PMID- 38057772 OWN - NLM STAT- MEDLINE DCOM- 20231219 LR - 20231219 IS - 1471-2407 (Electronic) IS - 1471-2407 (Linking) VI - 23 IP - 1 DP - 2023 Dec 6 TI - 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. PG - 1200 LID - 10.1186/s12885-023-11578-8 [doi] LID - 1200 AB - 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. CI - (c) 2023. The Author(s). FAU - Wang, Jiani AU - Wang J AD - 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. FAU - Gui, Lin AU - Gui L AD - 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. FAU - Mu, Yuxin AU - Mu Y AD - 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. FAU - Wang, Jiayu AU - Wang J AD - 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. FAU - Chi, Yihebali AU - Chi Y AD - 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. FAU - Liu, Zhenteng AU - Liu Z AD - Shandong Luoxin Pharmaceutical Group Co., Ltd., Linyi, 276017, China. FAU - Li, Qing AU - Li Q AD - 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. cheryliqing@126.com. FAU - Xu, Binghe AU - Xu B AD - 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. xubinghebm@163.com. AD - State Key Laboratory of Molecular 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. xubinghebm@163.com. LA - eng SI - ClinicalTrials.gov/NCT03125746 GR - 2018YFC1312101/National Key Research and Development Program of China/ GR - CIFMS-2021-I2M-1-014/Chinese Academy of Medical Science Innovation Fund for Medical Sciences/ PT - Clinical Trial, Phase I PT - Journal Article DEP - 20231206 PL - England TA - BMC Cancer JT - BMC cancer JID - 100967800 RN - EC 2.6.1.2 (Alanine Transaminase) RN - 0 (Antineoplastic Agents) RN - 0 (Enzyme Inhibitors) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Humans MH - Alanine Transaminase MH - *Antineoplastic Agents/therapeutic use MH - East Asian People MH - Enzyme Inhibitors/therapeutic use MH - Maximum Tolerated Dose MH - *Neoplasms/drug therapy MH - Phosphatidylinositol 3-Kinases MH - TOR Serine-Threonine Kinases PMC - PMC10702058 OTO - NOTNLM OT - First-in-human trial OT - LXI-15029 OT - Metastatic solid tumors OT - mTORC1/2 dual inhibitor COIS- The authors declare no competing interests. EDAT- 2023/12/07 00:42 MHDA- 2023/12/11 12:43 PMCR- 2023/12/06 CRDT- 2023/12/06 23:59 PHST- 2023/04/24 00:00 [received] PHST- 2023/10/27 00:00 [accepted] PHST- 2023/12/11 12:43 [medline] PHST- 2023/12/07 00:42 [pubmed] PHST- 2023/12/06 23:59 [entrez] PHST- 2023/12/06 00:00 [pmc-release] AID - 10.1186/s12885-023-11578-8 [pii] AID - 11578 [pii] AID - 10.1186/s12885-023-11578-8 [doi] PST - epublish SO - BMC Cancer. 2023 Dec 6;23(1):1200. doi: 10.1186/s12885-023-11578-8.