| Title: | A phase Ib clinical trial of metformin and chloroquine in patients with IDH1-mutated solid tumors |
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| 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) |
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| Files: |  URL - Source URL, visit https://www.mdpi.com/2072-6694/13/10/2474
 PDF - Presentation file, download (3,11 MB)
MD5: 30853BE4A98387F63009427B6A5F9665
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| Language: | English |
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| Typology: | 1.01 - Original Scientific Article |
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| Organization: |  NIB - National Institute of Biology
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| 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. |
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| Keywords: | metformin, chloroquine, cancer, isocitrate dehydrogenase, pharmacokinetics, glioblastoma, intrahepatic cholangiocarcinoma, chondrosarcoma |
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| Publication status: | Published |
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| Publication version: | Version of Record |
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| Publication date: | 19.05.2021 |
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| Year of publishing: | 2021 |
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| Number of pages: | str. 1-16 |
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| Numbering: | Vol. 13, iss. 10 |
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| PID: | 20.500.12556/DiRROS-19451  |
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| UDC: | 577.2 |
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| ISSN on article: | 2072-6694 |
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| COBISS.SI-ID: | 97801987 |
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| Note: | Nasl. z nasl. zaslona;
Opis vira z dne 17. 2. 2022;
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| Publication date in DiRROS: | 19.07.2024 |
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| Views: | 284 |
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| Downloads: | 191 |
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