在先进的固体瘤中使用双硬性mTORC1选择性抑制剂RMC-5552:一期试验
Alison M Schram1, Abdul Rafeh Naqash2,3, Eric B Haura4
1Memorial Sloan Kettering Cancer Center, New York, New York.
概括
新型mTORC1抑制剂RMC-5552在先进的固体瘤中显示出有前途的活性和耐受性. 塔克罗利斯口水有效降低了粘膜炎,证明了有选择性的,对机制的抗瘤作用.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 在癌症的发展和进展中,PI3K/mTOR通路至关重要.
- RMC-5552是一种新型双抑制剂,针对mTOR复合体1 (mTORC1) 选择性地超过mTOR复合体2 (mTORC2).
研究的目的:
- 评估RMC-5552的安全性,耐受性,药理动力学和初步抗瘤活性,在首次对人类进行剂量升级研究中.
- 评估塔克罗利斯口水 (TM) 预防RMC-5552引起的口腔粘膜炎的疗效.
主要方法:
- 对RMC-5552 (1.6-16毫克每周一次) 的剂量升级研究在57名晚期固体瘤患者中进行.
- 评估了安全性,耐受性,药理动力学和初步活性.
- 塔克罗利斯口水被测试为粘膜炎预防.
主要成果:
- 最常见的不良事件包括粘膜炎 (49%),恶心 (44%) 和疲劳 (42%).
- 过高血糖的发病率很低 (4%),与mTORC1选择性相一致.
- 在8至12毫克剂量之间,塔克罗利斯口水可以将粘膜炎的发病率从65%降低到31%.
- 疾病控制率为64%,其中一个是子宫内膜癌的完整反应.
- 在循环瘤DNA (ctDNA) 中观察到PI3K/mTOR途径变异的清除.
结论:
- RMC-5552是第一个经过临床测试的双固态mTORC1选择性抑制剂,在可容忍剂量下显示活性.
- 使用RMC-5552进行选择性mTORC1抑制克服了早期mTOR抑制剂的高血糖限制.
- 塔克罗利莫斯口水预防和ctDNA变异清除支持RMC-5552的选择性,在机制上的抗瘤活性.
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