A phase Ib clinical trial of metformin and chloroquine in patients with IDH1-mutated solid tumorsKhurshed, Mohammed (Avtor) Molenaar, Remco J. (Avtor) Linde, Myra E van (Avtor) Mathôt, Ron A (Avtor) Struys, Eduard A. (Avtor) Wezel, Tom van (Avtor) Noorden, Cornelis J. F. van (Avtor) Klümpen, Heinz-Josef (Avtor) Bovée, Judith V. M. G. (Avtor) Wilmink, Johanna W (Avtor) metforminchloroquinecancerisocitrate dehydrogenasepharmacokineticsglioblastomaintrahepatic cholangiocarcinomachondrosarcomaBackground: 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.20212024-07-18 03:50:19Neznano19451sl