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Title:A phase Ib clinical trial of metformin and chloroquine in patients with IDH1-mutated solid tumors
Authors:ID Khurshed, Mohammed (Author)
ID Molenaar, Remco J. (Author)
ID Linde, Myra E van (Author)
ID Mathôt, Ron A (Author)
ID Struys, Eduard A. (Author)
ID Wezel, Tom van (Author)
ID Noorden, Cornelis J. F. van (Author)
ID Klümpen, Heinz-Josef (Author)
ID Bovée, Judith V. M. G. (Author)
ID Wilmink, Johanna W (Author)
Files:URL URL - Source URL, visit https://www.mdpi.com/2072-6694/13/10/2474
 
.pdf PDF - Presentation file, download (3,11 MB)
MD5: 30853BE4A98387F63009427B6A5F9665
 
Language:English
Typology:1.01 - Original Scientific Article
Organization:Logo NIB - National Institute of Biology
Abstract:Background: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. These solid IDH1-mutated tumors produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are more vulnerable to disruption of their metabolism. Methods: Patients with IDH1-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma received oral combinational treatment with the antidiabetic drug metformin and the antimalarial drug chloroquine. The primary objective was to determine the occurrence of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD). Radiological and biochemical tumor responses to metformin and chloroquine were investigated using CT/MRI scans and magnetic resonance spectroscopy (MRS) measurements of D-2HG levels in serum. Results: Seventeen patients received study treatment for a median duration of 43 days (range: 7–74 days). Of twelve evaluable patients, 10 patients discontinued study medication because of progressive disease and two patients due to toxicity. None of the patients experienced a DLT. The MTD was determined to be 1500 mg of metformin two times a day and 200 mg of chloroquine once a day. A serum D/L-2HG ratio of ≥4.5 predicted the presence of an IDH1 mutation with a sensitivity of 90% and a specificity of 100%. By utilization of digital droplet PCR on plasma samples, we were able to detect tumor-specific IDH1 hotspot mutations in circulating tumor DNA (ctDNA) in investigated patients. Conclusion: Treatment of advanced IDH1-mutated solid tumors with metformin and chloroquine was well tolerated but did not induce a clinical response in this phase Ib clinical trial.
Keywords:metformin, chloroquine, cancer, isocitrate dehydrogenase, pharmacokinetics, glioblastoma, intrahepatic cholangiocarcinoma, chondrosarcoma
Publication status:Published
Publication version:Version of Record
Publication date:19.05.2021
Year of publishing:2021
Number of pages:str. 1-16
Numbering:Vol. 13, iss. 10
PID:20.500.12556/DiRROS-19451 New window
UDC:577.2
ISSN on article:2072-6694
COBISS.SI-ID:97801987 New window
Note:Nasl. z nasl. zaslona; Opis vira z dne 17. 2. 2022;
Publication date in DiRROS:19.07.2024
Views:445
Downloads:280
Metadata:XML DC-XML DC-RDF
:
KHURSHED, Mohammed, MOLENAAR, Remco J., LINDE, Myra E van, MATHÔT, Ron A, STRUYS, Eduard A., WEZEL, Tom van, NOORDEN, Cornelis J. F. van, KLÜMPEN, Heinz-Josef, BOVÉE, Judith V. M. G. and WILMINK, Johanna W, 2021, A phase Ib clinical trial of metformin and chloroquine in patients with IDH1-mutated solid tumors. Cancers [online]. 2021. Vol. 13, no. 10, p. 1–16. [Accessed 10 April 2025]. Retrieved from: https://dirros.openscience.si/IzpisGradiva.php?lang=eng&id=19451
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Record is a part of a journal

Title:Cancers
Shortened title:Cancers
Publisher:MDPI
ISSN:2072-6694
COBISS.SI-ID:517914137 New window

Document is financed by a project

Funder:SNSF - Swiss National Science Foundation
Project number:10460
Name:Soziale Situation, sozialmedizinische Orientierungen und Inanspruchnahme medizinischer Dienstleistungen
Funder:ARIS - Slovenian Research and Innovation Agency
Project number:J3-2526-2020
Name:Razkrivanje niše matičnih glioma celic v iskanju novih terapevtskih ciljev pri bolnikih z glioblastomom
Funder:Other - Other funder or multiple funders
Funding programme:Academic Medical Center
Name:PhD Scholarship
Funder:Other - Other funder or multiple funders
Project number:KWF grant 10460

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License:CC BY 4.0, Creative Commons Attribution 4.0 International
Link:http://creativecommons.org/licenses/by/4.0/
Description:This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

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