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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02805-1

摘要内容如下：

癌基因MYC是癌症治疗中“最想要的”靶点之一，它协调肿瘤发展和维持中的关键转录程序。然而，它一直被认为是不可用药的。Omo-103是一种由91个氨基酸组成的MYC抑制剂。在此，我们介绍了Omo-103在晚期实体瘤中的第1阶段研究结果，该研究旨在检查作为主要结果的安全性和耐受性，以及作为次要结果的药代动力学、推荐的第2阶段剂量和初步活性迹象。经典的3+3设计用于在21天周期内每周静脉注射单药Omo-103的剂量递增，包括6个剂量水平（DLS）。共有22名患者入选，治疗持续至疾病进展。最常见的不良事件是1级输液相关反应，发生在10名患者中。DL5出现一种剂量限制性毒性。药代动力学显示非线性，在DL5时出现组织饱和征，在血清中的终末半衰期为40小时。在19例可评价疗效的患者中，12例达到了预先确定的9周药物抗肿瘤活性评价时间点，其中8例经计算机断层扫描显示病情稳定。根据实体瘤疗效评估标准，一名患者被定义为病情稳定，在最佳疗效时，肿瘤总体积减少了49%。转录组分析支持肿瘤活检中的靶点参与。此外，我们确定了作为潜在药效学和预测反应标志物的可溶性因子。基于所有这些数据，推荐的第2阶段剂量确定为DL5（6.48mgkg-1）。ClinicalTrials.gov标识符：NCT04808362。

英文原文如下：

Abstracts

Among the 'most wanted' targets in cancer therapy is the oncogene MYC, which coordinates key transcriptional programs in tumor development and maintenance. It has, however, long been considered undruggable. OMO-103 is a MYC inhibitor consisting of a 91-amino acid miniprotein. Here we present results from a phase 1 study of OMO-103 in advanced solid tumors, established to examine safety and tolerability as primary outcomes and pharmacokinetics, recommended phase 2 dose and preliminary signs of activity as secondary ones. A classical 3 + 3 design was used for dose escalation of weekly intravenous, single-agent OMO-103 administration in 21-day cycles, encompassing six dose levels (DLs). A total of 22 patients were enrolled, with treatment maintained until disease progression. The most common adverse events were grade 1 infusion-related reactions, occurring in ten patients. One dose-limiting toxicity occurred at DL5. Pharmacokinetics showed nonlinearity, with tissue saturation signs at DL5 and a terminal half-life in serum of 40 h. Of the 19 patients evaluable for response, 12 reached the predefined 9-week time point for assessment of drug antitumor activity, eight of those showing stable disease by computed tomography. One patient defined as stable disease by response evaluation criteria in solid tumors showed a 49% reduction in total tumor volume at best response. Transcriptomic analysis supported target engagement in tumor biopsies. In addition, we identified soluble factors that are potential pharmacodynamic and predictive response markers. Based on all these data, the recommended phase 2 dose was determined as DL5 (6.48 mg kg-1).ClinicalTrials.gov identifier: NCT04808362 .

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