A Randomized, Double-blind, Placebo-controlled Study of the Safety and Efficacy of Amatuximab in Combination With Pemetrexed and Cisplatin in Subjects With Unresectable Malignant Pleural Mesothelioma

This study was originally designed as a multicenter, double-blind, randomized, parallel-group study, using a placebo control or amatuximab 5 milligrams per kilogram (mg/kg), administered weekly, designed to evaluate the safety and efficacy of amatuximab in combination with pemetrexed and cisplatin in participants with unresectable Malignant Pleural Mesothelioma (MPM) who have not received prior systemic therapy.
Per a business decision made by the Sponsor, participants who were randomized to amatuximab and were still on active treatment at the time of the protocol amendment may have consented to continue to receive weekly treatment with amatuximab until disease progression or intolerable toxicity at the discretion of the principal investigator. Participants randomized to placebo or who were in follow-up at the time of the amendment have been discontinued from the study.

开始日期2015-11-03

申办/合作机构

Morphotek, Inc.

EUCTR2014-004489-85-DE / Not yet recruiting临床2期

A Randomized, Double-blind, Placebo-controlled Study of the Safety and Efficacy of Amatuximab in Combination with Pemetrexed and Cisplatin in Subjects with Unresectable Malignant Pleural Mesothelioma

开始日期2015-11-03

申办/合作机构

Morphotek, Inc.

NCT01521325 / Completed临床1期

A Single-Dose Pilot Study of Radiolabeled Amatuximab (MORAb-009) in Mesothelin Over Expressing Cancers

This research is being conducted to determine the biodistribution of radiolabeled amatuximab in tumor and non-tumor tissues in subjects with mesothelin over expressing cancer including mesothelioma, pancreatic, ovarian or non small cell lung cancer.

开始日期2011-09-01

申办/合作机构

Morphotek, Inc.

100 项与 Amatuximab 相关的临床结果

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100 项与 Amatuximab 相关的转化医学

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100 项与 Amatuximab 相关的专利（医药）

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项与 Amatuximab 相关的文献（医药）

2023-04-01·International Journal of Gynecologic Cancer

Safety and activity of anti-mesothelin antibody–drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study

Article

作者: Walter, Annette O ; Romero, Ignacio ; Copeland, Larry J ; Schulz, Anke ; Schlicker, Andreas ; Santin, Alessandro D ; Elbi, Cem ; Childs, Barrett H ; Köchert, Karl ; Coleman, Robert L ; Herzog, Thomas J ; Vergote, Ignace ; Moore, Kathleen ; Monk, Bradley J ; Oaknin, Ana ; González-Martín, Antonio ; Siegel, Jonathan ; Kasten, Linda ; Bulat, Iurie ; Diab, Sami

Objectives:

Anetumab ravtansine is an antibody-drug conjugate consisting of a fully human anti-mesothelin monoclonal antibody conjugated to cytotoxic maytansinoid tubulin inhibitor DM4. Mesothelin is highly expressed in ovarian cancer. This phase Ib study determines the safety, pharmacokinetics, and anti-tumor activity of anetumab ravtansine and pegylated liposomal doxorubicin in mesothelin-expressing platinum-resistant ovarian cancer.

Methods:

Anetumab ravtansine (5.5 or 6.5 mg/kg) and pegylated liposomal doxorubicin (30 mg/m2) were administered intravenously every 3 weeks to 65 patients with platinum-resistant epithelial ovarian cancer. Mesothelin expression was assessed by central immunohistochemistry. Adverse events, tumor response (RECIST 1.1), and progression-free survival were determined. Biomarker samples were assessed by ELISA and next-generation sequencing.

Results:

In dose escalation, nine patients received anetumab ravtansine across two doses (5.5 or 6.5 mg/kg). The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg every 3 weeks and no dose-limiting toxicities were observed. In dose expansion, 56 patients were treated at the maximum tolerated dose. The most common treatment-emergent adverse events of any grade were nausea (47.7%), decreased appetite (43.1%), fatigue (38.5%), diarrhea (32.3%), and corneal disorder (29.2%). In all treated patients the objective response rate was 27.7% (95% CI 17.3% to 40.2%), including one complete (1.5%) and 17 partial responses (26.2%), with median duration of response of 7.6 (95% CI 3.3 to 10.2) months and median progression-free survival of 5.0 (95% CI 3.2 to 6.0) months. In an exploratory analysis of a sub-set of patients (n=19) with high mesothelin expression who received ≤3 prior lines of systemic therapy, the objective response rate was 42.1% (95% CI 20.3% to 66.5%) with a median duration of response of 8.3 (95% CI 4.1 to 12.0) months and median progression-free survival of 8.5 (95% CI 4.0 to 11.4) months.

Conclusions:

Anetumab ravtansine and pegylated liposomal doxorubicin showed tolerability and promising clinical activity. These results established the dose schedule and the mesothelin-positive target population of this combination for a phase III study in platinum-resistant ovarian cancer.

Trial registration number:

NCT02751918.

2023-02-01·Cancer Research Communications

Structures of Cancer Antigen Mesothelin and Its Complexes with Therapeutic Antibodies

Article

作者: Tang, Wai Kwan ; Shajahan, Asif ; Watson, Nathan ; Lin, Dong ; Liu, Xiufen ; Esser, Lothar ; Gleinich, Anne ; Hassan, Raffit ; Azadi, Parastoo ; Zhan, Jingyu ; Xia, Di ; Pastan, Ira ; Zhang, Alex

Significance::

The structures of full-length mesothelin and its complexes with antibodies reported here are the first to be determined experimentally, providing atomic models for structural organization of this protein and its interactions with antibodies. It offers insights into the function of mesothelin and guidance for further development of therapeutic antibodies.

2023-01-01·Frontiers in immunology

Rapid nanobody-based imaging of mesothelin expressing malignancies compatible with blocking therapeutic antibodies.

Article

作者: Balasse, Laure ; Guillet, Benjamin ; Castellano, Rémy ; Goubard, Armelle ; Meyer, Damien ; Kerfelec, Brigitte ; Chames, Patrick ; Benloucif, Abdennour ; Danner, Lucile ; Bouhlel, Ahlem

Introduction:

Mesothelin (MSLN) is overexpressed in a wide variety of cancers with few therapeutic options and has recently emerged as an attractive target for cancer therapy, with a large number of approaches currently under preclinical and clinical investigation. In this respect, developing mesothelin specific tracers as molecular companion tools for predicting patient eligibility, monitoring then response to mesothelin-targeting therapies, and tracking the evolution of the disease or for real-time visualisation of tumours during surgery is of growing importance.

Methods:

We generated by phage display a nanobody (Nb S1) and used enzymatic approaches were used to site-directed conjugate Nb S1 with either ATTO 647N fluorochrome or NODAGA chelator for fluorescence and positron emission tomography imaging (PET) respectively.

Results:

We demonstrated that Nb S1 displays a high apparent affinity and specificity for human mesothelin and demonstrated that the binding, although located in the membrane distal domain of mesothelin, is not impeded by the presence of MUC16, the only known ligand of mesothelin, nor by the therapeutic antibody amatuximab. In vivo experiments showed that both ATTO 647N and [⁶⁸Ga]Ga-NODAGA-S1 rapidly and specifically accumulated in mesothelin positive tumours compared to mesothelin negative tumours or irrelevant Nb with a high tumour/background ratio. The ex vivo biodistribution profile analysis also confirmed a significantly higher uptake of Nb S1 in MSLN-positive tumours than in MSLN^low tumours.

Conclusion:

We demonstrated for the first time the use of an anti-MSLN nanobody as PET radiotracer for same day imaging of MSLN⁺ tumours, targeting an epitope compatible with the monitoring of amatuximab-based therapies and current SS1-derived-drug conjugates.

项与 Amatuximab 相关的新闻（医药）

2024-01-30

·药渡

当ADC遇上铂耐药卵巢癌，会擦出怎样的火花？

来源：药渡撰文：双氧水编辑：维他命2024年1月3日，第一三共CDH6 ADC DS-6000国内获批临床，用于治疗既往接受过至少一线系统治疗的铂耐药高级别卵巢癌、原发性腹膜癌或输卵管癌。同年1月8日，荣昌生物开发的MSLN ADC RC88获得FDA授予的快速通道资格，用于铂耐药复发性上皮性卵巢癌、输卵管癌和原发性腹膜癌。卵巢癌为高发病率、高死亡率妇科肿瘤，根据组织病理学分类以上皮性肿瘤最为常见，其又可细分为高级别浆液性癌、子宫内膜样癌等[1]。此外，无铂间期（PFI）也是卵巢癌常见的分类标准。PFI即患者完成化疗疗程后，肿瘤不再复发的间期或者复发的间期延长。一般地，当PFI超过6个月复发的定义为铂敏感型，而PFI在6个月内复发的则称为铂耐药卵巢癌[2]。其中，后者相较于前者不论是应答率还是无进展生存期（PFS）、总生存期（OS）均显著减少，治疗选择有限，是目前卵巢癌的治疗难点和焦点。PART.01PARP抑制剂和免疫检查点抑制剂的起起伏伏众所周知，自2014年首个PARP抑制剂奥拉帕利的上市，为卵巢癌的治疗带来了新的突破，一度成为明星产品。国内外各大企业也开始研发属于自己的PARP抑制剂。其在卵巢癌的应用范围上也在不断扩大，从复发铂敏感后线治疗、复发铂敏感的维持治疗、复发铂耐药卵巢癌的后线治疗到卵巢癌的一线维持治疗，可谓是大放异彩。但好景不长，随着验证性临床数据的披露，发现PARP抑制剂在临床疗效上并无获益，使得多个PARP抑制剂，如奥拉帕利、尼拉帕利和芦卡帕利，被FDA撤销复发铂敏感和复发铂耐药卵巢癌后线治疗的适应症。而铂耐药卵巢癌便再次进入无药可用的阶段。尽管研究热点免疫检查点抑制剂也一直在涉猎卵巢癌领域，积极探索单药以及与各种机制药物联合，如免疫联合化疗、免疫联合抗血管、免疫联合PARP抑制剂，但结果却不像在非小细胞肺癌适应症那样顺风顺水，反而是一片惨淡，未见突破。PART.02各类ADC药物百花齐放ImmunoGen公司开发的叶酸受体α（FRα）ADC Mirvetuximab的获批上市，可谓是一石激起千层浪，为卵巢癌领域带来新的突破和机遇。此外，其他新型靶点ADC也陆续进入大众视野，为铂耐药卵巢癌治疗开疆拓土。2024年1月3日，第一三共CDH6 ADC DS-6000国内获批临床，用于治疗既往接受过至少一线系统治疗的铂耐药高级别卵巢癌、原发性腹膜癌或输卵管癌。同年1月8日，荣昌生物开发的MSLN ADC RC88获得FDA授予的快速通道资格，用于铂耐药复发性上皮性卵巢癌、输卵管癌和原发性腹膜癌。详情可见：荣昌生物又一款重量级ADC获美国FDA快速通道资格，靶向MSLN，治疗卵巢癌等肿瘤。01FRα ADC2022年11月14日，FDA基于一项名为0417的单臂临床研究批准Mirvetuximab（索米妥昔单抗）上市，用于治疗接受过1到3种系统治疗且FRα阳性、铂耐药的上皮性卵巢癌、输卵管癌或原发性腹膜癌[3]，这也是首款获批上市的FRα ADC药物。2023年SGO大会上更新了其单臂数据，共计105例患者为疗效可评估，ORR为32.4%，中位DOR 6.9个月，中位OS 15个月[4]。2023年12月，其验证性临床III期研究MIRASOL数据发表在新英格兰杂志上[5]，与对照组化疗相比，索米妥昔单抗中位PFS延长1个多月（5.62 vs 3.98），中位OS延长近4个月（16.46 vs 12.75）。中美华东制药则更是以独到的眼光在其上市前，以3亿美元引进该款ADC。国内外已有多款FRα ADC处于临床阶段。目前，除已上市的索米妥昔单抗外，研发进展较靠前的是百时美施贵宝的MORAb-202和Sutro Biopharma的STRO-002。相较于开展妇科肿瘤适应症，MORAb-202可谓是独树一帜，其优先在非小细胞肺癌中开展了临床II期研究，可能也是想在众多FRα ADC中脱颖而出，让我们期待后续的临床结果。而国内企业普方生物研发的PRO1184在今年1月初获得FDA授予快速通道资格，用于治疗表达FRα的高级别浆液性或子宫内膜样铂耐药的卵巢癌。表1. 临床在研的FRα ADC02CDH6 ADCCDH6（人钙粘蛋白-6）是一种钙粘蛋白家族蛋白，大约在65%至85%的卵巢肿瘤细胞中有所表达[6]。该领域目前已处于临床阶段的产品仅两个，如表2所示。其中，进展最快的即第一三共开发的Raludotatug（DS-6000），目前处于临床II/III期，以研究者选择的化疗作为对照组，纳入约650例至少接受过1线不超过3线系统治疗的复发铂耐药卵巢癌。临床II期主要终点为BICR评估（盲态独立中心评估）的ORR，临床III期则为BICR评估的PFS，预计2027年完成。早期数据在2023 ESMO大会上有所披露，在复发铂耐药卵巢癌中ORR为46%，中位DOR为11.2个月，中位PFS为7.9个月[7]。值得注意的是，相较于Mirvetuximab，Raludotatug并未筛选生物标志物，意味着其适用人群可能广于Mirvetuximab。AMT-707于2023年12月26日获NMPA临床许可，拟开发治疗晚期实体瘤，成为首个国内自主研发进入临床的CDH6 ADC。CDH6 ADC尚未有上市药物，疗效和安全性尚未得到确证，其成药性有待进一步确认，药渡后续将会持续跟踪报道。表2. 临床在研的CDH6 ADC03MSLN ADCMSLN又称间皮素，已发现MSLN蛋白在85％-90％的间皮瘤，80％-85％的胰腺癌和60％-65％的肺癌、卵巢癌和胆管癌中均有表达。但该靶点ADC药物的开发并不顺利，拜耳的Anetumab和Amatuximab以及百时美施贵宝的BMS-986148完成临床研究后就再无进一步临床进展，RG-7600临床I期终止。目前仅国内两家企业开发的MSLN ADC处于临床阶段。其中，荣昌生物开发的MSLN ADC RC88处于关键临床II期，用于治疗复发铂耐药卵巢癌。其实，对于MSLN ADC药物的开发更像是一场豪赌，结局如何尚未可知。表3. 临床在研的MSLN ADCPART.03小结综上，从目前来看，针对这类卵巢癌的治疗还得是以细胞毒药物作为backbone才能显现疗效。而各类ADC百家争鸣，是否真的能成为铂耐药卵巢癌的主场，让我们共同期待。铂耐药卵巢癌的药物开发和探索之路道阻且长，希望有更多新靶点、新机制的药物出现，为这类患病人群带来更多治疗选择。参考资料：1. Lindsey A. Torre et al. CA Cancer J Clin. 2018, 68:284–296.2. Bouberhan S, et al. J Clin Oncol. 2019, 37(27):2424-2436.3. Mirvetuximab, FDA label.4. Robert L Coleman, et al. 2023 SGO.5. Moore KN, et al. N Engl J Med. 2023, 389(23):2162-2174.6. Bartolome RA, et al. Mol Oncol. 2021, 15(7):1849-18865.7. K.N. Moore, et al. 2023 ESMO. Abstract 745MO.*声明：本文仅是介绍医药疾病领域研究进展或简述研究概况或分享医药相关讯息，并非也不会进行治疗或诊断方案推荐，也不对相关投资构成任何建议。内容如有疏漏，欢迎沟通指出！占据五分之一！2023年FDA批准的含氟新药全盘点一文解读：礼来重磅JAK抑制剂巴瑞替尼，被判专利全部无效强生23年财报：乌司奴单抗108亿美元，达雷妥尤单抗近百亿美元，自免、肿瘤等赛道多点开花

快速通道抗体药物偶联物临床研究临床1期临床结果

2023-09-08

·PipelineReview

Mesothelin: an old solid tumor target for next generation drug modalities – a pipeline review

BARCELONA, Spain I September 08, 2023 I La Merie Publishing released its newest product reviewing the pipeline of mesothelin-targeted immunotherapy candidates in R&D: Mesothelin-Targeted Immunotherapy Pipeline Review Target: Mesothelin Product Category: Antibody; Cells; Vaccine This product provides basic information on immunotherapy candidates in research and development targeting mesothelin. This product consists of: This product is delivered on the very same day of purchase by e-mail containing competitor and project history reports in pdf format and database credentials. Reports are prepared on the same day. Mesothelin, is a 40 kD glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein overexpressed in many cancers, potentially involved in adhesion and metastasis. The well-known interacting partner of mesothelin is CA125/MUC16, a member of the mucin family of glycoproteins which is expressed in ovarian cancer and malignant mesothelioma Given the limited expression of mesothelin in normal tissues and overexpression in several tumor cells, mesothelin presents a desirable target for tumor-specific therapy. Mesothelin expression has been identified in approximately 30% of cancers, including mesothelioma, ovarian, pancreatic, gastric, and non–small cell lung tumors, uterine malignancies as well as cholangiocarcinoma. In high grade ovarian cancer, mesothelin is overexpressed in 75% to 80% of patients. Normal expression of mesothelin is on mesothelial cells lining pleura, peritoneum, and pericardium. Low expression may be found on some other tissues, but anti-mesothelin antibodies or antibody-toxin conjugates have not shown much toxicity. Although several first generation drug modalities used for targeting mesothelin eventually have failed in clinical studies, such as immunotoxins, thorium-targeted therapies, antibody-drug conjugates, chimeric antigen receptor T cells, natural killer cells as well as T-cell engaging antibodies, improved next generation versions of such drug modalities have been developed and are applied to novel immunotherapy candidates for mesothelin-expressing cancers. The report “ Mesothelin-Targeted Immunotherapy Pipeline Review ” can be acquired at La Merie Publishing’s online store: https://lamerie.com/report/mesothelin-targeted-immunotherapy-pipeline-review/ About La Merie Publishing La Merie Publishing is an independent business information provider for the biotechnology and pharmaceutical industry. La Merie Publishing prepares brief and full reports. La Merie Publishing products can be purchased in the online store www.lamerie.com and from selected Resellers. La Merie Publishing offers the service of custom report preparation for corporate clients, including, but not limited to, pipeline analysis reports, drug profiles and any other competitive intelligence elaboration of interest. SOURCE: La Merie Publishing

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100 项与 Amatuximab 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D09767	Amatuximab	-	DB12845

研发状态

适应症	最高研发状态	国家/地区	公司
间皮瘤	临床2期	-	National Cancer Institute 更多
胰腺癌	临床2期	-	National Cancer Institute 更多
不可切除的胸膜恶性间皮瘤	终止	意大利更多	Morphotek, Inc. 更多
恶性胸膜间皮瘤	无进展	加拿大更多	Morphotek, Inc. 更多
Mesothelin阳性肿瘤	无进展	美国更多	Morphotek, Inc. 更多

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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


NCT00738582 (CTgov)	临床2期	恶性胸膜间皮瘤	89	amatuximab+cisplatin+pemetrexed (All Participants)	壓夢製鏇遞鑰膚願選憲(糧簾淵糧膚憲範窪鏇鑰) = 醖鑰鏇鹽廠壓繭製觸艱廠餘壓淵願餘獵獵鏇簾 (淵醖鏇願艱製簾醖鑰鹽, 築鏇壓積鹹齋簾衊廠鑰 ~ 鹽廠簾餘膚構齋願餘顧) 更多	-	2022-09-22
NCT00738582 (CTgov)	临床2期	恶性胸膜间皮瘤	89	Amatuximab+Cisplatin+Pemetrexed (Amatuximab/Pemetrexed/Cisplatin)	淵蓋餘製淵鏇鑰窪鬱鏇(遞膚蓋衊鑰淵鹹鏇獵繭) = 鏇窪積衊衊願餘鹽壓膚蓋糧衊構繭獵衊製願顧 (廠範範築鏇齋鹽鹽鹹醖, 簾選製憲蓋膚網簾獵蓋 ~ 積願餘鬱夢襯襯夢遞膚) 更多	-	2022-09-22
NCT02357147 (CTgov)	临床2期	不可切除的胸膜恶性间皮瘤	124	Amatuximab+Cisplatin+Pemetrexed (Combination Treatment Phase:Amatuximab + Pemetrexed +Cisplatin)	衊積衊遞膚鹹鬱範憲膚(觸範醖壓衊廠夢淵願獵) = 齋鏇網網鑰鹽憲獵鬱襯選獵獵網艱窪窪窪願餘 (糧顧襯衊夢蓋襯簾淵襯, 餘廠鹹鏇鹹願繭選顧淵 ~ 餘選壓襯遞鹽蓋積醖築) 更多	-	2020-03-17
NCT02357147 (CTgov)	临床2期	不可切除的胸膜恶性间皮瘤	124	Placebo+Cisplatin+Pemetrexed (Combination Treatment Phase: Placebo + Pemetrexed + Cisplatin)	衊積衊遞膚鹹鬱範憲膚(觸範醖壓衊廠夢淵願獵) = 鑰顧醖膚壓積淵鏇憲衊選獵獵網艱窪窪窪願餘 (糧顧襯衊夢蓋襯簾淵襯, 膚觸顧糧積襯餘襯顧衊 ~ 鏇鹽窪艱顧廠構醖鹹鹽) 更多	-	2020-03-17
NCT02357147 (ASCO2016)	临床2期	恶性胸膜间皮瘤	560	Amatuximab + P/C	願願蓋鑰築餘積醖齋壓(淵糧鹹窪淵願膚願鹽築) = 廠製鬱淵選鬱選觸網齋夢簾繭遞衊醖廠鏇範遞 (壓遞衊鬱廠顧糧衊膚積 )	-	2016-05-20
NCT01018784 (Pubmed \| Invest New Drugs)	临床1期	HR阳性/HER2低表达实体瘤	17	Amatuximab	積淵積鏇繭簾鑰鹽鬱遞(醖鏇廠顧築壓窪鹹憲觸) = 築衊積積鑰鹽獵鑰廠蓋繭選積獵構夢淵膚遞網 (遞餘範範鹽積夢遞壓鬱 ) 更多	-	2015-04-01
WCLC2013	N/A	不可切除的胸膜恶性间皮瘤	89	Amatuximab 5mg/kg	願構顧範廠遞觸蓋網壓(鏇觸齋憲壓壓選齋憲衊) = 鏇製夢範範獵鏇廠選鹹遞顧繭醖糧鑰窪蓋範範 (膚蓋繭遞窪鏇醖艱壓衊 ) 更多	-	2013-10-29
ASCO2012	临床2期	不可切除的胸膜恶性间皮瘤	89	Amatuximab + Pemetrexed + Cisplatin	膚鏇顧鏇窪糧鹽網顧蓋(襯網鹹壓鹽鑰齋觸夢齋) = 網蓋淵鏇艱願顧鹹繭獵窪齋襯艱鹹夢淵遞衊積 (廠膚壓網蓋壓鹹獵繭窪 ) 更多	-	2012-05-20