An Open-label Phase 1 PET Imaging Trial to Investigate [89Zr]Zr-BI 764532 Biodistribution and Tumour Uptake in Patients With Small-cell Lung Carcinoma or Neuroendocrine Carcinoma

This study is open to adults with small cell lung cancer and other neuroendocrine cancers. The study is in people with advanced cancer for whom previous treatment was not successful or no standard treatment exists. The purpose of this study is to find out how a medicine called BI 764532 gets distributed in the body and in tumours.
Participants get BI 764532 when starting treatment. In the first weeks, doctors check how BI 764532 is taken up in tumours by means of an imaging method. If there is benefit for the participants and if they can tolerate it, the treatment is given up to the maximum duration of the study. During this time, participants visit the study site regularly. The total number of visits depends on how they respond to and tolerate the treatment. Doctors record any unwanted effects and regularly check the general health of the participants.

开始日期2024-02-22

申办/合作机构

Boehringer Ingelheim GmbH

NCT05990738 / Recruiting临床1期

DAREON™-9: A Phase Ib Open-label Dose Escalation and Dose Confirmation Safety Study of Intravenous BI 764532 in Combination With Topotecan for the Treatment of Patients With Small Cell Lung Cancer

This study is open to adults with extensive stage small cell lung cancer. The study is in people with advanced cancer that had previously received platinum-based chemotherapy and are eligible to receive topotecan treatment.
The purpose of this study is to find out the highest dose of BI 764532 that people can tolerate when taken together with topotecan. BI 764532 is an antibody-like molecule that may help the immune system fight cancer. Participants get BI 764532 and topotecan as infusions into a vein. As an alternative, topotecan may also be taken orally (tablets).
Participants may continue to take BI 764532 as long as they benefit from treatment and can tolerate it. During this time, participants visit the study site regularly. The visits also depend on the response to the treatment. At the study visits, the doctors check the health of the participants, take necessary laboratory tests, and note any health problems that could have been caused by the study treatment.

开始日期2024-01-15

申办/合作机构

Boehringer Ingelheim GmbH

NCT06077500 / Recruiting临床1期

DAREONᵀᴹ-8: A Phase I, Open-label, Dose Escalation and Expansion Trial of Repeated Intravenous Infusions of BI 764532 Combined With Standard of Care (Platinium, Etoposide, and Anti-PD-L1) in Patients With Extensive-stage Small Cell Lung Carcinoma

This study is open to adults with extensive stage small cell lung cancer. The study is in people with advanced cancer that are eligible for standard of care including chemotherapy and anti-PD-L1 (Programmed Cell Death Ligand 1) immunotherapy.
The purpose of this study is to find out the highest dose of BI 764532 that people can tolerate when taken together with standard of care. BI 764532 is an antibody-like molecule that may help the immune system fight cancer. Participants get BI 764532 and different standard treatments as infusions into a vein.
If there is benefit for the participants and if they can tolerate it, the treatment is given for the entire duration of the study. During this time, participants visit the study site regularly. The visits also depend on the response to the treatment. At the study visits, the doctors check the health of the participants, take necessary laboratory tests, and note any health problems that could have been caused by the study treatment.

开始日期2024-01-11

申办/合作机构

Boehringer Ingelheim GmbH

100 项与 Obrixtamig 相关的临床结果

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项与 Obrixtamig 相关的文献（医药）

2022-08-01·Future oncology (London, England)

Phase I trial of the DLL3/CD3 bispecific T-cell engager BI 764532 in DLL3-positive small-cell lung cancer and neuroendocrine carcinomas

Article

作者: Owonikoko, Taofeek K ; Hamed, Zohra Oum’ ; Studeny, Matus ; Wermke, Martin ; Felip, Enriqueta ; Gambardella, Valentina ; Liu, Meiruo ; Kuboki, Yasutoshi ; Morgensztern, Daniel

Poorly differentiated neuroendocrine carcinomas such as small-cell lung cancer (SCLC) have poor survival and high relapse rates. DLL3 is found on these carcinomas and has become a target of increasing interest in recent years. The bispecific DLL3/CD3 T-cell engager BI 764532 has been shown to induce complete tumor regression in a human T cell-engrafted mouse model. Here, we describe the study design of a first-in-human, phase I, multicenter, open-label, non-randomized, dose-escalation study in patients with SCLC or other DLL3-positive neuroendocrine carcinomas. The study will determine the maximum tolerated dose and evaluate safety, tolerability, pharmacokinetics and preliminary efficacy of BI 764532 monotherapy.

Journal of hematology & oncology

Emerging therapies targeting the delta-like ligand 3 (DLL3) in small cell lung cancer

Review

作者: Goldrick, Amanda ; Paz-Ares, Luis ; Rudin, Charles M ; Yang, James Chih-Hsin ; Umejiego, John ; Reck, Martin ; Bailis, Julie M ; Blackhall, Fiona ; Hann, Christine L ; Johnson, Melissa L ; Bebb, Gwyn

Abstract:

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a poor prognosis. Initial responses to standard-of-care chemo-immunotherapy are, unfortunately, followed by rapid disease recurrence in most patients. Current treatment options are limited, with no therapies specifically approved as third-line or beyond. Delta-like ligand 3 (DLL3), a Notch inhibitory ligand, is an attractive therapeutic target because it is overexpressed on the surface of SCLC cells with minimal to no expression on normal cells. Several DLL3-targeted therapies are being developed for the treatment of SCLC and other neuroendocrine carcinomas, including antibody-drug conjugates (ADCs), T-cell engager (TCE) molecules, and chimeric antigen receptor (CAR) therapies. First, we discuss the clinical experience with rovalpituzumab tesirine (Rova-T), a DLL3-targeting ADC, the development of which was halted due to a lack of efficacy in phase 3 studies, with a view to understanding the lessons that can be garnered for the rapidly evolving therapeutic landscape in SCLC. We then review preclinical and clinical data for several DLL3-targeting agents that are currently in development, including the TCE molecules—tarlatamab (formerly known as AMG 757), BI 764532, and HPN328—and the CAR T-cell therapy AMG 119. We conclude with a discussion of the future challenges and opportunities for DLL3-targeting therapies, including the utility of DLL3 as a biomarker for patient selection and disease progression, and the potential of rational combinatorial approaches that can enhance efficacy.

项与 Obrixtamig 相关的新闻（医药）

2024-06-05

·药时代

ASCO 2024中的黄金靶点CD3双抗

错过了「星起点」宣讲会？问答实录拿走不谢～正文共： 3391字 7图预计阅读时间： 9分钟 2024年6月3日医麦客新闻 eMedClub News 备受全球瞩目的 2024 年美国临床肿瘤学会（ASCO）年会将于美国东部时间 5 月 31 日至 6 月 4 日在芝加哥盛大召开。本届 ASCO 年会的主题为癌症治疗的艺术与科学：从舒适医疗到疾病治愈。ASCO一直是抗肿瘤药物的盛宴，可以看作是各家药企肿瘤药物的“秀场”让大家能够欣赏其亮眼的临床数据。其中抗体药物方兴未艾，一直以来都具有很高的热度。在近几年的抗体药研发中，双抗一直备受关注。双特异性抗体是指可以同时结合两个不同抗原或一个抗原不同表位的抗体，可通过其特有的作用方式，如衔接T细胞和肿瘤细胞、协同抑制信号通路、形成蛋白复合物等，发挥单抗无法实现的生物学功能。简单来讲，双抗药物是两个不同的单抗结构融合而形成，一直具有很高的热度，有望成为未来临床的重要选择。下表不完全总结了在2024 ASCO年会中国上展示的双抗。 CD3位居双抗靶点热度榜首 eMedClub 从表格中，可以看出，双抗中有PD1靶点的有康方生物，健信生物，荣昌生物等。PDL1靶点的有天境生物，原启生物，齐鲁制药等，4-1BB的有天境生物，齐鲁制药，维立志博等，这些靶点也都具有很高的热度。其中，可以看到CD3在多个四分之一的双抗中都有出现，数量居高，可以说是位居榜首，备受人们关注。 CD3蛋白是免疫系统中关键的分子之一，参与激活细胞毒性T细胞(CD8+初始T细胞)和T辅助细胞(CD4+初始T细胞)，负责监测和抵御体内的感染和异常细胞。CD3靶向药研究最多的就是双抗，CD3双抗能够使CD3+ T细胞重定向靶向杀伤癌细胞。目前，海内外布局CD3靶点相关生物药研究管线的公司和机构很多。在国内市场，CD3同样是药物研发的热门靶点。 2024ASCO大会上CD3双抗关键管线盘点 eMedClub BI 764532 eMedClub 2023年7月24日,勃林格殷格翰靶向DLL3/CD3双抗BI 764532用于治疗复发性/难治性广泛期小细胞肺癌（ES-SCLC）和其他复发性/难治性神经内分泌癌患者的II期临床试验获得中国国家药品监督管理局（NMPA）药品审评中心批准。 DLL3是Notch信号通路的配体，能够选择性地在小细胞肺癌和肺外神经内分泌肿瘤细胞中表达。BI 764532 （NCT04429087）在预处理的 DLL3 阳性肿瘤患者中的 I 期试验显示，总体缓解率为 28%，疾病控制率为54%，安全性可控。据公开信息显示，截止2023年7月7日，全球共有 5 款（Tarlatamab,B1 764532,89ZrZr-B1 764532,PT217,QLS31904）靶向 DLL3 的双特异性抗体进入临床阶段，包括 4 款 DLL3/CD3 双抗。其中进展最快的当属 Tarlatamab，其余均处于早期临床阶段。 CN201 eMedClub CN201是同润生物医药有限公司的一款CD19/CD3双抗。同润生物医药是一家肿瘤免疫治疗药物研发商，致力于研发下一代肿瘤免疫治疗药物，其研发管线中拥有数个具有竞争力的全新肿瘤免疫治疗分子。 2018年7月27日，同润生物医药有限责任公司宣布完成1.5亿美元A轮融资，本次融资由通和毓承、博裕资本以及淡马锡共同投资。同润生物致力于研发下一代肿瘤免疫治疗药物，应用独特生物技术及多种协同组合联合疗法，研发针对恶性肿瘤的下一代创新疗法，使癌症成为可控的慢性疾病。现已布局并构建丰富且极具竞争力的产品管线，拥有数个具有创新性的新一代肿瘤免疫治疗分子，其研发管线中拥有数个具有竞争力的全新肿瘤免疫治疗分子。 CN201在针对复发或难治性急性淋巴细胞白血病患者中的Ⅰ期临床实验显示，完全缓解率（CR）为30%，37位受试者中，有1例有完全缓解和不完全血液恢复（CRi），75% 的应答者有 MRD 阴性。针对CD3×CD19靶点，国内多家企业也在加速创制，包括绿竹生物、健能隆、爱思迈、同润生物等公司（据不完全统计）： IBI389 eMedClub 2022年3月30日，信达生物制药集团宣布其自主研发的重组靶向紧密蛋白连接蛋白18.2(Claudin18.2，CLDN18.2)和分化抗原簇3(CD3)的双特异性抗体IBI389在治疗晚期恶性肿瘤的I期临床试验中完成首例患者给药。IBI389通过连接T细胞受体复合物中的CD3分子和肿瘤细胞膜上的CLDN18.2抗原，诱导免疫突触的形成。截至 2024 年 1 月 31 日，IBI389的ORR为30.4%（95%CI：13.2-52.9），DCR为69.6%（95%CI：47.1-86.8）。有关安全性和有效性的更多最新数据将在会议上公布。当前全球共有 13 个 CD3/CLDN18.2 双特异性抗体和 1 个抗体类融合蛋白在研，其中最快的 4 个项目处于 I 期临床阶段，分别来自安斯泰来（ASP2138）、信达生物（IBI389）、齐鲁制药（QLS31905）和安进/百济神州（AMG910）；AZD5863 / HBM7022 如今也已申报临床。可以看出，在第一梯队里中国企业身影频现。 M701 eMedClub 2024年3月4日，国家药品监督管理局药品审评中心（CDE）官网显示，由武汉友芝友生物制药有限公司研发的注射用重组抗EpCAM和CD3人鼠嵌合双特异性抗体（M701）已经开始Ⅲ期的临床研究，正在招募晚期上皮性恶性实体瘤（包括卵巢癌、胃癌、结直肠癌）伴恶性腹水患者入组。武汉友芝友生物制药股份有限公司是一家致力于开发用于治疗癌症相关并发症、癌症及老年性眼科疾病的基于双特异性抗体(BsAb)疗法的生物技术公司，以解决肿瘤学及老年眼科病领域的医疗需求。 M701是友芝友生物通过自主专利非对称双特异性抗体YBODY®平台开发的同时靶向EpCAM和CD3的生物一类新药，已于2016年获批开展治疗恶性腹水的临床研究，是中国第2个由国内企业研制并获批进入临床的双特异性抗体。M701双抗一端靶向EpCAM抗原，同时通过另一端CD3抗体可以桥接T细胞并激活T细胞杀伤EpCAM阳性肿瘤细胞。目前，M701正在开展联合全身治疗对恶性腹水的II期安全性和疗效研究，与腹腔化疗组相比已初步显示出更好的腹水控制效果。基于全身肿瘤治疗的 M701 IP 输注耐受性良好，不会造成更高的风险。接受 M701 治疗的 MA 上皮癌患者具有更长的 PuFS （无穿刺生存期）和 OS（总生存期）。这些结果是有希望的，并支持M701作为MA新疗法的关键试验。在同靶点的研究中，2023年3月24日，据CDE官网显示，天劢源和生物医药有限公司提交的“重组抗EpCAM-CD3抗体注射液”新药研究性申请获得受理。 epcoritamab-bysp eMedClub 艾可瑞妥单抗，是由Genmab 和艾伯维共同开发的一种皮下注射的 CD20×CD3 T 细胞接合双特异性抗体，通过与T细胞表面的CD3及B细胞表面的CD20相结合，激活T细胞表面的CD3及B细胞表面的CD20，发挥免疫抑制作用。用于治疗成熟 B 细胞非霍奇金淋巴瘤亚型（B- NHL），包括弥漫性大 B 细胞淋巴瘤 (DLBCL)。试验结果证明，艾可瑞妥单抗（Epkinly）的客观缓解率（ORR）为63.1%，完全缓解率（CR）在38.9%。安全性良好。 CD20/CD3双抗已有同类药物上市，罗氏开发的Mosunetuzumab，靶向CD20/CD3，利用Knob-In-Hole技术防止抗体重链错配，该抗体的Fc同样进行了突变沉默ADCC等效应。目前该抗体已经被FDA授予突破性药物资格。结语 eMedClub 相信随着更多靶点的发现和更多样化设计的分子形式的涌现，双抗在实体瘤领域也必将迎来重大的突破。当然，药物开发要平衡有效性和安全性，CD3多特异性细胞连接器普遍出现发生率比较高的CRS（细胞因子释放综合征），毒性问题是一个挑战，很多公司也想出来了很多应对方法。CD3靶点一直热度颇高，这么多款CD3靶点的双特异性抗体真的很值得期待。参考资料： [1]https://www.asco.org/ 声明：本文旨在于传递行业发展信息、探究生物医药前沿进展。文章内容仅代表作者观点，并不代表医麦客立场，亦不构成任何价值判断、投资建议或医疗指导，如有需求请咨询专业人士投资或前往正规医院就诊。封面图来源：123rf 版权声明/免责声明本文为授权转载文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢! 药时代官方网站:www.drugtimes.cn 联系方式: 电话:13651980212 微信:27674131 邮箱:contact@drugtimes.cn 股价一度跌近10%，市值蒸发80亿美元！GSK或将面临巨额索赔 ASCO速递：从“低表达”到“更低表达”，最畅销 ADC进入next level！全球首款mRNA RSV疫苗获批，但公司股价却大跌，为何？从1000亿到1580亿，全球「减重药」市场又增重了！点击阅读原文，把握BD机会！

ASCO会议临床1期临床结果免疫疗法

2024-05-17

·BioSpace

Amgen’s T-Cell Engager Wins FDA Approval for Difficult-to-Treat Lung Cancer

The FDA on Thursday approved Amgen’s bispecific T-cell engager tarlatamab, which will now carry the brand name Imdelltra, for the treatment of extensive-stage small lung cancer in patients with disease progression on or after platinum chemotherapy. Imdelltra is approved under the regulator’s accelerated pathway based on treatment response and duration of response data. To maintain the approval, Amgen will need to verify Imdelltra’s clinical benefits in a Phase III confirmatory trial. The FDA also gave Imdelltra a boxed warning for cytokine release syndrome and neurologic toxicity. Jay Bradner, CSO and executive vice president of R&D at Amgen, called Thursday’s regulatory win a “pivotal moment” for patients with extensive-stage small lung cancer (ES-SCLC), with Imdelltra a “transformative option demonstrating long-lasting responses,” especially in patients exposed to prior treatments. Designed as an intravenous infusion, Imdelltra is a first-in-class bispecific antibody that can bind to both the DLL3 protein on tumor cells and the CD3 antigen on T cells. This mechanism of action allows Imdelltra to activate the body’s immune players and induce the destruction of DLL3-expressing cancer cells. DLL3 is expressed in 85% to 96% of SCLC cases but the protein is rarely found on healthy cells, according to Amgen. The company is also developing tarlatamab for neuroendocrine prostate cancer, for which the candidate is currently in Phase I. Thursday’s accelerated approval was backed by data from the Phase II DeLLphi-301 trial, which administered Imdelltra at a 10-mg or 100-mg dose every two weeks. In October 2023, Amgen published data from the mid-stage study in The New England Journal of Medicine, touting an objective response rate of 40% and 32% in the 10-mg and 100-mg dose groups, respectively. Of those with objective response to Imdelltra, 59% sustained the response for a median duration of at least six months. Median progression-free survival was 4.9 months in the 10-mg group, while overall survival was 14.3 months. With these data in hand, Amgen filed its Biologics License Application with the FDA which accepted the submission in December 2023 and granted it priority review. The regulator’s verdict was initially due on June 12, 2024. Imdelltra’s approval on Thursday puts Amgen ahead of its competitors including Boehringer Ingelheim, whose own SCLC bi-specific T-cell engager BI 764532 is currently being assessed in a Phase II trial. In November 2023, Novartis and Legend Biotech also joined the race with a potential $1-billion agreement to develop a DLL3-targeting CAR-T therapy. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

临床2期上市批准临床3期临床结果免疫疗法

2024-05-17

·Pharma Manufacturing

FDA approves Amgen T-cell engager for small cell lung cancer

The FDA has approved Amgen’s Imdelltra, a T-cell engager therapy for the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) who have experienced disease progression after platinum-based chemotherapy. This marks the first FDA-approved therapy targeting DLL3 in ES-SCLC. The approval was granted under the FDA's accelerated approval pathway, and continued approval will depend on further verification of clinical benefits in additional trials. Imdelltra's approval is based on results from the phase 2 DeLLphi-301 clinical trial, which reported a 40% objective response rate, a median duration of response of 9.7 months, and a median overall survival of 14.3 months among patients. The drug works by targeting DLL3, a protein expressed on the surface of SCLC cells, and activating T-cells to attack these tumor cells. Several drugmakers are currently developing DLL3-targeting therapies for cancer treatment as well; Boehringer Ingelheim is working on BI 764532, a DLL3-targeting T-cell engager for treating small cell lung cancer and other neuroendocrine carcinomas, currently in phase 2 trials. Molecular Partners, in collaboration with Orano Med, is also developing DLL3-targeting therapies, leveraging the protein's expression in tumor cells for selective treatment. Additionally, Zai Lab is investigating ZL-1310, an antibody-drug conjugate targeting DLL3 for solid tumors.

临床2期上市批准临床结果加速审批抗体药物偶联物

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适应症	最高研发状态	国家/地区	公司	日期
小细胞肺癌	临床2期	美国	Boehringer Ingelheim Pharma GmbH & Co., KG	2023-10-13
小细胞肺癌	临床2期	美国	Boehringer Ingelheim International GmbH	2023-10-13
小细胞肺癌	临床2期	中国	Boehringer Ingelheim Pharma GmbH & Co., KG	2023-10-13
小细胞肺癌	临床2期	中国	Boehringer Ingelheim International GmbH	2023-10-13
小细胞肺癌	临床2期	日本	Boehringer Ingelheim International GmbH	2023-10-13
小细胞肺癌	临床2期	日本	Boehringer Ingelheim Pharma GmbH & Co., KG	2023-10-13
小细胞肺癌	临床2期	比利时	Boehringer Ingelheim Pharma GmbH & Co., KG	2023-10-13
小细胞肺癌	临床2期	比利时	Boehringer Ingelheim International GmbH	2023-10-13
小细胞肺癌	临床2期	保加利亚	Boehringer Ingelheim Pharma GmbH & Co., KG	2023-10-13
小细胞肺癌	临床2期	保加利亚	Boehringer Ingelheim International GmbH	2023-10-13

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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


NCT04429087 (ESMO_ASIA2023)	临床1期	DLL3阳性小细胞肺癌 DLL3+	107	BI 764532	餘齋憲構憲蓋廠製觸鏇(壓顧壓夢鏇築簾膚餘鹽) = 夢淵網繭齋網遞鑰糧鑰壓壓繭艱蓋鏇鹽鑰壓網 (衊憲獵顧齋範憲鑰蓋製 )	-	2023-12-01
NCT04429087 (ESMO2023) 人工标引	临床1期	神经内分泌癌 DLL3-positive	129	BI 764532	構鑰顧範願艱繭衊壓築(鏇糧膚壓齋鏇膚夢網襯) = 顧製襯憲繭築廠憲蓋範艱鏇顧繭艱蓋艱壓簾襯 (憲選鏇衊淵鏇膚糧齋鏇 )	积极	2023-10-22
NCT04429087 (ESMO2023) 人工标引	临床1期	神经内分泌癌 DLL3-positive	129	BI 764532 (epNEC)	艱製築網壓網製鏇鹹鹹(艱襯網醖鹽製積網蓋蓋) = 鹹憲鹹願蓋觸鏇蓋築觸鑰壓鑰顧鑰願齋壓淵鹹 (顧繭糧鏇艱膚構廠範築 ) 更多	积极	2023-10-22
NCT04429087 (WCLC2023) 人工标引	临床1期	小细胞肺癌 \| DLL3阳性小细胞肺癌 DLL3 Positive	90	BI 764532	衊淵築築糧糧鹹簾積夢(餘齋鹽構憲鏇艱築壓壓) = DLTs were seen in one patient on Regimen A (Grade 3 confusion) and four patients on Regimen B2 (Grade 4 cytokine release syndrome [CRS]; Grade 3 CRS; Grade 3 nervous system disorder; and Grade 2 infusion-related reaction). 壓壓鑰觸齋獵餘鑰鹽範 (膚餘廠願壓獵繭積窪繭 ) 更多	积极	2023-09-10
NCT04429087 (ASCO2023) 人工标引	临床1期	小细胞肺癌 \| 神经内分泌癌 DLL3 Expression	90	BI 764532 (RA)	網鹽獵簾觸齋築窪構膚(艱鏇遞鬱積憲鬱構鏇願) = 築範餘願願選簾製範網壓積衊夢艱簾餘遞衊鑰 (製網觸蓋鹽壓遞製醖淵 ) 更多	积极	2023-05-31
NCT04429087 (ASCO2023) 人工标引	临床1期	小细胞肺癌 \| 神经内分泌癌 DLL3 Expression	90	BI 764532 (RB1)	網鹽獵簾觸齋築窪構膚(艱鏇遞鬱積憲鬱構鏇願) = 築繭網顧遞簾膚膚醖窪壓積衊夢艱簾餘遞衊鑰 (製網觸蓋鹽壓遞製醖淵 ) 更多	积极	2023-05-31