Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours.,British Journal of Cancer

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Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours.
British Journal of Cancer ( IF 6.4 ) Pub Date : 2020-04-02 , DOI: 10.1038/s41416-020-0802-1
David S Hong ₁ , Yoon-Koo Kang ₂ , Mitesh Borad ₃ , Jasgit Sachdev ₄ , Samuel Ejadi ₅ , Ho Yeong Lim ₆ , Andrew J Brenner ₇ , Keunchil Park ₆ , Jae-Lyun Lee ₂ , Tae-You Kim ₈ , Sangjoon Shin ₉ , Carlos R Becerra ₁₀ , Gerald Falchook ₁₁ , Jay Stoudemire ₁₂ , Desiree Martin ₁₂ , Kevin Kelnar ₁₂ , Heidi Peltier ₁₂ , Vinicius Bonato ₁₂ , Andreas G Bader ₁₂ , Susan Smith ₁₂ , Sinil Kim ₁₂ , Vincent O'Neill ₁₂ , Muhammad S Beg ₁₃

Affiliation

The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Asan Medical Center, Seoul, South Korea.
Mayo Clinic Cancer Center, Scottsdale, AZ, USA.
Scottsdale Healthcare Research Institute, Scottsdale, AZ, USA.
University of California Irvine Medical Center, Orange, CA, USA.
Samsung Medical Center, Seoul, Korea.
The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Seoul National University Hospital, Seoul, South Korea.
Severance Hospital, Seoul, South Korea.
Texas Oncology-US Oncology-Baylor University Medical Center, Dallas, TX, USA.
Sarah Cannon Research Institute at HealthONE, Denver, CO, USA.
Mirna Therapeutics, Austin, TX, USA.
The University of Texas Southwestern Medical Center, Dallas, TX, USA.

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/m2 for hepatocellular carcinoma (HCC) and 93 mg/m2 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. CLINICAL TRIAL REGISTRATION NCT01829971.

中文翻译：

MRX34（一种脂质体 miR-34a 模拟物）在晚期实体瘤患者中的 1 期研究。

背景在这项基于 microRNA 的癌症治疗的首次人体 1 期研究中，确定了 MRX34（microRNA-34a (miR-34a) 的脂质体模拟物）的推荐 2 期剂量 (RP2D)，并在患者中进行了评估患有晚期实体瘤。方法将患有各种标准治疗难治性实体瘤的成人纳入 3 + 3 剂量递增队列，并在 RP2D 测定后纳入扩展队列。 MRX34 联合口服地塞米松术前用药，每天静脉注射，持续 5 天，周期为 3 周。结果在 85 名入组患者中观察到的常见全因不良事件包括发烧（% 所有级别/G3：72/4）、寒战（53/14）、疲劳（51/9）、背部/颈部疼痛（36/5）、恶心（36/1）和呼吸困难（25/4）。肝细胞癌 (HCC) 的 RP2D 为 70 mg/m2，非 HCC 癌症的 RP2D 为 93 mg/m2。药效学结果显示 miR-34a 被递送至肿瘤，并对白细胞中靶基因表达进行剂量依赖性调节。 3 名患者获得 PR，16 名患者获得持续≥4 个周期的 SD（中位时间为 19 周，范围为 11-55）。结论地塞米松术前用药的 MRX34 治疗在大多数患者中表现出可控的毒性特征，并具有一定的临床活性。尽管由于严重的免疫介导的 AE 导致四名患者死亡，该试验提前结束，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。临床试验注册NCT01829971。

更新日期：2020-04-24

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