在缺乏DNA损伤反应的先进固体瘤中使用Camonsertib:第一阶段试验结果
Timothy A Yap1, Elisa Fontana2, Elizabeth K Lee3
1Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. tyap@mdanderson.org.
Nature medicine
|June 5, 2023
概括
这一Camonsertib (ATRi) 的第一阶段试验表明,在具有DNA损伤反应 (DDR) 基因变异的先进固体瘤中,有前景的安全性和初步疗效. 观察到临床益处,特别是在卵巢癌和具有特定DDR变化的瘤中.
科学领域:
- 在瘤学瘤学.
- 药理学 药理学是指药理学的学科.
- 遗传学 是一个遗传学.
背景情况:
- 向癌症治疗需要预测生物标志物来选择治疗.
- ATAXIA 电磁切除症和Rad3相关激酶抑制剂 (ATRi) 在ATAXIA 电磁切除症突变 (ATM) 激酶中表现出具有功能丧失 (LOF) 的合成致死性.
- 临床前数据表明,其他DNA损伤反应 (DDR) 基因改变可以使瘤对ATRi敏感.
研究的目的:
- 评估ATR抑制剂camonsertib (RP-3500) 的安全性并确定推的第二阶段剂量 (RP2D).
- 为了评估camonsertib的初步抗瘤活性,药理动力学和药理动力学生物标志物.
- 探索在患有晚期固体瘤的患者中识别ATRi敏感化生物标志物的方法.
主要方法:
- 一个第一阶段试验 (模块1) 涉及120名患有DDR基因LOF变异的高级固体瘤的患者.
- 患者接受了camonsertib,并增加剂量以确定安全性和RP2D.
- 在接受生物有效剂量的患者中,评估了临床反应,益处和分子反应率.
主要成果:
- 卡蒙塞尔蒂布一般耐受性很好,3级贫血是最常见的毒性 (32%).
- 初步推的第二阶段剂量 (RP2D) 确定为每周160毫克.
- 在接受有效剂量的患者中,总体临床反应,临床益处和分子反应率分别为13%,43%和43%.
- 在卵巢癌和双性LOF变异的瘤中观察到的临床益处最高.
结论:
- 卡蒙塞尔蒂布在患有特定DDR改变的高级固体瘤的患者中显示出可管理的安全性和初步抗瘤活性.
- 该研究确定了潜在的RP2D,并突出了特定的患者群体和瘤类型,这些患者群体和瘤类型可能从ATR抑制中获益最多.
- 需要在第二阶段试验中进行进一步的研究,以确认疗效,并根据DDR变化改进患者选择.
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