy. The objectives of the study are to first identify, in open-label single-arm Phase I, a recommended Phase II dose of GSK525762 that may be combined safely with fulvestrant. Phase I will follow a modified toxicity probability interval (mTPI) design, and a sentinel group will be evaluated first for dose-limiting toxicity and further expanded to collect additional safety data. This will be followed by a double-blind, randomized controlled Phase II, to identify the clinical activity of the two study treatments when given in combination. The composition of Phase II will be selected at the end of Phase I.

开始日期2019-09-26

申办/合作机构

GSK Plc

100 项与 Molibresib 相关的临床结果

登录后查看更多信息

100 项与 Molibresib 相关的转化医学

登录后查看更多信息

100 项与 Molibresib 相关的专利（医药）

登录后查看更多信息

项与 Molibresib 相关的文献（医药）

2024-05-20·Cancer research communications

Pharmacologic Targeting of Histone H3K27 Acetylation/BRD4-dependent Induction of ALDH1A3 for Early-phase Drug Tolerance of Gastric Cancer

Article

作者: Inaba, Saori ; Seimiya, Hiroyuki ; Mashima, Tetsuo ; Takeuchi, Kengo ; Yamamoto, Noriko ; Yamaguchi, Kensei ; Morino, Shun ; Lee, Jin ; Wakatsuki, Takeru ; Kawata, Naomi ; Nakamura, Ayane ; Kumagai, Koshi

Abstract:

Anticancer drug-tolerant persister (DTP) cells at an early phase of chemotherapy reshape refractory tumors. Aldehyde dehydrogenase 1 family member A3 (ALDH1A3) is commonly upregulated by various anticancer drugs in gastric cancer patient-derived cells (PDC) and promotes tumor growth. However, the mechanism underlying the generation of ALDH1A3-positive DTP cells remains elusive. Here, we investigated the mechanism of ALDH1A3 expression and a combination therapy targeting gastric cancer DTP cells. We found that gastric cancer tissues treated with neoadjuvant chemotherapy showed high ALDH1A3 expression. Chromatin immunoprecipitation (ChIP)-PCR and ChIP sequencing analyses revealed that histone H3 lysine 27 acetylation was enriched in the ALDH1A3 promoter in 5-fluorouracil (5-FU)-tolerant persister PDCs. By chemical library screening, we found that the bromodomain and extraterminal (BET) inhibitors OTX015/birabresib and I-BET-762/molibresib suppressed DTP-related ALDH1A3 expression and preferentially inhibited DTP cell growth. In DTP cells, BRD4, but not BRD2/3, was recruited to the ALDH1A3 promoter and BRD4 knockdown decreased drug-induced ALDH1A3 upregulation. Combination therapy with 5-FU and OTX015 significantly suppressed in vivo tumor growth. These observations suggest that BET inhibitors are efficient DTP cell–targeting agents for gastric cancer treatment.

Significance::

Drug resistance hampers the cure of patients with cancer. To prevent stable drug resistance, DTP cancer cells are rational therapeutic targets that emerge during the early phase of chemotherapy. This study proposes that the epigenetic regulation by BET inhibitors may be a rational therapeutic strategy to eliminate DTP cells.

2024-03-01·Advanced biology

Cytoplasmic Accumulation of Histones Induced by BET Inhibition Protects Cells from C9orf72 Poly(PR)‐Induced Cell Death

Article

作者: Guo, Xiaohong ; Mao, Renfang ; Chen, Liuting ; Fan, Yihui ; Shi, Conglin ; Chen, Miaomiao ; Wu, Yuanyuan ; Guo, Jinjing

Abstract:

Repeat dipeptides such as poly(proline‐arginine) (polyPR) are generated from the hexanucleotide GGGGCC repeat expansions in the C9orf72 gene. These dipeptides are often considered as the genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In the study, fluorescein isothiocyanate (FITC) labeled PR20 is used to investigate PR20‐induced cell death. The findings reveal that the cell death induced by PR20 is dependent on its nuclear distribution and can be blocked by a nuclear import inhibitor called importazole. Further investigation reveals that BRD4 inhibitors, such as JQ‐1 and I‐BET762, restrict cytoplasmic localization of PR20, thereby reducing its cytotoxic effect. Mechanistically, the inhibition of BRD4 leads to an increase in the expression of numerous histones, resulting in the accumulation of histones in the cytoplasm. These cytoplasmic histones associate with PR20 and limit its distribution within the nucleus. Notably, the ectopic expression of histones alone is enough to confer protection to cells treated with PR20. In addition, phenylephrine (PE) induces cellular hypertrophy and cytoplasmic distribution of histone, which also helps protect cells from PR20‐induced cell death. The research suggests that temporarily inducing the presence of cytoplasmic histones may alleviate the neurotoxic effects of dipeptide repeat proteins.

2024-01-17·Clinical cancer research : an official journal of the American Association for Cancer Research

A Phase I/II Study of GSK525762 Combined with Fulvestrant in Patients with Hormone Receptor–positive/HER2-negative Advanced or Metastatic Breast Cancer

Article

作者: Morales Murilo, Serafin ; Dhar, Arindam ; Yeo, Belinda ; Im, Young-Hyuck ; Khaled, Ahmed ; Barbash, Olena ; Zhang, Qu ; Oliveira, Mafalda ; Horner, Thierry ; Sparano, Joseph A. ; Hilton, John ; Layman, Rachel M. ; Wyce, Anastasia ; Krishnatry, Anu Shilpa ; Hicks, Kirsty ; Kim, Sung-Bae ; Cescon, David W. ; Park, In Hae ; Provencher, Louise ; Pluard, Timothy

Abstract:

Purpose::

Endocrine-based therapy is the initial primary treatment option for hormone receptor–positive and human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (mBC). However, patients eventually experience disease progression due to resistance to endocrine therapy. Molibresib (GSK525762) is a small-molecule inhibitor of bromodomain and extraterminal (BET) family proteins (BRD2, BRD3, BRD4, and BRDT). Preclinical data suggested that the combination of molibresib with endocrine therapy might overcome endocrine resistance. This study aimed to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy [objective response rate (ORR)] of molibresib combined with fulvestrant in women with HR+/HER2− mBC.

Patients and Methods::

In this phase I/II dose-escalation and dose-expansion study, patients received oral molibresib 60 or 80 mg once daily in combination with intramuscular fulvestrant. Patients enrolled had relapsed/refractory, advanced/metastatic HR+/HER2− breast cancer with disease progression on prior treatment with an aromatase inhibitor, with or without a cyclin-dependent kinase 4/6 inhibitor.

Results::

The study included 123 patients. The most common treatment-related adverse events (AE) were nausea (52%), dysgeusia (49%), and fatigue (45%). At a 60-mg dosage of molibresib, >90% of patients experienced treatment-related AE. Grade 3 or 4 treatment-related AE were observed in 47% and 48% of patients treated with molibresib 60 mg and molibresib 80 mg, respectively. The ORR was 13% [95% confidence interval (CI), 8–20], not meeting the 25% threshold for proceeding to phase II. Among 82 patients with detected circulating tumor DNA and clinical outcome at study enrollment, a strong association was observed between the detection of copy-number amplification and poor progression-free survival (HR, 2.89; 95% CI, 1.73–4.83; P < 0.0001).

Conclusions::

Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study.

项与 Molibresib 相关的新闻（医药）

2023-03-14

·CPHI制药在线

关注 | 裁员17%，管线砍掉大半，这家德国药企的“保留项目”有何看点？

关注并星标CPHI制药在线近日，德国慕尼黑MorphoSys AG宣布计划停止所有临床前管线，并裁减17%的员工，以延长其现金跑道，届时MorphoSys将有110名员工失业。公司表示，后续将其主要资源集中于3款抗肿瘤药物。这三款仅存的产品分别是已上市的CD19抗体tafasitamab，在研产品BET抑制剂pelabresib及EZH2抑制剂CPI-0209。 CD19抗体tafasitamab Tafasitamab是一款靶向CD19的人源化单克隆抗体，也是目前MorphoSys AG唯一商业化上市的产品。2020年8月，FDA加速批准Tafasitamab上市，用来与来那度胺联用二线治疗成人复发或难治性（r/r）弥漫性大B细胞淋巴瘤（DLBCL）。2021年6月，欧洲药品管理局CHMP发表了积极意见，建议有条件批准tafasitamab和来那度胺联合治疗及后续tafasitamab单药治疗，用于不符合自体干细胞移植（ASCT）条件的r/r DLBCL成人患者的治疗。 Tafasitamab在开发过程中，使用Xmab技术平台，对抗体的Fc段进行改造，通过改造抗体的Fc端，能够将抗体与Fcγ受体的亲和力提高数十倍，从而更好地激活NK细胞、巨噬细胞等免疫细胞。临床数据表明，在使用来那度胺和Tafasitamab联合治疗r/r DLBCL成人患者中，试验数据显示：客观缓解率（ORR）为55%，完全缓解率（CR）为37％，部分缓解率（PR）为18％；中位缓解持续时间（mDOR）为21.7个月。最常见的不良反应是中性粒细胞减少。看到CD19这个靶点以及DLBCL，就会联想到CD19-CAR-T。虽然Tafasitamab临床效果稍逊一筹，但Tafasitamab的安全性更好，目前上市的CAR-T具有免疫相关不良反应，严重者甚至收到FDA的黑框警告，而Tafasitamab相关的不良反应主要为中性粒细胞减少。另外，目前上市的CAR-T产品多为自体来源，耗时长且价格昂贵，Tafasitamab则是一种工业化生产的即用型产品。 BET抑制剂pelabresib Pelabresib是一款潜在FIC的BET抑制剂，其用于治疗骨髓纤维化的III期MANIFEST-2研究正在进行中，将于明年初公布关键数据。 BET（溴结构域和超末端结构域）属于BD（溴结构域）大家族的一员，BD是一类由约110个氨基酸组成的、能够特异性识别组蛋白中乙酰化赖氨酸（KAc）的高度保守的蛋白结构域，其包含八大家族，其中BET是被研究较多的一个家族。 BET蛋白家族包含四个异构体，分别是：BRD2、BRD3、BRD4和BRDT。每个家族成员含有两个溴结构域（BD1、BD2）和一个超末端结构域（ET）。其中BD1和BD2识别并结合KAc从而发挥生理作用，ET结构域与辅助因子相互作用。BET家族蛋白通过BD1、BD2与乙酰化的染色质结合，从而在表观遗传学水平上对基因表达进行调控，广泛参与细胞周期、细胞分化、信号转导等过程，在许多肿瘤的发生、发展中起着重要作用。目前，一系列BET抑制剂正在研发中，不过BET抑制剂的研发极具挑战。这是因为BD1和BD2具有高度同源性，之前报道的大多BET抑制剂对BD1和BD2具有相似的亲和活性，这类抑制剂通常被称为泛BET抑制剂，如二氮杂及其衍生物（JQ1、IBET762、OTX015）等。这类抑制剂不但具有剂量限制性毒性而且其抗肿瘤活性比临床前观察到的弱。为了解决这些问题，开发高亚型选择性的BET抑制剂是未来的研发方向，这些高亚型选择性抑制剂包括BD1、BD2以及BRD4选择性抑制剂等。 Pelabresib就是在泛BET抑制剂JQ1的基础上进行优化改造而得。化合物JQ1是一种研发较早的BET小分子抑制剂，其作用疾病范围广泛，但是半衰期短且治疗过程中毒性较大，为了得到药效持久且毒性较低的高选择性BET抑制剂，Pelabresib在JQ1的基础上，用苯环替换代谢不稳定的噻吩环改造而来，它对BD1的抑制活性是BD2的6倍以上。在治疗骨髓纤维化患者的II期临床试验中，Pelabresib表现出积极的疗效，其与JAK抑制剂ruxolitinib联用，在未接受过JAK抑制剂治疗的患者中能够让67%的患者脾脏体积缩小35%以上。目前全球III期临床研究正在进行中。目前，多款高选择性BET抑制剂正在研发中。如GSK的BD1选择性抑制剂GSK779、艾伯维的BD2选择性抑制剂ABBV-744、以及靶向BRD4的PROTACs等。在国内，也有多家企业在进行相关产品的研发，如贝达药业的BET抑制剂BPI-23314，其能抑制BET相关多种癌症基因表达及降解靶蛋白BRD4等；文达医药的NHWD-870 HCl，是一款靶向BRD4的选择性抑制剂，拟开发用于治疗晚期复发非霍奇金淋巴瘤、非小细胞肺癌和小细胞肺癌等；加科思的BET抑制剂JAB-8263，临床前研究表明其对多种实体瘤和血液瘤均能发挥抗肿瘤作用。总之，BET抑制剂赛道已变得非常拥挤，不过以上BET抑制剂大多处于临床早期阶段。MorphoSys AG的Pelabresib是为数不多进入临床III期的高选择性BET抑制剂，未来有望率先撞线，是一款潜在FIC的骨髓纤维化疗法。 EZH2抑制剂CPI-0209 EZH2是一种组蛋白赖氨酸甲基转移酶，其通过催化组蛋白H3赖氨酸27（H3K27）的甲基化以控制各种基因表达，从而调节细胞的正常生理功能。在多种癌症中均存在EZH2的失调，另外EZH2的表达还与临床的不良预后和疗效相关。自EZH2在临床上发现其与肿瘤的发生及预后相关后，科学家们就尝试利用EZH2抑制剂来干预肿瘤发生的甲基化水平。2012年开始，Epizyme、诺华、GSK、辉瑞、第一三共等陆续入局EZH2抑制剂的研发。 MorphoSys AG的CPI-0209是一款新一代EZH2抑制剂，临床前研究显示，CPI-0209具有比其他EZH2抑制剂强10-500倍的效力，目前，它正在开展I/II期临床试验，治疗多种血液瘤和实体瘤患者。目前，大多EZH2抑制剂仍处于临床开发的前期，很多临床试验正在摸索中前进，尚未形成同质化恶性竞争，MorphoSys AG的CPI-0209尚有突围机会。上述三款产品是目前MorphoSys AG仅剩的三款产品，从分析可知，三款产品各有优势，且在研产品在领域内研发进度均靠前，未来很有希望分到市场的一杯羹。事实上，在资本寒冬下，缩减管线，及时调整研发策略是再正常不过的一件事，就连大厂也在不断瘦身，如辉瑞在2022年财报披露中曾透露，公司将剔除8个研发项目；BMS也在2022年财报中表示将削减9项资产；国内三叶草生物也在去年年中对外宣布，将优先把所有资源配置给新冠疫苗这一管线，减少非新冠项目的投入。如今，MorphoSys AG由于市场变化，欲将有限的资源集中到更具希望的临床后期管线项目上，虽然砍掉临床前团队这一决策的影响要在多年后才会得到验证，但就当下来说，这一决策不失为明智之举。毕竟，在资本寒冬下，如何活下去，活得好，才是当下创新biotech要思考的第一要义。参考来源： 1. https://www.morphosys.com/media-investors/media-center/fda-approves-monjuvir-tafasitamab-cxix-in-combination-with-lenalidomide; 2. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study [published online ahead of print, 2020 Jun 5]. Lancet Oncol. 2020;S1470-2045(20)30225-4. doi:10.1016/S1470-2045(20)30225-4; 3. Pan Tang,Jifa Zhang et al.（2021）. Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development.Journal of Medicinal Chemistry,DOI: 10.1021/acs.jmedchem.0c01487； 4. 陈金晶，赵晓丽等.（2017）.含溴结构域和额外终端域家族蛋白--表观遗传领域的新型治疗靶点。《药学学报》DOI：：10.16438/j.05l3-4870.2017-0143； 5. 宫玉芳等. 新兴抗肿瘤靶点EZH2作用机制及研究进展.《现代肿瘤医学》，2020, 28（10）, 1757-1760. 智药研习社近期研习会报名来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

免疫疗法加速审批临床3期临床2期细胞疗法

100 项与 Molibresib 相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
D11326	-	-	DB16239

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
FGF19阳性实体瘤	临床2期	-	GSK Plc	2017-11-27
RAS/RAF 突变的实体瘤	临床2期	-	GSK Plc	2017-11-27
小细胞肺癌	临床2期	-	GSK Plc	2017-11-27
血液肿瘤	临床2期	美国	GSK Plc	2014-05-14
血液肿瘤	临床2期	澳大利亚	GSK Plc	2014-05-14
血液肿瘤	临床2期	韩国	GSK Plc	2014-05-14
血液肿瘤	临床2期	西班牙	GSK Plc	2014-05-14
血液肿瘤	临床2期	英国	GSK Plc	2014-05-14
乳腺癌	临床2期	英国	GSK Plc	-
HR阳性/HER2阴性乳腺癌	临床1期	美国	GSK Plc	2019-09-26

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02964507 (ASCO2023) 人工标引	临床1/2期	HR阳性HER2阴性淋巴结阳性乳腺癌 HR positive \| HER2 Negative	123	Molibresib 60 mg	廠廠壓餘鑰構夢糧繭膚(鏇簾夢鏇鏇膚壓願選餘) = The 3 most common molibresib-related adverse events (AEs) were nausea (52%), dysgeusia (49%), and fatigue (44%) 構積淵淵選願廠窪衊窪 (餘蓋夢鑰壓願繭夢獵餘 )	不佳	2023-05-31
NCT01943851 (Pubmed)	临床1/2期	血液肿瘤	111	Molibresib	膚衊糧簾窪餘鹹鹽鏇積(獵鑰齋鹽淵鑰鏇繭鹽鹽) = 願鏇獵餘艱餘築蓋廠積網艱顧餘願夢範觸範遞 (齋觸鏇遞襯膚齋窪鏇衊, 4.8 ~ 18.7) 更多	积极	2022-11-09
NCT02964507 (CTgov)	临床1期	HR阳性/HER2阴性乳腺癌	124	FUL+GSK525762 (Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure))	壓窪鬱鬱衊構夢觸簾夢(鏇鹹鹽醖觸鏇壓蓋願齋) = 鬱淵窪選願齋窪築鹹蓋壓製餘構廠壓淵鏇遞廠 (鹹製鹹繭壓遞艱網壓觸, 鹽淵願糧窪糧簾網餘遞 ~ 製選願膚選觸製壓遞膚) 更多	-	2022-01-27
NCT02964507 (CTgov)	临床1期	HR阳性/HER2阴性乳腺癌	124	FUL+GSK525762 (Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M))	壓窪鬱鬱衊構夢觸簾夢(鏇鹹鹽醖觸鏇壓蓋願齋) = 壓構積淵蓋蓋鏇網構醖壓製餘構廠壓淵鏇遞廠 (鹹製鹹繭壓遞艱網壓觸, 鹽壓蓋糧鏇窪鏇夢簾鏇 ~ 醖鏇網獵觸顧齋鏇憲醖) 更多	-	2022-01-27
NCT03150056 (CTgov)	临床1期	去势抵抗性前列腺癌	73	GSK525762+Abiraterone (GSK525762 60 mg+Abiraterone 1000 mg)	鬱遞願艱壓壓願鬱繭壓(鏇繭簾艱艱網襯鑰蓋壓) = 繭網淵鏇遞觸鑰選窪廠網糧鬱製醖範襯構蓋範 (鏇窪觸鏇餘糧遞膚繭觸, 夢網鑰積淵夢憲範憲選 ~ 鬱範壓襯鏇網鏇膚衊簾) 更多	-	2021-08-26
NCT03150056 (CTgov)	临床1期	去势抵抗性前列腺癌	73	GSK525762+Abiraterone (GSK525762 60 mg Alternate+Abiraterone 1000 mg)	鬱遞願艱壓壓願鬱繭壓(鏇繭簾艱艱網襯鑰蓋壓) = 鹹憲淵製醖繭廠鹹衊夢網糧鬱製醖範襯構蓋範 (鏇窪觸鏇餘糧遞膚繭觸, 餘鹹衊構醖遞網淵餘顧 ~ 築鏇壓鏇糧憲獵壓餘齋) 更多	-	2021-08-26
NCT01587703 (ASCO2020)	临床1/2期	HR阳性/HER2低表达实体瘤	196	Molibresib	醖顧鹹糧簾鹹製獵簾選(膚糧鹽鏇鹹醖網鏇構選) = AEs were experienced by 193/196 (98%) patients; 180/196 (92%) had a treatment-related AE (TRAE). AEs led to permanent treatment discontinuation in 38/196 (19%) patients. 衊鏇夢遞鬱鏇膚餘鑰構 (壓襯獵鬱糧構顧積獵鹹 ) 更多	积极	2020-05-25
NCT01587703 (Pubmed) 人工标引	临床1期	实体瘤 \| NUT中线癌	65	Molibresib	遞繭網構衊淵範顧願構(夢範觸選齋網簾觸範簾) = 80 mg once daily was selected as the recommended 衊遞糧獵範憲窪窪積鑰 (繭繭鹽齋構獵簾觸簾鑰 ) 更多	积极	2019-11-06