Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors.
Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors.
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DOI：
10.1007/s10637-016-0407-y
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发表时间：
2017-04
影响因子：
3.4
通讯作者：
Hong DS
中科院分区：
文献类型：
--
作者：
Beg MS;Brenner AJ;Sachdev J;Borad M;Kang YK;Stoudemire J;Smith S;Bader AG;Kim S;Hong DS
天然存在的肿瘤抑制microRNA-34 a（miR-34 a）下调多个致癌途径中的>30种癌基因以及参与肿瘤免疫逃避的基因的表达，但在许多恶性肿瘤中丢失或表达不足。这项首次非人I期研究评估了MRX 34（一种脂质体miR-34 a模拟物）在晚期实体瘤患者中的最大耐受剂量（MTD）、安全性、药代动力学和临床活性。标准治疗难治性实体瘤成人患者入组标准3+3剂量递增试验。MRX 34静脉给药，每周两次（BIW），持续3周，以4周为一个周期。入组了47例各种实体瘤患者，包括肝细胞癌（HCC; n=14）。中位年龄为60岁，中位既往治疗为4次（范围，1-12次），大多数为白人（68%）和男性（57%）。最常见的不良事件（AE）包括发热（所有级别%/G3%：64/2）、疲乏（57/13）、背痛（57/11）、恶心（49/2）、腹泻（40/11）、厌食（36/4）和呕吐（34/4）。实验室检查异常包括淋巴细胞减少症（G3%/G4%：23/9）、中性粒细胞减少症（13/11）、血小板减少症（17/0）、AST升高（19/4）、高血糖症（13/2）和低钠血症（19/2）。需要地塞米松前驱用药以管理输注相关AE。非HCC患者的MTD为110 mg/m2，2例患者在124 mg/m2时出现G3缺氧和肠炎的剂量限制性毒性。半衰期>24 h，Cmax和AUC随剂量增加而增加。1例HCC患者实现了持续48周的长期确认PR，4例患者发生了持续≥4个周期的SD。在难治性晚期实体瘤患者亚组中，MRX 34联合地塞米松前驱用药治疗具有可接受的安全性，并显示出抗肿瘤活性的证据。BIW方案的MTD为非HCC患者110 mg/m2，HCC患者93 mg/m2。已探索了其他剂量方案或MRX 34以改善耐受性。
Naturally occurring tumor suppressor microRNA-34a (miR-34a) downregulates the expression of >30 oncogenes across multiple oncogenic pathways, as well as genes involved in tumor immune evasion, but is lost or under-expressed in many malignancies. This first-inhuman, phase I study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumors. Adult patients with solid tumors refractory to standard treatment were enrolled in a standard 3+3 dose escalation trial. MRX34 was given intravenously twice weekly (BIW) for three weeks in 4-week cycles. Forty-seven patients with various solid tumors, including hepatocellular carcinoma (HCC; n=14), were enrolled. Median age was 60 years, median prior therapies was 4 (range, 1–12), and most were Caucasian (68%) and male (57%). Most common adverse events (AEs) included fever (all grade %/G3 %: 64/2), fatigue (57/13), back pain (57/11), nausea (49/2), diarrhea (40/11), anorexia (36/4), and vomiting (34/4). Laboratory abnormalities included lymphopenia (G3 %/G4 %: 23/9), neutropenia (13/11), thrombocytopenia (17/0), increased AST (19/4), hyperglycemia (13/2), and hyponatremia (19/2). Dexamethasone premedication was required to manage infusion-related AEs. The MTD for non-HCC patients was 110 mg/m2, with two patients experiencing dose-limiting toxicities of G3 hypoxia and enteritis at 124 mg/m2. The half-life was >24 h, and Cmax and AUC increased with increasing dose. One patient with HCC achieved a prolonged confirmed PR lasting 48 weeks, and four patients experienced SD lasting ≥4 cycles. MRX34 treatment with dexamethasone premedication was associated with acceptable safety and showed evidence of antitumor activity in a subset of patients with refractory advanced solid tumors. The MTD for the BIW schedule was 110 mg/m2 for non-HCC and 93 mg/m2 for HCC patients. Additional dose schedules or MRX34 have been explored to improve tolerability.
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影响因子：
11.2
作者：
Bader AG;Brown D;Winkler M
通讯作者：
Winkler M
影响因子：
6.4
作者：
Hagman, Zandra;Larne, Olivia;Ceder, Yvonne
通讯作者：
Ceder, Yvonne
影响因子：
10.3
作者：
Cortez, Maria Angelica;Ivan, Cristina;Welsh, James W.
通讯作者：
Welsh, James W.
影响因子：
64.8
作者：
He, Lin;He, Xingyue;Hannon, Gregory J.
通讯作者：
Hannon, Gregory J.
DOI：
10.1073/pnas.1420955112
发表时间：
2015-03-10
影响因子：
11.1
作者：
Londin, Eric;Loher, Phillipe;Rigoutsos, Isidore
通讯作者：
Rigoutsos, Isidore