{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T13:12:04Z","timestamp":1783775524869,"version":"3.55.0"},"reference-count":72,"publisher":"BMJ","issue":"6","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2017,3,3]]},"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>IDH1<\/jats:italic>\n                      and\n                      <jats:italic>IDH2<\/jats:italic>\n                      (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II\u2013IV glioma and 20% of intrahepatic cholangiocarcinoma.\n                      <jats:italic>IDH1\/2<\/jats:italic>\n                      -mutated cancer cells produce the oncometabolite\n                      <jats:italic>D<\/jats:italic>\n                      -2-hydroxyglutarate (\n                      <jats:italic>D<\/jats:italic>\n                      -2HG) and are metabolically vulnerable to treatment with the oral antidiabetic metformin and the oral antimalarial drug chloroquine.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>\n                      We describe a dose-finding phase Ib\/II clinical trial, in which patients with\n                      <jats:italic>IDH1\/2<\/jats:italic>\n                      -mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma are treated with a combination of metformin and chloroquine. Dose escalation is performed according to a 3+3\u2009dose-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\n                      <jats:italic>IDH1\/2<\/jats:italic>\n                      -mutated cancers using CT\/MRI scans; and (3) whether tumour responses can be measured by non-invasive\n                      <jats:italic>D<\/jats:italic>\n                      -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\n                      <jats:italic>IDH1\/2<\/jats:italic>\n                      -mutated high-grade chondrosarcoma, glioma and intrahepatic cholangiocarcinoma by repurposing the combination of two inexpensive drugs that are already approved for other indications.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      This article was registered at ClinicalTrials.gov identifier (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT02496741\">NCT02496741<\/jats:ext-link>\n                      ): Pre-results.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2016-014961","type":"journal-article","created":{"date-parts":[[2017,6,10]],"date-time":"2017-06-10T20:10:17Z","timestamp":1497125417000},"page":"e014961","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":74,"title":["Study protocol of a phase IB\/II clinical trial of metformin and chloroquine in patients with\n           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