Administration of Repurposed Ketoconazole in Glioma Patients

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.

Inclusion criteria

• Participants aged 18 years or older.
• Radiological confirmation of an intra-axial primary brain tumor (all grades) requiring surgical intervention.
• Karnofsky Performance Status (KPS) of ≥60 and projected life expectancy exceeding 12 weeks.
• Normal liver function, indicated by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels within 1.5x the upper limit of normal (ULN).
• Normal renal function, defined as urea within 16.6-48.5 mg/dL, creatinine within 0.67-1.17 mg/dL, and/or eGFR ≥90 (within 1.5x the institutional ULN) .
• Capacity to take oral medications.
• Women of reproductive age and all male participants must commit to effective contraception (e.g., hormonal methods) throughout the trial.
• Willingness and ability to provide written informed consent.
• Commitment to adhere to the protocol, including treatment, procedures, and scheduled follow-ups.

Exclusion criteria

• Known hypersensitivity to ketoconazole.
• Prior severe reactions (e.g., agranulocytosis, neutropenia) to ketoconazole or other azole antifungals used for parasitic conditions.
• History of acute or chronic hepatitis.
• Elevated liver enzymes (ALT, AST) or impaired renal function (urea, creatinine, eGFR) exceeding 1.5x ULN per local lab standards.
• Current use of metronidazole without ability to switch to an alternative antibiotic at least 7 days prior to ketoconazole initiation.
• Azole antifungal use within the preceding 3 months.
• Pregnancy or breastfeeding.
• Any coexisting medical, psychiatric, or lab abnormality that, per investigator judgment, heightens study risks or confounds data interpretation.
• Unavailability for follow-up or inability to fulfill protocol demands.
• Concurrent use of ketoconazole metabolic inducers (e.g., isoniazid, nevirapine, rifampin, rifabutin) without discontinuation option.