A Phase 0 Clinical Trial to Evaluate the Neuro-Pharmacological Profile of Posaconazole for Glioblastoma
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ID: 319487
2026
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Abstract
Abstract Background Glioblastoma (GBM) is the most common malignant primary brain tumor and is associated with a poor prognosis. Repurposed posaconazole (PCZ) has demonstrated efficacy in vitro by targeting key metabolic pathways. The aim of this study was to determine the neuro-pharmacological profile of PCZ in patients with GBM through a Phase 0 first-in-human trial for this indication (NCT04825275). Methods We conducted an open-label, non-randomized, parallel-arm trial in participants with primary or recurrent GBM. Patients in the treatment arm received oral PCZ for 7–10 days presurgically to achieve steady-state concentrations. Microdialysis catheters were implanted to measure interstitial drug levels. Postoperative tissue and fluid samples were analyzed to evaluate PCZ pharmacokinetics (mass spectrometry) and pharmacodynamics, including vascular density, apoptosis, and metabolite concentrations (lactate and pyruvate) compared to controls. Results The trial was closed early due to slow accrual, enrolling two participants in the PCZ arm and three in the control arm. No drug-related safety issues were observed. Although PCZ was undetectable in microdialysate fluid, it accumulated in tumor tissue, with concentrations showing an association with CD31-measured endothelial content. PCZ-treated tumors exhibited trends toward lower BCL2 expression indicative of increased apoptosis, and significantly lower pyruvate levels in the tumor periphery compared to controls. Plasma lactate levels in treated patients normalized to control levels over 24 hours. Conclusions Despite limited accrual, this trial provides the first clinical evidence that oral PCZ accumulates in human GBM tissue and shows preliminary signals of metabolic modulation. These findings provide biological rationale warranting further clinical investigation, potentially utilizing direct tissue sampling rather than microdialysis.
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| Authors | Alireza Mansouri, Leonardo De Macedo Filho, Emily Tufano, Harrison Laukhuff, Brad Zacharia, Jeffrey Neighbors, Michele Green, Nicole Derosia, Dongxiao Sun, Debarati Bhanja, Kyle Tuohy, J F Connor, Dawit Aregawi, Michael Glantz, Gelareh Zadeh |
| Journal | Neuro-Oncology Advances |
| Year | 2026 |
| DOI |
10.1093/noajnl/vdag174
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| URL | |
| Keywords | Keywords not found |
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