Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours
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…
How strong is the evidence?
Evidence Hub reads this as a clinical trial, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence.
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