Phase 1/2 Modular Dose Escalation With Cohort Expansion of CP-506 (HAP) in Patients With Solid Tumor Types With High Incidence of HRD/FAD in Monotherapy or With Carboplatin or Patients With Solid Tumour and OPD Receiving ICI

A modular, first time in human, open label, multiple dose, accelerated escalation with cohort expansion study of the safety and pharmacokinetics of intravenous infusion of CP-506, a tumor agnostic Hypoxia Activated Prodrug in patients with HRD/FAD solid tumours or tumor types with high incidence of HRD/FAD in monotherapy or in combination with carboplatin or patients with solid tumour and oligoprogressive disease receiving immune checkpoint inhibitors (ICI): a phase I-IIa clinical trial

开始日期2023-04-25

申办/合作机构

Maastricht UMC+

[+3]

100 项与 CP-506 相关的临床结果

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100 项与 CP-506 相关的转化医学

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100 项与 CP-506 相关的专利（医药）

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项与 CP-506 相关的文献（医药）

2023-11-09·ACS medicinal chemistry letters

Design and Biological Evaluation of Piperazine-Bearing Nitrobenzamide Hypoxia/GDEPT Prodrugs: The Discovery of CP-506

Article

作者: Guise, Christopher P. ; Ashoorzadeh, Amir ; Patterson, Adam V. ; Mowday, Alexandra M. ; Abbattista, Maria R. ; Silva, Shevan ; Smaill, Jeff B. ; Bull, Matthew R.

Off-target aerobic activation of PR-104A by human aldo-keto reductase 1C3 (AKR1C3) has confounded the development of this dual hypoxia/gene therapy prodrug. Previous attempts to design prodrugs resistant to AKR1C3 activation have resulted in candidates that require further optimization. Herein we report the evaluation of a lipophilic series of PR-104A analogues in which a piperazine moiety has been introduced to improve drug-like properties. Octanol-water partition coefficients (LogD_7.4) spanned >2 orders of magnitude. 2D antiproliferative and 3D multicellular clonogenic assays using isogenic HCT116 and H1299 cells confirmed that all examples were resistant to AKR1C3 metabolism while producing an E. coli NfsA nitroreductase-mediated bystander effect. Prodrugs 16, 17, and 20 demonstrated efficacy in H1299 xenografts where only a minority of tumor cells express NfsA. These prodrugs and their bromo/mesylate counterparts (25-27) were also evaluated for hypoxia-selective cell killing in vitro. These results in conjunction with stability assays recommended prodrug 26 (CP-506) for Phase I/II clinical trial.

2023-09-01·Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology

Overcoming radioresistance with the hypoxia-activated prodrug CP-506: A pre-clinical study of local tumour control probability.

Article

作者: Koi, Lydia ; Yaromina, Ala ; Schuitmaker, Lesley ; Lambin, Philippe ; Krause, Mechthild ; Dubois, Ludwig Jerome ; van der Wiel, Alexander Marie-Madeleine Adrianus

BACKGROUND AND PURPOSE:

Tumour hypoxia is an established radioresistance factor. A novel hypoxia-activated prodrug CP-506 has been proven to selectively target hypoxic tumour cells and to cause anti-tumour activity. The current study investigates whether CP-506 improves outcome of radiotherapy in vivo.

MATERIALS AND METHODS:

Mice bearing FaDu and UT-SCC-5 xenografts were randomized to receive 5 daily injections of CP-506/vehicle followed by single dose (SD) irradiation. In addition, CP-506 was combined once per week with fractionated irradiation (30 fractions/6 weeks). Animals were followed-up to score all recurrences. In parallel, tumours were harvested to evaluate pimonidazole hypoxia, DNA damage (γH2AX), expression of oxidoreductases.

RESULTS:

CP-506 treatment significantly increased local control rate after SD in FaDu, 62% vs. 27% (p = 0.024). In UT-SCC-5, this effect was not curative and only marginally significant. CP-506 induced significant DNA damage in FaDu (p = 0.009) but not in UT- SCC-5. Hypoxic volume (HV) was significantly smaller (p = 0.038) after pretreatment with CP-506 as compared to vehicle in FaDu but not in less responsive UT-SCC-5. Adding CP-506 to fractionated radiotherapy in FaDu did not result in significant benefit.

CONCLUSION:

The results support the use of CP-506 in combination with radiation in particular using hypofractionation schedules in hypoxic tumours. The magnitude of effect depends on the tumour model, therefore it is expected that applying appropriate patient stratification strategy will further enhance the benefit of CP-506 treatment for cancer patients. A phase I-IIA clinical trial of CP-506 in monotherapy or in combination with carboplatin or a checkpoint inhibitor has been approved (NCT04954599).

2022-02-21·Chemical research in toxicology3区 · 医学

In Vivo Identification of Adducts from the New Hypoxia-Activated Prodrug CP-506 Using DNA Adductomics

3区 · 医学

Article

作者: Solivio, Morwena J. ; Dubois, Ludwig ; Gilissen, Julie ; Deschoemaeker, Sofie ; Stornetta, Alessia ; Villalta, Peter W. ; Heyerick, Arne ; Balbo, Silvia

Many chemotherapeutic drugs exert their cytotoxicity through the formation of DNA modifications (adducts), which interfere with DNA replication, an overactive process in rapidly dividing cancer cells. Side effects from the therapy are common, however, because these drugs also affect rapidly dividing noncancerous cells. Hypoxia-activated prodrugs (HAPs) have been developed to reduce these side effects as they preferentially activate in hypoxic environments, a hallmark of solid tumors. CP-506 is a newly developed DNA-alkylating HAP designed to exert strong activity under hypoxia. The resulting CP-506-DNA adducts can be used to elucidate the cellular and molecular effects of CP-506 and its selectivity toward hypoxic conditions. In this study, we characterize the profile of adducts resulting from the reaction of CP-506 and its metabolites CP-506H and CP-506M with DNA. A total of 39 putative DNA adducts were detected in vitro using our high-resolution/accurate-mass (HRAM) liquid chromatography tandem mass spectrometry (LC-MS³) adductomics approach. Validation of these results was achieved using a novel strategy involving ¹⁵N-labeled DNA. A targeted MS/MS approach was then developed for the detection of the 39 DNA adducts in five cancer cell lines treated with CP-506 under normoxic and hypoxic conditions to evaluate the selectivity toward hypoxia. Out of the 39 DNA adducts initially identified, 15 were detected, with more adducts observed from the two reactive metabolites and in cancer cells treated under hypoxia. The presence of these adducts was then monitored in xenograft mouse models bearing MDA-MB-231, BT-474, or DMS114 tumors treated with CP-506, and a relative quantitation strategy was used to compare the adduct levels across samples. Eight adducts were detected in all xenograft models, and MDA-MB-231 showed the highest adduct levels. These results suggest that CP-506-DNA adducts can be used to better understand the mechanism of action and monitor the efficacy of CP-506 in vivo, as well as highlight a new role of DNA adductomics in supporting the clinical development of DNA-alkylating drugs.

项与 CP-506 相关的新闻（医药）

2022-06-08

·生物制药小编

罗氏/BNT强强联合|个体化癌症疫苗临床初战告捷

随着mRNA技术的发展，这一技术在癌症疫苗方面似乎正准备证明其卓越的功效。近日（6月5日），此前以新冠mRNA疫苗技术名声大噪的BioNTech公司在美国临床肿瘤学会（ASCO）年会上报告了其个体化mRNA癌症疫苗Autogene Cevumeran与罗氏PD-L1检查点抑制剂atezolizumab和化疗在接受手术切除导管的腺癌患者中联合应用的第一阶段初步数据。结果显示，早期数据显示了良好的安全性和令人鼓舞的临床活动指征。Autogene Cevumeran及其iNeST技术平台Autogene Cevumeran（前名RO7198457）是基于BNT的iNeST技术平台开发的个体化mRNA疫苗。（iNeST=Individualized Neoantigen Specific Immunotherapy个体化新抗原特异性免疫治疗）人体的T细胞能够针对肿瘤突变导致的抗原新表位，驱动癌症免疫。然而这一突发的自发免疫识别是低效的，常常在肿瘤及其附近受到抑制，因此BNT引入了个体化癌症疫苗的概念。他们通过建立了从对个体突变的全面识别，新表位的计算预测，到为每个患者设计和制造独特的疫苗这一完整体系构筑了iNeST的技术平台。其中的平台的全流程包括：1.首先需要从患者体内提取血液和癌症组织；2.通过血液分析获取患者的基因组材料，且研究肿瘤分子组分；并通过将两者对比分析发现肿瘤的基因突变；经过比对后，由于这些突变需要被用来帮助免疫系统识别肿瘤细胞，因此只有同时发生在癌细胞的DNA和RNA中的突变才有资格接受BNT的mRNA癌症疫苗治疗；3.BNT将从这些突变中，通过软件挑选其中至多20个能让免疫系统最可能识别的突变抗原，并通过这种方式设计个性化疫苗；4.疫苗经过按需定制的生产线，需要花费4-6个星期并最终交付给患者。5.在给药后，患者的免疫系统将通过产生T细胞反应，诱发针对肿瘤细胞特定的个体靶结构的免疫反应。而T细胞会攻击肿瘤并摧毁肿瘤细胞。图：Autogene Cevumeran生产的全流程从黑色素瘤临床到现在的胰腺癌临床此前这一疗法曾经在黑色素瘤中进行首次应用，研究于2017年发表在了Nature，临床结果显示所有患者都完成了最多20剂新表位疫苗的治疗，他们耐受良好，没有相关的严重不良事件。单独的新表位疫苗可以预防高危患者的疾病复发。此外，它们提供了将疫苗与PD-1/PD-L1阻断组合的基本原理。研究人员发现，在新表位疫苗接种后，由于其中一位P07号患者疾病进展迅速，进行同情性抗PD-1（帕博利珠单抗）治疗时，这位患者中被报告发现了迅速产生完全应答。该患者在两个月内经历了多发性黑色素瘤病变大小减少80%,并且最终完全缓解。疫苗诱导的T细胞在疫苗接种结束后持续长达9个月研究人员认为这一情况是由于新表位特异性T细胞亚群为PD-1阳性和记忆表型，疫苗后肿瘤遭到损伤会上调PD-L1并抑制这些T细胞亚群。因此患者在接种疫苗后使用PD-1抗体治疗时，迅速产生了免疫应答反应。2017年这项研究为现在疫苗与PD-1/PD-L1免疫检查点抑制剂联用的临床提供了依据。此次发布的临床数据又为这一联合用药的可行性增加了几分：来自16名手术后接受疫苗接种的患者数据表明，这一疗法耐受性良好，只有一名患者出现了疫苗相关的3级发热和高血压。该疗法在一半的患者中诱导了新抗原特异性T细胞反应。而与以前检测不到的水平相比，针对新抗原的T细胞水平上升到了总水平的2.9%。此外，在18个月的早期中位随访中，与没有疫苗诱导的免疫反应的患者相比，有重新免疫反应的患者显示出显著更长的无复发生存期(RFS)。罗氏的Tecentriq（atezolizumab）在胰腺癌上的联用胰腺癌被称为癌症之王，而PD-1/PD-L1抑制剂单药在胰腺癌中的表现不尽如人意。近年来随着对PD-1/PD-L1免疫检查点分子机制研究的逐渐深入，各种联合治疗方法如PD-1/PD-L1抑制剂和其他检查点抑制剂联合或在阻断PD-1/PD-L1信号通路的同时使用激动剂，抗体，疫苗等方式治疗胰腺癌的临床试验也在不断进行。除了此次的癌症疫苗，在胰腺癌这一癌种上，在化疗药物之外，Tecentriq的联合治疗还选择了赛诺菲ICOS单抗KY1044，舒泰神的 C5a单抗BDB-001，Lokon公司的溶瘤病毒LOAd703，iPSC衍生的CAR-NK细胞疗法FT500和FT536，缺氧激活前药CP-506共同进行。 Tecentriq可以说是在K药和O药之外销售额最高的PD-1/PD-L1抑制剂，如果能够在胰腺癌的联合治疗中证明联合疗法的疗效有助于开拓这一难治癌种的巨大市场。小编总结肿瘤疫苗的好处在于能够将体内T细胞激发后，产生新生抗原，能够在肿瘤组织内富集，并有效杀伤肿瘤细胞。虽然癌症疫苗的尝试一直以失败告终，但最近OSE-2101（Tedopi）的积极阳性结果以及此次的捷报可能使得癌种疫苗的可行性得到进一步的认可。参考来源：Sahin, U., Derhovanessian, E., Miller, M. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017). https://doi.org/10.1038/nature23003https://investors.biontech.de/news-releases/news-release-details/positive-phase-1-data-mrna-based-individualized-neoantigen——END——由中国医药质量管理协会和佰傲谷发起主办的2022QbD生物药质量科学大会，特设全球药品政策法规论坛将于8月12日下午至8月13日全天在北京召开！本次大会以“坚守质量高地，剑指国际化”为主题，特设四大专场论坛，并邀请到了罗氏/基因泰克公司全球质量控制部产品质控负责人焦吉祥莅临大会现场做演讲报告！点击“阅读原文”，进入官网立即报名~

疫苗免疫疗法抗体信使RNA细胞疗法

100 项与 CP-506 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
耳-腭-指综合征2型	临床2期	比利时	Maastricht UMC+	2023-04-25
耳-腭-指综合征2型	临床2期	荷兰	Maastricht UMC+	2023-04-25
实体瘤	临床2期	比利时	Maastricht UMC+	2023-04-25
实体瘤	临床2期	荷兰	Maastricht UMC+	2023-04-25

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适应症

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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


NCT04954599 (Pubmed \| Radiother Oncol)	临床1期	实体瘤 \| 耳-腭-指综合征2型	-	CP-506	觸窪憲鬱醖鏇壓願艱艱(壓餘蓋蓋膚範製窪簾膚) = 廠製窪壓蓋鹽範鑰網憲醖網遞蓋鏇鬱膚憲簾鹹 (遞夢鏇鹹鹹鹽醖艱窪襯 )	-	2023-06-12
				Vehicle	觸窪憲鬱醖鏇壓願艱艱(壓餘蓋蓋膚範製窪簾膚) = 廠積蓋繭顧衊繭廠遞壓醖網遞蓋鏇鬱膚憲簾鹹 (遞夢鏇鹹鹹鹽醖艱窪襯 )