Friday, May 9, 2025
5/9/2025
Neuro-pharmacological Properties of Repurposed Posaconazole in Glioblastoma: A Phase 0 Clinical Trial - Project Summary Background: We have used high-throughput drug screening to identify posaconazole (PCZ) as a repurposed drug that can inhibit high grade glioma tumor cell growth, attributable to inhibition of hexokinase 2 enzyme (HK2)-mediated pathways. HK2 is typically up-regulated in high-grade gliomas (HGGs) but not normal human astrocytes. In further pre-clinical in vitro and in vivo studies, we have shown that PCZ can down-regulate glycolysis, reduce angiogenesis, and induce HGG tumor cell apoptosis. Objectives: Our primary objective is to establish tumor tissue penetrance by PCZ, following preoperative steady-state oral dosing. Our secondary objectives are to establish its neuro- pharmacokinetics and pharmacodynamic profile. Methods: This will be a single-center, Phase 0, proof-of-concept study. Five eligible and evaluable participants, suspected of having HGGs and requiring surgical resection on a non-emergent basis, will be enrolled for preoperative PCZ administration. Five control subjects will also be enrolled. To achieve steady-state dosing, at least 5 half-lives of drug are needed. PCZ dosing will be 300mg PO BID on the first day, followed by 300mg PO daily, beginning 168-240 hours before scheduled surgery. Control subjects will receive no drug. Surgical samples, along with blood samples, will be taken for analysis from both contrast-enhancing and non-enhancing regions. 1-2 microdialysis catheters will then be inserted into the tumor resection boundary. After administering the last dose of drug the morning after surgery, collection of dialysate fluid and arterial blood will immediately begin (Time 0). Additional samples will be collected at 15 and 30 minutes, along with 1, 2, 4, 6, 8, 18, and 24 hours after ‘Time 0’. Control subjects will also have catheters implanted for measurement of lactate and pyruvate. Mass spectrometry will be used to assess for concentration of drug, lactate, and pyruvate in tumor tissue, dialysate fluid, and blood. HK2 activity assay, TUNEL staining, and Ki67 index will be used to study pharmacodynamics. Long-term objectives and potential impact: Demonstration of PCZ accumulation of ≥500ng/g of tumor tissue in ≥2 of 5 participants would warrant further investigation into its role in HGGs. Evidence of associated anti-tumor effect would warrant a Phase II trial to assess tumor response and survival, while signal for biological effect in a sub-set of patients but lower than expected intra-tumoral drug concentrations would warrant a Phase I dose-escalation trial. Establishment of the neuro-pharmacokinetic parameters of PCZ in individuals with HGGs would provide valuable information toward the design of either a Phase I or Phase II trial.
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