OxPhos抑制剂ME-344联合贝伐单抗治疗难治性转移性结直肠癌的1b期研究

IF 3 3区 医学 Q2 ONCOLOGY
Investigational New Drugs Pub Date : 2025-02-01 Epub Date: 2024-12-27 DOI:10.1007/s10637-024-01489-1
Patrick M Boland, Heinz-Josef Lenz, Kristen K Ciombor, Vaia Florou, Michael J Pishvaian, Michael Cusnir, Deirdre Cohen, Jessie Y Guo, Min Tang, Prabhu Rajagopalan, Sandra E Wiley, Richard G Ghalie, Howard S Hochster
{"title":"OxPhos抑制剂ME-344联合贝伐单抗治疗难治性转移性结直肠癌的1b期研究","authors":"Patrick M Boland, Heinz-Josef Lenz, Kristen K Ciombor, Vaia Florou, Michael J Pishvaian, Michael Cusnir, Deirdre Cohen, Jessie Y Guo, Min Tang, Prabhu Rajagopalan, Sandra E Wiley, Richard G Ghalie, Howard S Hochster","doi":"10.1007/s10637-024-01489-1","DOIUrl":null,"url":null,"abstract":"<p><p>Antiangiogenic drugs may cause vascular normalization and correct hypoxia in tumors, shifting cells to mitochondrial respiration as the primary source of energy. In turn, the addition of an inhibitor of mitochondrial respiration to antiangiogenic therapy holds potential to induce synthetic lethality. This study evaluated the mitochondrial inhibitor ME-344 in combination with bevacizumab in patients with refractory metastatic colorectal cancer (mCRC). Patients were eligible if they had disease progression after standard therapies, adequate hematologic, hepatic and renal function, and no contraindications to bevacizumab. ME-344 was administered intravenously on days 1, 8 and 15 and bevacizumab on days 1 and 15 of 28-day cycles until disease progression or intolerance. The primary efficacy endpoint was progression-free survival (PFS) at week 16. In the 23 patients enrolled, the median age was 58 years, median number of prior lines of therapy was 4, and median interval from last therapy was 3 months. The most common adverse events (all grades/grade ≥ 3) were fatigue (48%/13%), abdominal pain (35%/4%), diarrhea (30%/4%) and constipation (30%/0%). No patient had an objective response; 9 patients (39%) achieved stable disease. The 16-week PFS was 30.6% (95% confidence interval [CI]: 12.2-51.3), the median PFS was 1.9 months (95% CI: 1.6-4.7), and the median overall survival was 6.7 months (95% CI: 3.4-not reached). ME-344 plus bevacizumab was well tolerated. Disease control was limited in this heavily pretreated patient population. Additional investigations in earlier lines are indicated, and extended-release ME-344 formulations may provide longer drug exposure to maximize benefit. (Trial registration number ClinicalTrials.gov NCT05824559. Registration date 22 March 2022).</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"60-68"},"PeriodicalIF":3.0000,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11868331/pdf/","citationCount":"0","resultStr":"{\"title\":\"A Phase 1b study of the OxPhos inhibitor ME-344 with bevacizumab in refractory metastatic colorectal cancer.\",\"authors\":\"Patrick M Boland, Heinz-Josef Lenz, Kristen K Ciombor, Vaia Florou, Michael J Pishvaian, Michael Cusnir, Deirdre Cohen, Jessie Y Guo, Min Tang, Prabhu Rajagopalan, Sandra E Wiley, Richard G Ghalie, Howard S Hochster\",\"doi\":\"10.1007/s10637-024-01489-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Antiangiogenic drugs may cause vascular normalization and correct hypoxia in tumors, shifting cells to mitochondrial respiration as the primary source of energy. In turn, the addition of an inhibitor of mitochondrial respiration to antiangiogenic therapy holds potential to induce synthetic lethality. This study evaluated the mitochondrial inhibitor ME-344 in combination with bevacizumab in patients with refractory metastatic colorectal cancer (mCRC). Patients were eligible if they had disease progression after standard therapies, adequate hematologic, hepatic and renal function, and no contraindications to bevacizumab. ME-344 was administered intravenously on days 1, 8 and 15 and bevacizumab on days 1 and 15 of 28-day cycles until disease progression or intolerance. The primary efficacy endpoint was progression-free survival (PFS) at week 16. In the 23 patients enrolled, the median age was 58 years, median number of prior lines of therapy was 4, and median interval from last therapy was 3 months. The most common adverse events (all grades/grade ≥ 3) were fatigue (48%/13%), abdominal pain (35%/4%), diarrhea (30%/4%) and constipation (30%/0%). No patient had an objective response; 9 patients (39%) achieved stable disease. The 16-week PFS was 30.6% (95% confidence interval [CI]: 12.2-51.3), the median PFS was 1.9 months (95% CI: 1.6-4.7), and the median overall survival was 6.7 months (95% CI: 3.4-not reached). ME-344 plus bevacizumab was well tolerated. Disease control was limited in this heavily pretreated patient population. Additional investigations in earlier lines are indicated, and extended-release ME-344 formulations may provide longer drug exposure to maximize benefit. (Trial registration number ClinicalTrials.gov NCT05824559. Registration date 22 March 2022).</p>\",\"PeriodicalId\":14513,\"journal\":{\"name\":\"Investigational New Drugs\",\"volume\":\" \",\"pages\":\"60-68\"},\"PeriodicalIF\":3.0000,\"publicationDate\":\"2025-02-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11868331/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Investigational New Drugs\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s10637-024-01489-1\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/12/27 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Investigational New Drugs","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10637-024-01489-1","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/12/27 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

抗血管生成药物可能导致肿瘤血管正常化和纠正缺氧,将细胞转移到线粒体呼吸作为主要的能量来源。反过来,在抗血管生成治疗中加入线粒体呼吸抑制剂有可能诱导合成致死。这项研究评估了线粒体抑制剂ME-344联合贝伐单抗在难治性转移性结直肠癌(mCRC)患者中的应用。如果患者在标准治疗后出现疾病进展,血液学、肝脏和肾脏功能正常,且无贝伐单抗禁忌症,则符合条件。ME-344在28天周期的第1、8和15天静脉注射,贝伐单抗在第1和15天静脉注射,直到疾病进展或不耐受。主要疗效终点是第16周的无进展生存期(PFS)。在入选的23例患者中,中位年龄为58岁,先前治疗的中位行数为4条,与上次治疗的中位间隔为3个月。最常见的不良事件(所有等级/等级≥3)是疲劳(48%/13%)、腹痛(35%/4%)、腹泻(30%/4%)和便秘(30%/0%)。没有患者有客观反应;9例(39%)病情稳定。16周PFS为30.6%(95%可信区间[CI]: 12.2-51.3),中位PFS为1.9个月(95% CI: 1.6-4.7),中位总生存期为6.7个月(95% CI: 3.4-未达到)。ME-344联合贝伐单抗耐受性良好。在这一大量预处理的患者群体中,疾病控制是有限的。在早期的研究表明,缓释ME-344制剂可能提供更长的药物暴露时间,以最大限度地提高效益。试验注册号:ClinicalTrials.gov NCT05824559。注册日期为2022年3月22日)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A Phase 1b study of the OxPhos inhibitor ME-344 with bevacizumab in refractory metastatic colorectal cancer.

Antiangiogenic drugs may cause vascular normalization and correct hypoxia in tumors, shifting cells to mitochondrial respiration as the primary source of energy. In turn, the addition of an inhibitor of mitochondrial respiration to antiangiogenic therapy holds potential to induce synthetic lethality. This study evaluated the mitochondrial inhibitor ME-344 in combination with bevacizumab in patients with refractory metastatic colorectal cancer (mCRC). Patients were eligible if they had disease progression after standard therapies, adequate hematologic, hepatic and renal function, and no contraindications to bevacizumab. ME-344 was administered intravenously on days 1, 8 and 15 and bevacizumab on days 1 and 15 of 28-day cycles until disease progression or intolerance. The primary efficacy endpoint was progression-free survival (PFS) at week 16. In the 23 patients enrolled, the median age was 58 years, median number of prior lines of therapy was 4, and median interval from last therapy was 3 months. The most common adverse events (all grades/grade ≥ 3) were fatigue (48%/13%), abdominal pain (35%/4%), diarrhea (30%/4%) and constipation (30%/0%). No patient had an objective response; 9 patients (39%) achieved stable disease. The 16-week PFS was 30.6% (95% confidence interval [CI]: 12.2-51.3), the median PFS was 1.9 months (95% CI: 1.6-4.7), and the median overall survival was 6.7 months (95% CI: 3.4-not reached). ME-344 plus bevacizumab was well tolerated. Disease control was limited in this heavily pretreated patient population. Additional investigations in earlier lines are indicated, and extended-release ME-344 formulations may provide longer drug exposure to maximize benefit. (Trial registration number ClinicalTrials.gov NCT05824559. Registration date 22 March 2022).

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
7.60
自引率
0.00%
发文量
121
审稿时长
1 months
期刊介绍: The development of new anticancer agents is one of the most rapidly changing aspects of cancer research. Investigational New Drugs provides a forum for the rapid dissemination of information on new anticancer agents. The papers published are of interest to the medical chemist, toxicologist, pharmacist, pharmacologist, biostatistician and clinical oncologist. Investigational New Drugs provides the fastest possible publication of new discoveries and results for the whole community of scientists developing anticancer agents.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信