Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Khurshed M

PROVIDER: S-EPMC8161333 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Publications

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

Khurshed Mohammed M Molenaar Remco J RJ van Linde Myra E ME Mathôt Ron A RA Struys Eduard A EA van Wezel Tom T van Noorden Cornelis J F CJF Klümpen Heinz-Josef HJ Bovée Judith V M G JVMG Wilmink Johanna W JW

Cancers 20210519 10

<h4>Background</h4>Mutations in isocitrate dehydrogenase 1 (<i>IDH1</i>) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. These solid <i>IDH1</i>-mutated tumors produce the oncometabolite <i>D</i>-2-hydroxyglutarate (<i>D</i>-2HG) and are more vulnerable to disruption of their metabolism.<h4>Methods</h4>Patients with <i>IDH1</i>-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma received oral combinational treatment with th ...[more]

PMID: 34069550

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