Siqing Fu, R. Sanborn, Minxia Cai, Lijia Zhang, Yanhua Xu, Kui Lin
{"title":"摘要 CT116:新型泛PIM激酶抑制剂NB004/GDC-0570在晚期实体瘤患者中的临床前抗肿瘤活性和首次人体I期研究","authors":"Siqing Fu, R. Sanborn, Minxia Cai, Lijia Zhang, Yanhua Xu, Kui Lin","doi":"10.1158/1538-7445.am2024-ct116","DOIUrl":null,"url":null,"abstract":"\n PIM proto-oncogenes encode a family of three serine/threonine kinases (PIM1, PIM2, PIM3), which are frequently overexpressed in human hematological malignancies and solid cancers. PIM kinases are promising cancer therapeutic targets for pharmacological inhibition. NB004 (aka GDC-0570) is a novel, potent, selective, orally available small molecule pan-PIM inhibitor, which exhibits antiproliferative activity as a single agent in a variety of preclinical models and can augment the activity of standard of care or targeted therapies, both in vitro and in vivo. In multiple patient-derived xenograft (PDX) models of human solid tumors, NB004 demonstrates both single agent and combination activity with agents targeting the RTK/RAS/MAPK pathways, including synergistic effects with KRAS inhibitors (KRASis). Remarkably, in NSCLC PDX models with acquired resistance to KRASis, strong combination efficacy was observed between NB004 and sotorasib, resulting in complete tumor regression. Based on the promising preclinical data, NB004 is currently being assessed in an open-label, first-in-human phase I clinical trial as monotherapy or combination therapy in patients with advanced solid tumors. The primary objective is to characterize the safety and tolerability and to recommend the phase 2 dose (RP2D). Secondary objectives include PK characterization and preliminary antitumor activity evaluation. In the phase I monotherapy dose escalation part, NB004 was administered daily in 5 dose levels, ranging from 75mg to 600mg, following a standard 3+3 design. As of December 22, 2023, a total of 18 patients were treated. Of the 13 patients (72.2%) who reported any treatment-related adverse events (TRAEs), 12 (66.7%) had Grade 1 or 2 TRAEs, 1 patient (5.6%) experienced Grade 3 neutrophil count decrease and white blood cell count decrease. No dose-limiting toxicity (DLT) or treatment-related serious adverse event (SAE) was reported, and PK exposure is in general dose proportional. These results warrant further evaluation of this drug in combination with other therapeutic agents. The combination part of the trial is currently open for enrollment (NCT05036291).\n Citation Format: Siqing Fu, Rachel E. Sanborn, Minxia Cai, Lijia Zhang, Yanhua Xu, Kui Lin. Preclinical antitumor activity and first-in-human phase I study of NB004/GDC-0570, a novel pan-PIM kinase inhibitor, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT116.","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"29 3","pages":""},"PeriodicalIF":2.9000,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Abstract CT116: Preclinical antitumor activity and first-in-human phase I study of NB004/GDC-0570, a novel pan-PIM kinase inhibitor, in patients with advanced solid tumors\",\"authors\":\"Siqing Fu, R. 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Remarkably, in NSCLC PDX models with acquired resistance to KRASis, strong combination efficacy was observed between NB004 and sotorasib, resulting in complete tumor regression. Based on the promising preclinical data, NB004 is currently being assessed in an open-label, first-in-human phase I clinical trial as monotherapy or combination therapy in patients with advanced solid tumors. The primary objective is to characterize the safety and tolerability and to recommend the phase 2 dose (RP2D). Secondary objectives include PK characterization and preliminary antitumor activity evaluation. In the phase I monotherapy dose escalation part, NB004 was administered daily in 5 dose levels, ranging from 75mg to 600mg, following a standard 3+3 design. As of December 22, 2023, a total of 18 patients were treated. 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引用次数: 0
摘要
PIM 原癌基因编码三个丝氨酸/苏氨酸激酶家族(PIM1、PIM2 和 PIM3),它们在人类血液恶性肿瘤和实体癌中经常过度表达。PIM 激酶是很有希望的药物抑制癌症治疗靶点。NB004(又名 GDC-0570)是一种新型、强效、选择性、口服小分子泛 PIM 抑制剂,在多种临床前模型中作为单药表现出抗增生活性,在体外和体内均可增强标准疗法或靶向疗法的活性。在多种人类实体瘤患者衍生异种移植(PDX)模型中,NB004 表现出单药活性以及与靶向 RTK/RAS/MAPK 通路的药物联合使用的活性,包括与 KRAS 抑制剂(KRASis)的协同作用。值得注意的是,在对 KRASis 产生获得性耐药性的 NSCLC PDX 模型中,NB004 与 sotorasib 的联用疗效显著,使肿瘤完全消退。基于前景看好的临床前数据,NB004 目前正在一项开放标签、首次人体 I 期临床试验中接受评估,作为晚期实体瘤患者的单药或联合疗法。首要目标是确定安全性和耐受性,并推荐二期剂量(RP2D)。次要目标包括 PK 表征和初步抗肿瘤活性评估。在 I 期单药治疗剂量递增部分,NB004 采用标准 3+3 设计,每天给药 5 个剂量水平,从 75 毫克到 600 毫克不等。截至2023年12月22日,共有18名患者接受了治疗。13名患者(72.2%)报告了治疗相关不良事件(TRAEs),其中12名患者(66.7%)出现1级或2级TRAEs,1名患者(5.6%)出现3级中性粒细胞计数减少和白细胞计数减少。未报告剂量限制性毒性(DLT)或与治疗相关的严重不良事件(SAE),PK 暴露一般与剂量成正比。这些结果为进一步评估该药物与其他治疗药物的联合应用提供了依据。该试验的联合用药部分目前正在接受注册(NCT05036291)。引用格式:傅思清、Rachel E. Sanborn、蔡敏霞、张丽佳、徐艳华、林魁。新型泛 PIM 激酶抑制剂 NB004/GDC-0570 在晚期实体瘤患者中的临床前抗肿瘤活性和首次人体 I 期研究 [摘要].In:美国癌症研究协会 2024 年年会论文集;第 2 部分(晚期突破、临床试验和特邀摘要);2024 年 4 月 5-10 日;加利福尼亚州圣地亚哥。费城(宾夕法尼亚州):AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT116.
Abstract CT116: Preclinical antitumor activity and first-in-human phase I study of NB004/GDC-0570, a novel pan-PIM kinase inhibitor, in patients with advanced solid tumors
PIM proto-oncogenes encode a family of three serine/threonine kinases (PIM1, PIM2, PIM3), which are frequently overexpressed in human hematological malignancies and solid cancers. PIM kinases are promising cancer therapeutic targets for pharmacological inhibition. NB004 (aka GDC-0570) is a novel, potent, selective, orally available small molecule pan-PIM inhibitor, which exhibits antiproliferative activity as a single agent in a variety of preclinical models and can augment the activity of standard of care or targeted therapies, both in vitro and in vivo. In multiple patient-derived xenograft (PDX) models of human solid tumors, NB004 demonstrates both single agent and combination activity with agents targeting the RTK/RAS/MAPK pathways, including synergistic effects with KRAS inhibitors (KRASis). Remarkably, in NSCLC PDX models with acquired resistance to KRASis, strong combination efficacy was observed between NB004 and sotorasib, resulting in complete tumor regression. Based on the promising preclinical data, NB004 is currently being assessed in an open-label, first-in-human phase I clinical trial as monotherapy or combination therapy in patients with advanced solid tumors. The primary objective is to characterize the safety and tolerability and to recommend the phase 2 dose (RP2D). Secondary objectives include PK characterization and preliminary antitumor activity evaluation. In the phase I monotherapy dose escalation part, NB004 was administered daily in 5 dose levels, ranging from 75mg to 600mg, following a standard 3+3 design. As of December 22, 2023, a total of 18 patients were treated. Of the 13 patients (72.2%) who reported any treatment-related adverse events (TRAEs), 12 (66.7%) had Grade 1 or 2 TRAEs, 1 patient (5.6%) experienced Grade 3 neutrophil count decrease and white blood cell count decrease. No dose-limiting toxicity (DLT) or treatment-related serious adverse event (SAE) was reported, and PK exposure is in general dose proportional. These results warrant further evaluation of this drug in combination with other therapeutic agents. The combination part of the trial is currently open for enrollment (NCT05036291).
Citation Format: Siqing Fu, Rachel E. Sanborn, Minxia Cai, Lijia Zhang, Yanhua Xu, Kui Lin. Preclinical antitumor activity and first-in-human phase I study of NB004/GDC-0570, a novel pan-PIM kinase inhibitor, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT116.
期刊介绍:
The Journal of Chemical Health and Safety focuses on news, information, and ideas relating to issues and advances in chemical health and safety. The Journal of Chemical Health and Safety covers up-to-the minute, in-depth views of safety issues ranging from OSHA and EPA regulations to the safe handling of hazardous waste, from the latest innovations in effective chemical hygiene practices to the courts'' most recent rulings on safety-related lawsuits. The Journal of Chemical Health and Safety presents real-world information that health, safety and environmental professionals and others responsible for the safety of their workplaces can put to use right away, identifying potential and developing safety concerns before they do real harm.