Administration of Repurposed Ketoconazole in Glioma Patients

Overview

This early phase 1 clinical trial tests whether ketoconazole, an antifungal drug, can penetrate primary glioma brain tumors through the blood-brain barrier at levels sufficient to disrupt tumor growth, based on preclinical studies targeting glucose metabolism. Gliomas, especially aggressive high-grade types (WHO grades III-IV), have limited treatments like surgery, radiation, or chemotherapy. Patients with low- or high-grade gliomas will receive single or repeated low doses of ketoconazole before scheduled surgery, tailored to their health and procedure timing. During surgery, drug levels will be measured in tumor tissue and plasma. Results will guide future trials exploring azole drugs as glioma therapies.

Gliomas, particularly high-grade variants like glioblastoma multiforme (WHO grade IV), represent a major challenge in neuro-oncology, comprising over 50% of gliomas and 17% of all primary brain tumors with an incidence of 5 per 100,000. These tumors exhibit marked intra-tumoral heterogeneity, aggressive angiogenesis, and reliance on aerobic glycolysis-converting glucose to lactate irrespective of oxygen levels-to fuel proliferation, invasion, and survival despite maximal safe resection followed by temozolomide-radiotherapy (Stupp protocol), which yields median survival of only 14.6 months. Preclinical models of high-grade glioma (HGG) have demonstrated ketoconazole's disruption of this metabolic vulnerability by inhibiting hexokinase 2 (HK2), thereby curtailing glycolysis, promoting apoptosis, and curbing angiogenesis-effects achieved at pharmacologically safe doses without reliance on novel agents that struggle against the blood-brain barrier (BBB). Yet, critical gaps persist: ketoconazole's penetration into plasma and glioma tissue (both low- and high-grade) remains undocumented, precluding translation to efficacy trials amid BBB limitations that undermine many repurposed cancer therapies. This early phase 1 trial addresses these uncertainties in primary gliomas through individualised pre-surgical dosing (single or repeated low doses) tailored to patient status and operative timing-followed by direct intra-operative sampling of tumor tissue and plasma for ketoconazole quantification. By quantifying ketoconazole concentrations directly in tumor tissue and plasma across all grade of gliomas, this early phase 1 trial determines achievable drug exposure levels and informs safe, effective dosing for subsequent efficacy studies.