Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours
Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours
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DOI：
10.1038/s41416-020-0802-1
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发表时间：
2020-04-02
影响因子：
8.8
通讯作者：
Beg, Muhammad S.
中科院分区：
文献类型：
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作者：
Hong, David S.;Kang, Yoon-Koo;Beg, Muhammad S.
在这项基于microRNA的癌症治疗的首次人体I期研究中，在晚期实体瘤患者中确定并评价了MRX 34（microRNA-34 a（miR-34 a）的脂质体模拟物）的推荐II期剂量（RP 2D）。方法将患有标准治疗难治性各种实体瘤的成人入组3 + 3剂量递增队列，并在RP 2D确定后入组扩展队列。MRX 34联合口服地塞米松前驱给药，静脉给药，每日一次，持续5天，3周为一个周期。结果85例患者中常见的全因不良反应包括发热（%）、寒战（53/14）、乏力（51/9）、背痛（36/5）、恶心（36/1）和呼吸困难（25/4）。肝细胞癌（HCC）的RP 2D为70 mg/m2，非HCC癌症为93 mg/m2。药效学结果显示，miR-34 a可递送至肿瘤，并对白色血细胞中的靶基因表达进行剂量依赖性调节。3例患者PR，16例SD持续≥ 4个周期（中位数，19周，范围，11-55）。结论：MRX 34联合地塞米松前驱给药在大多数患者中表现出可管理的毒性特征，并具有一定的临床活性。尽管该试验由于导致4例患者死亡的严重免疫介导的AE而提前关闭，但相关靶基因的剂量依赖性调节为基于miRNA的癌症治疗提供了概念验证。
Background In this first-in-human, Phase 1 study of a microRNA-based cancer therapy, the recommended Phase 2 dose (RP2D) of MRX34, a liposomal mimic of microRNA-34a (miR-34a), was determined and evaluated in patients with advanced solid tumours. Methods Adults with various solid tumours refractory to standard treatments were enrolled in 3 + 3 dose-escalation cohorts and, following RP2D determination, expansion cohorts. MRX34, with oral dexamethasone premedication, was given intravenously daily for 5 days in 3-week cycles. Results Common all-cause adverse events observed in 85 patients enrolled included fever (% all grade/G3: 72/4), chills (53/14), fatigue (51/9), back/neck pain (36/5), nausea (36/1) and dyspnoea (25/4). The RP2D was 70 mg/m(2) for hepatocellular carcinoma (HCC) and 93 mg/m(2) for non-HCC cancers. Pharmacodynamic results showed delivery of miR-34a to tumours, and dose-dependent modulation of target gene expression in white blood cells. Three patients had PRs and 16 had SD lasting >= 4 cycles (median, 19 weeks, range, 11-55). Conclusion MRX34 treatment with dexamethasone premedication demonstrated a manageable toxicity profile in most patients and some clinical activity. Although the trial was closed early due to serious immune-mediated AEs that resulted in four patient deaths, dose-dependent modulation of relevant target genes provides proof-of-concept for miRNA-based cancer therapy.