Glioma, intrahepatic cholangiocarcinoma (IHCC) and chondrosarcoma (CS) are aggressive, malignant cancers with a dismal outcome, the two latter types especially in the locally-advanced or metastasized setting. This is due to a lack of effective treatment strategies and highlights the dire need for novel therapies.~A subset of these cancer types are characterized by the presence of mutations in the genes encoding for isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2). These mutations occur in 80% of world health organization (WHO) grade II and III glioma and secondary glioblastoma, 20% of IHCC and 60% of CS and, besides their oncogenic function, induce metabolic vulnerabilities to IDH1/2MT cancer cells that can be exploited in vitro by the oral antidiabetic metformin and the oral antimalarial drug chloroquine.~In the present study protocol, the investigators describe a phase Ib single-center clinical trial in which patients with glioma, IHCC or CS are being screened for IDH1/2MT using the surrogate marker D-2-hydroxyglutarate (D-2HG), which is exclusively produced in IDH1/2MT cancers, or DNA sequencing of tumor material. Eligible IDH1/2MT patients are then treated with a combination of metformin and chloroquine.~The study protocol uses a 3+3 dose-escalation scheme. The primary objective is to determine the maximum tolerated dose in order to establish a recommended dose for a phase II trial. Secondary objectives of the study include (1) to investigate the pharmacokinetics of the combination therapy of metformin plus chloroquine, (2) whether or not IDH1/2MT status can be determined by magnetic resonance spectroscopy and/or mass spectrometry of the serum, urine and/or bile or next-generation sequencing of circulating tumor DNA in glioma, IHCC or CS patients and to (3) investigate the tumor response and D-2HG concentration response to metformin plus chloroquine in IDH1/2MT cancers.~This study may open a novel treatment avenue for IDH1/2MT glioma, IHCC and CS by investigating two relatively safe drugs for these highly malignant tumors. In addition, this study may present novel therapies for other cancers that are regularly affected by IDH1/2MT, such as acute myeloid leukemia, acute lymphocytic leukemia and T-cell lymphoma.
This phase Ib, open-label, single-center, non-randomized clinical trial will evaluate the toxicity and efficacy of metformin and chloroquine in isocitrate dehydrogenase 1/2-mutated (IDH1/2MT) patients with a glioma, intrahepatic cholangiocarcinoma or chondrosarcoma.