A Phase II, Multicenter, Randomized, Open Label, Parallel-Arm, Umbrella Study of Avelumab (MSB0010718C) in Combination With Other AntiTumor Agents as a Maintenance Treatment in Participants With Locally Advanced or Metastatic Urothelial Carcinoma Whose Disease Did Not Progress With First Line Platinum-Containing Chemotherapy (JAVELIN Bladder Medley)

The purpose of this study is to assess the safety and efficacy of avelumab in combination with other anti-tumor agents as a maintenance treatment in participants with bladder cancer.

开始日期2022-08-17

申办/合作机构

EMD Serono Research & Development Institute, Inc.

[+3]

NCT04457778

/ Completed临床1期

Phase I, First-in-Human, Open-Label, Multiple Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Activity of M6223, an Inhibitor of TIGIT, as Single Agent and in Combination With Bintrafusp Alfa (Anti-PDL1/ TGFß Trap) in Participants With Metastatic or Locally Advanced Solid Unresectable Tumors

The main purpose of this study is to determine the safety, tolerability, pharmacokinetics (PK), immunogenicity and (if observed) the maximum tolerated dose (MTD) of M6223 as a single agent (Part 1A) for both the every 2 weeks (Q2W) regimen and the every 3 weeks (Q3W) regimen and of M6223 combined with bintrafusp alfa (Part 1B) for Q2W regimen in participants with metastatic or locally advanced solid unresectable tumors.

开始日期2020-07-10

申办/合作机构

EMD Serono Research & Development Institute, Inc.

[+1]

100 项与 M6223 相关的临床结果

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100 项与 M6223 相关的转化医学

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100 项与 M6223 相关的专利（医药）

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项与 M6223 相关的文献（医药）

2025-05-01·CLINICAL PHARMACOLOGY & THERAPEUTICS

Model‐Informed Selection of the Recommended Phase 2 Dosage for Anti‐TIGIT Immunotherapy Leveraging co‐Expressed PD‐1 Inhibitor Target Engagement

Article

作者: Hu, Ping ; Venkatakrishnan, Karthik ; Gao, Wei ; Kareva, Irina ; Victor, Anja ; Kitzing, Thomas ; Richter, Emilia ; Pierre, Vadryn ; Zutshi, Anup

Refining dose projections requires a deep understanding of drug‐target relationships at the site of action, which is often challenging to achieve. Here we present a case study of how one can refine dose projections for a TIGIT‐targeted immunotherapy by leveraging information from the well‐studied PD‐1 pathway since the co‐expression of PD‐1 and TIGIT on immune cells provides a unique opportunity to extrapolate data from one target to inform the dosing strategy for the other. We develop a fit‐for‐purpose mathematical model that captures the experimentally observed relationship between the concentration of a mouse PD‐1 antagonist in the plasma and PD‐1 target engagement within the tumor microenvironment (TME). We then assess the applicability of this PD‐1 model to elucidate the relationship between drug concentration and target engagement for tiragolumab, an anti‐TIGIT antibody, across various doses. This analysis aims to refine our understanding of the dose–response relationship for targeting TIGIT, a critical step in optimizing therapeutic efficacy, without conducting additional experiments. The approach is then extended to project efficacious doses for M6223, another anti‐TIGIT antibody, using the established PD‐1 model, by leveraging the M6223 clinical PK and PD data, as well as virtual population analysis. This work provides a case study of a possible framework for refining dose projections via quantitative estimation of drug‐target relationship at the site of action by leveraging established drug‐target relationships. Through extrapolating information from a well‐characterized pathway, we offer a method to inform dose optimization strategies with limited data using model‐informed drug development.

2025-02-01·Journal for ImmunoTherapy of Cancer

TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa in patients with advanced solid tumors: a first-in-human, phase 1, dose-escalation trial

Article

作者: Siu, Lillian L ; Naing, Aung ; McKean, Meredith ; Nogueira Filho, Marco A F ; Gao, Wei ; Tadjalli-Mehr, Keyvan ; Hu, Ping ; Richter, Emilia ; Tolcher, Anthony ; Gleicher, Stephan ; Victor, Anja ; Kitzing, Thomas ; Holland, Daniel

Background:

M6223 is an intravenous (IV), Fc-competent, fully human, antagonistic, anti-T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) antibody. Bintrafusp alfa (BA) is a bifunctional fusion protein that simultaneously blocks nonredundant immunosuppressive TGF-β and PD-(L)1 pathways.

Methods:

This first-in-human, dose-escalation study in patients with advanced solid tumors (N=58; aged ≥18 years, ECOG PS≤1) evaluated M6223 alone (Part 1A, n=40; M6223 10–2400 mg every 2 weeks, n=32; M6223 2400 mg every 3 weeks, n=8) or with BA (Part 1B, n=18; M6223 300–1600 mg with BA 1200 mg; both every 2 weeks, intravenous). Primary objectives were safety, tolerability, maximum tolerated dose (MTD) and recommended dose for expansion (RDE). Additional objectives included pharmacokinetics, pharmacodynamics and clinical activity (NCT04457778).

Results:

Two dose-limiting toxicities were observed: grade 3 adrenal insufficiency (Part 1A: M6223 900 mg every 2 weeks) and grade 3 anemia (Part 1B: M6223 300 mg, only BA related). MTD was not reached. Overall, median overall survival and progression-free survival were 7.6 (95% CI 4.9, 12.0) and 1.4 (95% CI 1.3, 1.8) months, respectively. Stable disease as best response was observed in 13 (32.5%) and 5 (27.8%) patients in parts 1A and 1B, respectively. M6223±BA displayed a linear pharmacokinetic profile. Anti-TIGIT mode-of-action-related pharmacodynamic effects were observed in peripheral blood and in tumor tissue. RDEs were 1600 mg every 2 weeks or 2400 mg every 3 weeks for M6223 monotherapy and 1600+1200 mg every 2 weeks for M6223+BA.

Conclusions:

M6223±BA had a manageable safety profile, with RDEs defined for both monotherapy and combination therapy. Further evaluation of M6223 is ongoing in combination with the PD-L1 inhibitor avelumab in patients with advanced urothelial carcinoma (JAVELIN Bladder Medley;NCT05327530).

Trial registration number:

NCT04457778.

2024-02-01·Future oncology (London, England)

The JAVELIN Bladder Medley Trial: Avelumab-Based Combinations as First-Line Maintenance in Advanced Urothelial Carcinoma

Article

作者: Powles, Thomas ; Mehr, Keyvan Tadjalli ; Seeberger, Sonja ; Jacob, Natalia ; Hoffman-Censits, Jean ; Hahn, Noah M ; Guenther, Silke ; Hawley, Jessica ; Grivas, Petros ; Tyroller, Karin

Results from JAVELIN Bladder 100 established avelumab (anti-PD-L1) first-line maintenance as the standard-of-care treatment for patients with advanced urothelial carcinoma (UC) that has not progressed with first-line platinum-based chemotherapy. We describe the design of JAVELIN Bladder Medley (NCT05327530), an ongoing phase II, multicenter, randomized, open-label, parallel-arm, umbrella trial. Overall, 252 patients with advanced UC who are progression-free following first-line platinum-based chemotherapy will be randomized 1:2:2:2 to receive maintenance therapy with avelumab alone (control group) or combined with sacituzumab govitecan (anti-Trop-2/topoisomerase inhibitor conjugate), M6223 (anti-TIGIT) or NKTR-255 (recombinant human IL-15). Primary end points are progression-free survival per investigator and safety/tolerability of the combination regimens. Secondary end points include overall survival, objective response and duration of response per investigator, and pharmacokinetics.

项与 M6223 相关的新闻（医药）

2024-02-20

·精准药物

默克肿瘤管线盘点，多个重磅级产品

来源：药渡撰文：Maskey 编辑：维他命默克是开发癌症治疗药物的领先制药公司之一。其重磅抗癌药物帕博利珠单抗已获得FDA批准用于治疗非小细胞肺癌、胆道肿瘤、黑色素瘤、乳腺癌、头颈癌和多种其他癌症。帕博利珠单抗（Pembrolizumab）是一种免疫治疗药物，可阻断程序性死亡受体1 (PD-1) 和程序性死亡配体1 (PD-L1) 之间的相互作用。默克还有其他拳头抗癌药物，例如仑伐替尼和奥拉帕尼。仑伐替尼是一种受体酪氨酸激酶（RTK）抑制剂，用于治疗晚期肾细胞癌、肝细胞癌和甲状腺癌。奥拉帕尼是一种聚（ADP-核糖）聚合酶（PARP）抑制剂，可防止受损DNA的修复。FDA已批准该药物用于治疗乳腺癌、胰腺癌、卵巢癌和前列腺癌。默克公司的药物研发管线中有几种新的抗癌疗法，可以治疗不同的难治性癌症。图1. 默克药物研发管线中的新抗癌药物，来源：参考文献101XevinapantXevinapant是一种细胞凋亡抑制蛋白（IAP）拮抗剂，可导致癌细胞凋亡[2]。这种一流的研究药物，使癌细胞对放疗和化疗更加敏感。该药物正在头颈鳞状细胞癌患者的III期临床试验中进行测试。超过90%的头颈癌患者患有头颈鳞状细胞癌，大多数头颈部鳞状细胞癌病例在诊断时已处于晚期。FDA已授予该药物突破性疗法认定，用于联合放疗和化疗治疗头颈部鳞状细胞癌。该药物最初由Ascenta Therapeutics开发。Debiopharm随后与Ascenta Therapeutics签署了开发该药物的许可协议。默克于 2021年与Debiopharm签署了许可协议[3]。根据该协议，Debiopharm获得了1.88亿欧元的预付款，如果该药物达到某些里程碑，则最多可以获得7.1亿欧元。图2. Xevinapant导致癌细胞凋亡，来源：参考文献2在II期临床试验中，48名头颈部鳞状细胞癌患者随机接受xevinapant治疗，47名患者随机接受安慰剂治疗，这两组患者均接受顺铂和放疗[4]。Xevinapan将疾病进展或死亡的风险降低了67%。在5年的随访中，接受安慰剂的患者中位总生存期（OS）为36.1个月，而接受xevinapan的患者未达到中位总生存期（OS）。同样，在3年随访中，接受安慰剂的患者中位无进展生存期为16.9个月，而接受xevinapant的患者未达到中位PFS。接受xevinapant和安慰剂治疗的患者出现的不良反应，包括：吞咽困难、口干、味觉障碍和纤维化。没有患者因xevinapant引起的不良反应而死亡。Xevinapant正在III期临床试验TrilynX中，对未切除的头颈鳞状细胞癌患者进行测试[5]。在另一项III期临床试验XRay Vision中，该药物也在具有高复发风险的头颈切除鳞状细胞癌患者中进行测试[6]。图3. 接受Xevinapant和安慰剂治疗的患者的无进展生存期，来源：参考文献4图4. 接受Xevinapan和安慰剂治疗的患者的总生存期，来源：参考文献402AvelumabAvelumab是一种单克隆抗体，可阻止PD-L1与PD-1相互作用。该药物最初由默克公司开发，但在2014年，默克与辉瑞签署了共同开发该药物的协议[7]。根据该协议，默克公司从辉瑞公司获得了8.5亿美元的预付款，如果该药物达到商业和监管里程碑，辉瑞同意支付20亿美元。2023年，两家公司结束了合作关系。默克公司拥有该药物的独家所有权，辉瑞公司获得净销售额15%的特许权使用费。Avelumab已被FDA批准用于尿路上皮癌的维持治疗。FDA还批准该药物用于治疗默克尔细胞癌和肾细胞癌。在一项III期临床试验JAVELIN Bladder 100中，700名尿路上皮癌患者被随机接受最佳支持治疗或最佳支持治疗与avelumab的组合（按1:1的比例）[8]。接受最佳支持治疗和Avelumab联合治疗的患者的中位总生存期为21.4个月。相比之下，仅接受最佳支持治疗的患者的中位总生存期为14.3个月。接受最佳支持治疗和Avelumab联合治疗的患者中，有71.3%在接受治疗一年后仍然存活。相比之下，仅接受最佳支持治疗的患者中，有58.4%在接受治疗一年后仍然存活。同样，接受最佳支持治疗和Avelumab联合治疗的患者的中位无进展生存期为3.7个月。仅接受最佳支持治疗的患者的中位无进展生存期为2.0个月。Avelumab还改善了PD-L1阳性肿瘤患者的无进展生存期和总生存期。接受Avelumab治疗的患者常见的不良反应是尿路感染、疲劳、关节痛和瘙痒。图5. 接受最佳支持治疗和avelumab组合以及仅接受最佳支持治疗的患者的无进展生存期，来源：参考文献803Tuvusertib (M1774)Tuvusertib也称为M1774，是共济失调毛细血管扩张和Rad3相关的 (ATR) 蛋白激酶抑制剂。默克公司正在开发这种药物来治疗实体瘤，包括非小细胞肺癌和乳腺癌。ATR激酶有助于修复受损的DNA，并提高肿瘤细胞的存活率。Tuvusertib通过阻止受损DNA的修复，来杀死肿瘤细胞。化疗药物会损伤肿瘤细胞的DNA，从而增加复制应激[9]。ATR蛋白激酶介导复制应激反应。当ATR蛋白激酶被抑制时，这些化疗药物的细胞毒性就会增加。该药物可作为单一疗法或与DNA损伤应答 (DDR) 抑制剂联合施用于患者。该药物在I期临床试验中，在晚期实体瘤患者中具有良好的耐受性[10]。在这项临床试验中，55名患者以21天为一个周期服用该药物，其中11名患者出现剂量限制性毒性。该药引起贫血、血小板计数下降等不良反应。一项II期临床试验正在测试tuvusertib和avelumab组合，在默克尔细胞癌患者中的疗效。另一项II期临床试验正在测试Tuvusertib对斑点型BTB/POZ蛋白（SPOP）突变的前列腺癌患者的疗效。其正在进行1/2期临床试验，以找出Tuvusertib和烷化剂替莫唑胺组合的适当剂量和副作用。正在进行的多项临床试验，以测试Tuvusertib与niraparib和Cemiplimab等其他药物的疗效。04Lartesertib (M4076)Lartesertib也称为M4076，是共济失调毛细血管扩张突变 (ATM) 的抑制剂。ATM是一种激酶，在修复双链断裂和调节细胞周期检查点方面发挥着重要作用。这种药物抑制ATM的活性，最终导致癌细胞死亡。M4076可以提高通过破坏DNA来杀死癌细胞的药物的功效。在一项I期临床试验中，22名实体瘤患者接受了4种不同剂量的M4076[11]。22名患者中有21名停止治疗，主要是因为不良反应和疾病进展。该药可引起斑丘疹、恶心、贫血、细菌性腹膜炎、过敏和淋巴细胞计数减少等不良反应。05M9140M9140是一种抗体药物偶联物（ADC），靶向表达癌胚抗原相关细胞粘附分子5 （CEACAM5）的癌细胞。CEACAM5是一种糖蛋白，在胰腺癌、胃肠道癌和肺癌中过度表达。ADC是新型抗癌药物，可直接向癌细胞传递细胞毒性有效负载并杀死这些细胞。ADC由细胞毒性有效负载、连接子和单克隆抗体组成。它还发挥旁观者效应，杀死周围的癌细胞。默克公司使用自己的技术来开发这种药物。该药物的治疗窗宽，并且在血液循环中也稳定，该药与DDR抑制剂合用可产生协同作用。M9140中的细胞毒性有效负载是拓扑异构酶1 (TOP1) 抑制剂，可防止DNA修复。M9140的Ia/b期临床试验正在结直肠癌患者中进行测试。赛诺菲开发了Tusamitamab ravtansine（SAR408701），这是一种ADC，也靶向表达CEACAM5的癌细胞。06M-6223M6223也称为Dargistotug，是一种靶向T细胞免疫球蛋白和ITIM结构域 (TIGIT) 的抗体。TIGIT是自然杀伤 (NK) 细胞和T细胞上表达的受体，TIGIT的过度表达会抑制这些免疫细胞的功能。M6223防止TIGIT与CD112和CD155结合。CD155和CD112是TIGIT和DNAX辅助分子-1(DNAM-1)的配体[12]。该药物还可以防止TIGIT与CD226相互作用。CD226也称为DNAM-1，是一种在NK细胞和T细胞等免疫细胞上表达的蛋白质。M6223阻断TIGIT通路，以诱导靶向癌细胞的免疫反应。在临床前研究中，M6223与bintrafusp alfa联合使用时，其抗肿瘤功效得到增强。Bintrafusp alfa是一种融合蛋白，由抗PD-L1单克隆抗体和转化生长因子 (TGF)-βRII组成。这种联合治疗增加了肿瘤微环境中CD8+T细胞的浸润。研究人员在一期临床试验中在实体瘤患者中，测试了这种联合治疗方法。在这项临床试验中，24名实体瘤患者接受了M6223治疗，17名患者接受了M6223和bintrafusp alfa的联合治疗[13]。9名仅接受M6223治疗的患者获得了临床获益。相比之下，接受联合治疗的2名患者获得了临床获益。仅接受M6223治疗的患者中，有33%出现3级或更高级别的不良反应。相比之下，接受联合治疗的患者中有71%出现3级或以上的不良反应。小结总之，默克正在开发抑制ATM和ATR等新靶点的新型抗癌药物。这些新的在研药物增强癌细胞对细胞凋亡的敏感性，向癌细胞传递有效负载并抑制癌细胞的DNA损伤修复。这些药物正在尿路上皮癌、头颈癌、结直肠癌和其他癌症患者中进行临床试验。这些药物的批准将使对标准治疗无反应的晚期癌症患者受益匪浅，药渡将与大家一起拭目以待。参考文献（可上下滑动）：[1]Merck pipeline (n.d.). https://www.merckgroup.com/business-specifics/ healthcare/ global/ Healthcare-Pipeline.pdf[2]Fleischmann, J., Hildebrand, L. S., Kuhlmann, L., Fietkau, R., & Distel, L. V. (2023). The Effect of Xevinapant Combined with Ionizing Radiation on HNSCC and Normal Tissue Cells and the Impact of Xevinapant on Its Targeted Proteins cIAP1 and XIAP. Cells, 12(12), 1653.[3]Adams, B. (2021, March 1). Merck KGaA pens $855M biobucks pact with Debiopharm for next-gen cancer asset. Fierce Biotech. https://www.fiercebiotech.com/biotech/merck-kgaa-pens-855m-upfront-biobucks-pact-debiopharm-for-next-gen-cancer-asset[4]Yungan, T. A. O., Sun, X. S., Pointreau, Y., Le Tourneau, C., Sire, C., Kaminsky, M. C., ... & Bourhis, J. (2023). Extended follow-up of a phase 2 trial of xevinapant plus chemoradiotherapy in high-risk locally advanced squamous cell carcinoma of the head and neck: a randomised clinical trial. European journal of cancer, 183, 24-37.[5]Bourhis, J., Burtness, B., Licitra, L. F., Nutting, C., Schoenfeld, J. D., Ait Sarkouh, R., ... & Cohen, E. E. (2021). TrilynX: A phase 3 trial of xevinapant and concurrent chemoradiation for locally advanced head and neck cancer.[6]Ferris, R. L., Mehanna, H. M., Schoenfeld, J. D., Tahara, M., Yom, S. S., Haddad, R. I., ... & Le Tourneau, C. (2023). XRay Vision: A phase 3 study of xevinapant plus radiotherapy (RT) for high-risk, cisplatin-ineligible patients with resected, locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).[7]Becker, Z. (2023, March 28). Duo no more: After M&A spree, Pfizer parts ways with Merck KGaA on Bavencio. Fierce Pharma. https://www.fiercepharma.com/pharma/duo-no-more-merck-kgaa-takes-back-full-bavencio-rights-ending-long-time-pfizer-partnership[8]Powles, T., Park, S. H., Voog, E., Caserta, C., Valderrama, B. P., Gurney, H., ... & Grivas, P. (2020). Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma.New England Journal of Medicine, 383(13), 1218-1230.[9]Zimmermann, A., Dahmen, H., Grombacher, T., Pehl, U., Blaukat, A., & Zenke, F. T. (2022). M1774, a novel potent and selective ATR inhibitor, shows antitumor effects as monotherapy and in combination.Cancer Research, 82(12_Supplement), 2588-2588.[10]Yap, T. A., Tolcher, A. W., Plummer, R., Mukker, J., Enderlin, M., Hicking, C., ... & de Bono, J. S. (2022). 457MO A phase I study of ATR inhibitor M1774 in patients with solid tumours (DDRiver Solid Tumours 301): Part A1 results.Annals of Oncology, 33, S747-S748.[11]Siu, L. L., Yap, T. A., Genta, S., Pennock, G., Hicking, C., You, X., ... & Tolcher, A. W. (2023). Abstract CT171: A first-in-human phase I study of the ATM inhibitor M4076 in patients with advanced solid tumors (DDRiver Solid Tumors 410): Part 1A results.Cancer Research, 83(8_Supplement), CT171-CT171.[12]Kaito, Y., Hirano, M., Futami, M., Nojima, M., Tamura, H., Tojo, A., & Imai, Y. (2022). CD155 and CD112 as possible therapeutic targets of FLT3 inhibitors for acute myeloid leukemia.Oncology letters, 23(2), 1-12.[13]Siu, L. L., Mckean, M. A., Tolcher, A. W., Victor, A., Kitzing, T., Pierre, V., ... & Naing, A. (2022). 750P Phase I study of TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa (BA) in patients (pts) with metastatic/locally advanced solid unresectable tumours.Annals of Oncology, 33, S887.声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

突破性疗法临床3期临床2期免疫疗法快速通道

100 项与 M6223 相关的药物交易

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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
转移性实体瘤	临床1期	美国	EMD Serono Research & Development Institute, Inc.	2020-07-10
转移性实体瘤	临床1期	加拿大	EMD Serono Research & Development Institute, Inc.	2020-07-10
实体瘤	临床1期	美国	Merck KGaA	2020-07-10
实体瘤	临床1期	加拿大	Merck KGaA	2020-07-10

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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


NCT04457778 (Pubmed \| J Immunother Cancer) 人工标引	临床1期	晚期恶性实体瘤	58	M6223 (Part 1A)	夢構鏇齋淵衊遞顧鏇窪(夢艱憲鹽繭願齋艱艱範) = Two dose-limiting toxicities were observed: grade 3 adrenal insufficiency (Part 1A: M6223 900 mg every 2 weeks) and grade 3 anemia (Part 1B: M6223 300 mg, only BA related). 餘獵遞鹹廠簾襯齋願觸 (獵簾鏇獵遞壓範願鹽鏇 ) 更多	积极	2025-02-01
				M6223+bintrafusp alfa (Part 1B)
NCT04457778 (AACR2024) 人工标引	临床1期	实体瘤	58	M6223	餘積築顧襯鹹鏇廠壓艱(醖鹽餘願鏇選築構齋鏇) = Overall, two dose-limiting toxicities were observed: a grade 3 adrenal insufficiency (M6223, 900 mg) and a grade 3 anemia (M6223+BA, 300 mg; unrelated to M6223). 願網鹽顧窪醖糧襯簾築 (築簾觸膚憲糧壓鑰廠築 ) 更多	积极	2024-04-05
				M6223+bintrafusp alfa
NCT04457778 (ESMO2022) 人工标引	临床1期	不可切除的实体瘤	41	M6223	鏇顧獵壓願顧構積醖壓(膚廠廠願糧構鑰淵壓積) = 鑰願選窪製廠襯夢憲範繭鹹鹽獵鏇製遞製憲遞 (積壓廠齋糧壓蓋鏇膚遞 ) 更多	积极	2022-09-10
				M6223+bintrafusp alfa	鏇顧獵壓願顧構積醖壓(膚廠廠願糧構鑰淵壓積) = 壓夢遞膚構繭蓋築選鏇繭鹹鹽獵鏇製遞製憲遞 (積壓廠齋糧壓蓋鏇膚遞 ) 更多