Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours

Remco J Molenaar, Robert J S Coelen, Mohammed Khurshed, Eva Roos, Matthan W A Caan, Myra E van Linde, Mathilde Kouwenhoven, Jos A M Bramer, Judith V M G Bovée, Ron A Mathôt, Heinz-Josef Klümpen, Hanneke W M van Laarhoven, Cornelis J F van Noorden, W Peter Vandertop, Hans Gelderblom, Thomas M van Gulik, Johanna W Wilmink, Remco J Molenaar, Robert J S Coelen, Mohammed Khurshed, Eva Roos, Matthan W A Caan, Myra E van Linde, Mathilde Kouwenhoven, Jos A M Bramer, Judith V M G Bovée, Ron A Mathôt, Heinz-Josef Klümpen, Hanneke W M van Laarhoven, Cornelis J F van Noorden, W Peter Vandertop, Hans Gelderblom, Thomas M van Gulik, Johanna W Wilmink

Abstract

Introduction: 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 IDH1 and IDH2 (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. IDH1/2-mutated cancer cells produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are metabolically vulnerable to treatment with the oral antidiabetic metformin and the oral antimalarial drug chloroquine.

Methods and analysis: We describe a dose-finding phase Ib/II clinical trial, in which patients with IDH1/2-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma are treated with a combination of metformin and chloroquine. Dose escalation is performed according to a 3+3 dose-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 IDH1/2-mutated cancers using CT/MRI scans; and (3) whether tumour responses can be measured by non-invasive D-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 IDH1/2-mutated high-grade chondrosarcoma, glioma and intrahepatic cholangiocarcinoma by repurposing the combination of two inexpensive drugs that are already approved for other indications.

Ethics and dissemination: 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.

Trial registration number: This article was registered at ClinicalTrials.gov identifier (NCT02496741): Pre-results.

Keywords: Adult oncology; Clinical trials; Hepatobiliary tumours; Magnetic resonance imaging; Neurological oncology; Sarcoma.

Conflict of interest statement

Competing interests: None declared.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

Figure 1
Figure 1
Cellular carbohydrate and glutamine metabolism showing the pathways in which wild-type IDH1 and IDH2 are functional. Isocitrate dehydrogenase 1, 2 and 3 (IDH1/2/3) catalyse the conversion of isocitrate to α-ketoglutarate (αKG) in the cytoplasm and mitochondria, respectively, where IDH1 and IDH2 are NADPH producing and IDH3 is NADH producing. This reaction occurs in tricarboxylic acid (TCA) cycle(-like) metabolism and is fed by glucose influx and/or glutamine influx. The conversion of glutamine into αKG occurs in the glutaminolysis pathway and the last step is catalysed by glutamate dehydrogenase (GDH), which is inhibited by chloroquine and metformin. The TCA cycle produces NADH, which is used in the electron transport chain (ETC) and oxidative phosphorylation to generate ATP. Complex I of the ETC is inhibited by metformin. Wild-type IDH1/2 (IDH1/2WT) differs from mutant IDH1/2 (IDH1/2MUT) because the latter enzyme converts αKG into a novel oncometabolite, D-2-hydroxyglutarate (D-2HG). CoA, coenzyme A; NADPH, nicotinamide adenine dinucleotide phosphate.
Figure 2
Figure 2
Dosing schedule and study design for patients who will not undergo tumour resection. D-2HG, D-2-hydroxyglutarate; IHC, immunohistochemistry; MRS, magnetic resonance spectroscopy; MS, mass spectrometry; NGS, next-generation sequencing; q.d., once a day.
Figure 3
Figure 3
Dosing schedule and study design for patients who have a tumour resection planned. Surgery will define the end of this time schedule (2 days before surgery). D-2HG, D-2-hydroxyglutarate; IHC, immunohistochemistry; MRS, magnetic resonance spectroscopy; MS, mass spectrometry; NGS, next-generation sequencing; q.d., once a day.

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