A Phase Ib Clinical Trial of Metformin and Chloroquine in Patients with IDH1-Mutated Solid Tumors.

Mohammed Khurshed,Tom Van Wezel,Remco J Molenaar,Eduard A Struys,Cornelis J F Van Noorden,Johanna W Wilmink,Myra E Van Linde,Ron A Mathôt,Judith V M G Bovée,Heinz-Josef Klümpen

doi:10.3390/cancers13102474

Mohammed Khurshed, Tom Van Wezel + Show 8 more

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https://doi.org/10.3390/cancers13102474

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Abstract

Simple SummaryMutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in high-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma. Due to the lack of effective treatment options, these aggressive types of cancer have a dismal outcome. The metabolism of IDH1-mutated cancer cells is reprogrammed in order to produce the oncometabolite D-2-hydroxyglutarate (D-2HG). In this clinical trial, we used the oral antidiabetic drug metformin and the oral antimalarial drug chloroquine to disrupt the vulnerable metabolism of IDH1-mutated solid tumors. We found that the combination regimen of metformin and chloroquine is well tolerated, but the combination did not induce a clinical response in this patient population. Secondly, we confirmed the clinical usefulness of D/L-2HG ratios in serum as a biomarker and the ddPCR-facilitated detection of an IDH1 mutation in circulating DNA from peripheral blood.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.

Highlights

Somatic heterozygous mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 occur in up to 60% of central conventional chondrosarcoma, 80% of WHO grade II–IV glioma, 20% of intrahepatic cholangiocarcinoma and 10% of acute myeloid leukemias (AML) [1]
The high rate of 53% of the patients with an IDH1 mutation in the pre-screened group is an exaggeration of the true prevalence of the IDH1 mutation, since patients with IDH1/2 mutation were referred to enroll in the study
The rationale of using metformin and chloroquine in order to disrupt the metabolism of IDH1-mutated solid tumors and to inhibit tumor growth was not supported by our clinical data, since ten out of twelve patients showed tumor progression during study treatment

Summary

Introduction

Somatic heterozygous mutations in IDH1 and IDH2 occur in up to 60% of central conventional chondrosarcoma, 80% of WHO grade II–IV glioma, 20% of intrahepatic cholangiocarcinoma and 10% of acute myeloid leukemias (AML) [1]. Appreciation of the causative role of IDH1/2 mutations in oncogenesis led to the development of the IDH1-mutation inhibitor agent ivosidenib (AG-120) [7] and the IDH2-mutation inhibitor enasidenib (AG-221) Both are FDA-approved for the treatment of relapsed or refractory. Mutations in isocitrate dehydrogenase 1 (IDH1) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. Methods: Patients with IDH1-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma received oral combinational treatment with the antidiabetic drug metformin and the antimalarial drug chloroquine.

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