Molenaar Remco J, Coelen Robert J S, Khurshed Mohammed, Roos Eva, Caan Matthan W A, van Linde Myra E, Kouwenhoven Mathilde, Bramer Jos A M, Bovée Judith V M G, Mathôt Ron A, Klümpen Heinz-Josef, van Laarhoven Hanneke W M, van Noorden Cornelis J F, Vandertop W Peter, Gelderblom Hans, van Gulik Thomas M, Wilmink Johanna W
Department of Medical Oncology, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands.
Department of Medical Biology, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands.
BMJ Open. 2017 Jun 10;7(6):e014961. doi: 10.1136/bmjopen-2016-014961.
High-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma are aggressive types of cancer with a dismal outcome. This is due to the lack of effective treatment options, emphasising the need for novel therapies. Mutations in the genes and (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. -mutated cancer cells produce the oncometabolite -2-hydroxyglutarate (-2HG) and are metabolically vulnerable to treatment with the oral antidiabetic metformin and the oral antimalarial drug chloroquine.
We describe a dose-finding phase Ib/II clinical trial, in which patients with -mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma are treated with a combination of metformin and chloroquine. Dose escalation is performed according to a 3+3 dose-escalation scheme. The primary objective is to determine the maximum tolerated dose to establish the recommended dose for a phase II clinical trial. Secondary objectives of the study include (1) determination of pharmacokinetics and toxic effects of the study therapy, for which metformin and chloroquine serum levels will be determined over time; (2) investigation of tumour responses to metformin plus chloroquine in -mutated cancers using CT/MRI scans; and (3) whether tumour responses can be measured by non-invasive -2HG measurements (mass spectrometry and magnetic resonance spectroscopy) of tumour tissue, serum, urine, and/or bile or next-generation sequencing of circulating tumour DNA (liquid biopsies). This study may open a novel treatment avenue for -mutated high-grade chondrosarcoma, glioma and intrahepatic cholangiocarcinoma by repurposing the combination of two inexpensive drugs that are already approved for other indications.
This study has been approved by the medical-ethical review committee of the Academic Medical Center, Amsterdam, The Netherlands. The report will be submitted to a peer-reviewed journal.
This article was registered at ClinicalTrials.gov identifier (NCT02496741): Pre-results.
高级别软骨肉瘤、高级别胶质瘤和肝内胆管癌是侵袭性癌症类型，预后不佳。这是由于缺乏有效的治疗选择，凸显了对新疗法的需求。异柠檬酸脱氢酶1和2（IDH1和IDH2）基因的突变存在于60%的软骨肉瘤、80%的世界卫生组织II-IV级胶质瘤以及20%的肝内胆管癌中。IDH突变的癌细胞产生致癌代谢物2-羟基戊二酸（2-HG），并且在代谢上易受口服抗糖尿病药物二甲双胍和口服抗疟药物氯喹治疗的影响。
我们描述了一项剂量探索性Ib/II期临床试验，其中IDH突变的软骨肉瘤、胶质瘤和肝内胆管癌患者接受二甲双胍和氯喹联合治疗。根据3+3剂量递增方案进行剂量递增。主要目标是确定最大耐受剂量，以确立II期临床试验的推荐剂量。该研究的次要目标包括：（1）确定研究疗法的药代动力学和毒性作用，为此将随时间测定二甲双胍和氯喹的血清水平；（2）使用CT/MRI扫描研究IDH突变癌症中肿瘤对二甲双胍加氯喹的反应；以及（3）肿瘤反应是否可以通过对肿瘤组织、血清、尿液和/或胆汁进行非侵入性2-HG测量（质谱和磁共振波谱）或循环肿瘤DNA（液体活检）的二代测序来衡量。本研究可能通过重新利用两种已被批准用于其他适应症的廉价药物的组合，为IDH突变的高级别软骨肉瘤、胶质瘤和肝内胆管癌开辟一条新的治疗途径。
本研究已获得荷兰阿姆斯特丹学术医疗中心医学伦理审查委员会的批准。报告将提交给同行评审期刊。
本文已在ClinicalTrials.gov上注册，标识符为（NCT02496741）：预结果。
