LXI-15029，一种新型 mTOR 双重抑制剂，在晚期恶性实体瘤中国受试者中的 I 期剂量递增研究和初步疗效分析。

Phase I dose escalation study and pilot efficacy analysis of LXI-15029, a novel mTOR dual inhibitor, in Chinese subjects with advanced malignant solid tumors.

机构信息

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuannanli, Chaoyang District, Beijing, 100021, China.

Shandong Luoxin Pharmaceutical Group Co., Ltd., Linyi, 276017, China.

出版信息

BMC Cancer. 2023 Dec 6;23(1):1200. doi: 10.1186/s12885-023-11578-8.

DOI:10.1186/s12885-023-11578-8

PMID:38057772

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10702058/

Abstract

BACKGROUND

The mammalian target of rapamycin (mTOR) kinase, a central component of the PI3K/AKT/mTOR pathway, plays a critical role in tumor biology as an attractive therapeutic target. We conducted this first-in-human study to investigate the safety, pharmacokinetics (PK), and pilot efficacy of LXI-15029, an mTORC1/2 dual inhibitor, in Chinese patients with advanced malignant solid tumors.

METHODS

Eligible patients with advanced, unresectable malignant solid tumors after failure of routine therapy or with no standard treatment were enrolled to receive ascending doses (10, 20, 40, 60, 80, 110, and 150 mg) of oral LXI-15029 twice daily (BID) (3 + 3 dose-escalation pattern) until disease progression or intolerable adverse events (AEs). The primary endpoints were safety and tolerability.

RESULTS

Between June 2017 and July 2021, a total of 24 patients were enrolled. LXI-15029 was well tolerated at all doses. Only one dose-limiting toxicity (grade 3 increased alanine aminotransferase) occurred in the 150 mg group, and the maximum tolerated dose was 110 mg BID. The most common treatment-related AEs were leukocytopenia (41.7%), increased alanine aminotransferase (20.8%), increased aspartate aminotransferase (20.8%), prolonged electrocardiogram QT interval (20.8%), and hypertriglyceridemia (20.8%). No other serious treatment-related AEs were reported. LXI-15029 was absorbed rapidly after oral administration. The increases in the peak concentration and the area under the curve were greater than dose proportionality over the dose range. Eight patients had stable disease. The disease control rate was 40.0% (8/20; 95% CI 21.7-60.6). In evaluable patients, the median progression-free survival was 29 days (range 29-141).

CONCLUSIONS

LXI-15029 demonstrated reasonable safety and tolerability profiles and encouraging preliminary antitumor activity in Chinese patients with advanced malignant solid tumors, which warranted further validation in phase II trials.

TRIAL REGISTRATION

NCT03125746(24/04/2017), http://ClinicalTrials.gov/show/NCT03125746.

摘要

背景

哺乳动物雷帕霉素靶蛋白（mTOR）激酶是 PI3K/AKT/mTOR 通路的核心组成部分，作为一种有吸引力的治疗靶点，在肿瘤生物学中发挥着关键作用。我们进行了这项首次人体研究，以评估 LXI-15029（一种 mTORC1/2 双重抑制剂）在中国晚期恶性实体瘤患者中的安全性、药代动力学（PK）和初步疗效。

方法

纳入标准为常规治疗失败的晚期、不可切除的恶性实体瘤患者，或无标准治疗的患者，接受每日两次（BID）口服 LXI-15029（LXI-15029）递增剂量（10、20、40、60、80、110 和 150 mg）（3+3 剂量递增模式），直至疾病进展或出现不可耐受的不良事件（AE）。主要终点为安全性和耐受性。

结果

2017 年 6 月至 2021 年 7 月，共纳入 24 例患者。所有剂量下 LXI-15029 均具有良好的耐受性。仅在 150 mg 组发生 1 例剂量限制性毒性（3 级丙氨酸氨基转移酶升高），最大耐受剂量为 110 mg BID。最常见的治疗相关不良事件为白细胞减少（41.7%）、丙氨酸氨基转移酶升高（20.8%）、天门冬氨酸氨基转移酶升高（20.8%）、心电图 QT 间期延长（20.8%）和高甘油三酯血症（20.8%）。未报告其他严重的治疗相关不良事件。LXI-15029 口服后吸收迅速。在研究剂量范围内，峰浓度和曲线下面积的增加大于剂量比例关系。8 例患者疾病稳定。疾病控制率为 40.0%（8/20；95%CI 21.7-60.6）。在可评估患者中，中位无进展生存期为 29 天（范围 29-141）。