钠-葡萄糖共转运蛋白2抑制剂(SGLT2i)达格列净联合标准化疗治疗晚期不能手术的胰腺腺癌患者的安全性、耐受性和有效性:一项1b期观察性研究

IF 6 3区 医学 Q1 CELL BIOLOGY
Lauren K Park, Kian-Huat Lim, Jonas Volkman, Mina Abdiannia, Hannah Johnston, Zack Nigogosyan, Marilyn J Siegel, Janet B McGill, Alexis M McKee, Maamoun Salam, Rong M Zhang, Da Ma, Karteek Popuri, Vincent Tze Yang Chow, Mirza Faisal Beg, William G Hawkins, Linda R Peterson, Joseph E Ippolito
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引用次数: 2

摘要

背景:胰腺导管腺癌(Pancreatic ductal adencarcinoma, PDAC)是一种致命的恶性肿瘤。因此,迫切需要安全有效的新疗法。PDAC过度依赖葡萄糖代谢来满足其代谢需求,这为代谢治疗提供了一个靶点。临床前PDAC模型表明,用达格列净靶向钠-葡萄糖共转运体-2 (SGLT2)可能是一种新的策略。达格列净对PDAC患者是否安全有效尚不清楚。方法:我们进行了一项1b期观察性研究(ClinicalTrials.gov ID NCT04542291;注册于2020年9月9日),以测试在局部晚期和/或转移性PDAC患者的标准吉西他滨和nab-紫杉醇(GnP)化疗中添加达格列清(5mg p.o./天× 2周,升级至10mg p.o./天× 6周)的安全性和耐受性。疗效指标包括实体肿瘤反应评价标准(RECIST 1.1)反应,基于ct的体积体成分测量,以及用于测量代谢和肿瘤负荷的血浆化学。结果:在筛选的23例患者中,有15例入组。1例患者在前4周内死亡(由于潜在疾病的并发症),2例患者退出(不能耐受大剂量化疗),12例患者完成治疗。使用达格列净没有意外或严重的不良事件。尽管没有出现酮症酸中毒的临床症状,但由于酮类升高,一名患者在6周后被告知停用达格列净。达格列净的依从性为99.4%。血浆胰高血糖素明显升高。虽然腹部肌肉和脂肪体积减少;肌肉脂肪比的增加与更好的治疗反应相关。治疗8周后,2例患者出现部分缓解(PR), 9例患者病情稳定(SD), 1例患者病情进展(PD)。在停用达格列净(和继续化疗)后,又有7名患者在随后的扫描中出现了进展性疾病,通过测量病变大小的增加和新病变的发展。定量影像学评估通过血浆CA19-9肿瘤标志物检测来支持。结论:达格列净在晚期不能手术的PDAC患者中具有良好的耐受性和高依从性。肿瘤反应和血浆生物标志物的总体有利变化表明它可能对PDAC有效,值得进一步研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Safety, tolerability, and effectiveness of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in combination with standard chemotherapy for patients with advanced, inoperable pancreatic adenocarcinoma: a phase 1b observational study.

Safety, tolerability, and effectiveness of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in combination with standard chemotherapy for patients with advanced, inoperable pancreatic adenocarcinoma: a phase 1b observational study.

Safety, tolerability, and effectiveness of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in combination with standard chemotherapy for patients with advanced, inoperable pancreatic adenocarcinoma: a phase 1b observational study.

Safety, tolerability, and effectiveness of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in combination with standard chemotherapy for patients with advanced, inoperable pancreatic adenocarcinoma: a phase 1b observational study.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Thus, there is an urgent need for safe and effective novel therapies. PDAC's excessive reliance on glucose metabolism for its metabolic needs provides a target for metabolic therapy. Preclinical PDAC models have demonstrated that targeting the sodium-glucose co-transporter-2 (SGLT2) with dapagliflozin may be a novel strategy. Whether dapagliflozin is safe and efficacious in humans with PDAC is unclear.

Methods: We performed a phase 1b observational study (ClinicalTrials.gov ID NCT04542291; registered 09/09/2020) to test the safety and tolerability of dapagliflozin (5 mg p.o./day × 2 weeks escalated to 10 mg p.o./day × 6 weeks) added to standard Gemcitabine and nab-Paclitaxel (GnP) chemotherapy in patients with locally advanced and/or metastatic PDAC. Markers of efficacy including Response Evaluation Criteria in Solid Tumors (RECIST 1.1) response, CT-based volumetric body composition measurements, and plasma chemistries for measuring metabolism and tumor burden were also analyzed.

Results: Of 23 patients who were screened, 15 enrolled. One expired (due to complications from underlying disease), 2 dropped out (did not tolerate GnP chemotherapy) during the first 4 weeks, and 12 completed. There were no unexpected or serious adverse events with dapagliflozin. One patient was told to discontinue dapagliflozin after 6 weeks due to elevated ketones, although there were no clinical signs of ketoacidosis. Dapagliflozin compliance was 99.4%. Plasma glucagon increased significantly. Although abdominal muscle and fat volumes decreased; increased muscle-to-fat ratio correlated with better therapeutic response. After 8 weeks of treatment in the study, partial response (PR) to therapy was seen in 2 patients, stable disease (SD) in 9 patients, and progressive disease (PD) in 1 patient. After dapagliflozin discontinuation (and chemotherapy continuation), an additional 7 patients developed the progressive disease in the subsequent scans measured by increased lesion size as well as the development of new lesions. Quantitative imaging assessment was supported by plasma CA19-9 tumor marker measurements.

Conclusions: Dapagliflozin is well-tolerated and was associated with high compliance in patients with advanced, inoperable PDAC. Overall favorable changes in tumor response and plasma biomarkers suggest it may have efficacy against PDAC, warranting further investigation.

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来源期刊
自引率
1.70%
发文量
17
审稿时长
14 weeks
期刊介绍: Cancer & Metabolism welcomes studies on all aspects of the relationship between cancer and metabolism, including: -Molecular biology and genetics of cancer metabolism -Whole-body metabolism, including diabetes and obesity, in relation to cancer -Metabolomics in relation to cancer; -Metabolism-based imaging -Preclinical and clinical studies of metabolism-related cancer therapies.
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