Neuro-pharmacological Properties of Repurposed Posaconazole in Glioblastoma: A Phase 0 Clinical Trial

This research is being done to find out if the study drug (posaconazole) can enter brain tumors at a high enough amount to stop the tumor cells from dividing. Posaconazole is a drug which doctors already use for fungal infections and is thought to be able to effect tumor cells. As treatments for this type of brain tumor are limited, it is hoped that the results of this study will help to determine if the study drug should be studied further as a possible treatment.

Study Overview

• Status: Terminated
• Conditions: Glioblastoma; Glioblastoma Multiforme; Glioblastoma Multiforme, Adult; Glioblastoma Multiforme of Brain
• Intervention / Treatment: Drug: Posaconazole Pill

Detailed Description

Both ketoconazole and posaconazole are FDA-approved anti-fungal agents with a well-established side effect and safety profile. Ketoconazole and posaconazole have shown efficacy in reducing tumor cell proliferation in in-vitro studies. Furthermore, both have also shown efficacy, mediated at least in part through inhibition of HK2 activity, in animal models with dosing concentration and schedules that are documented as safe in humans. As a drug, posaconazole has a more predictable half-life than ketoconazole and has less off-target effects. Therefore, the proposed trial will focus on the role of posaconazole exclusively. As a first step, demonstration of adequate penetrance of study drug in brain and tumor tissue (pharmacokinetics) and biological effect (inhibition of glycolysis and subsequent tumor cell death) is necessary prior to large scale clinical studies. A total of 5 control participants will be included in this study as the investigator specifically wants to assess for pharmacodynamic differences too. The addition of a control group to this study rather to both the studies (ketoconazole study is a separate protocol) is because the investigator feels posaconazole may be a more promising drug for moving forward.

Plasma drug concentration measurements are an unreliable method to assess delivery of drugs across the blood-brain barrier. In contrast, intracerebral MDC monitoring allows for approximate measurements within extracellular fluid (ECF) sampling of the brain. MDC placement within the brain is not a novel technique and has been utilized routinely in the ICU setting to measure brain metabolism by sampling of ECF of traumatic brain injury patients [59-61].

MDC are now FDA-approved and are being placed routinely with intracranial pressure monitors. This method allows for continuous measurement of ECF within a tumor or normal tissue. The dialysis probe has a semipermeable membrane which is less than 1 mm in diameter into which two sections of microcatheter are fused. Previous studies have demonstrated the feasibility of keeping the catheters in place of critically injured patients for up to 2 weeks [62-64].

When placed at the time of surgical resection, the microcatheters are stereotactically implanted, placing the probe within the desired brain and/or tumor region. Externally, the catheter is connected to a syringe pump, which delivers a low flow rate (μl/min) of continuous perfusion fluid (Lactated Ringers or artificial CSF) and dialysate is collected in a microvial from the outlet tube. This sterile, single use catheter is minimally invasive and developed to achieve optimal diffusing characteristics similar to passive diffusion of a capillary blood vessel. Just as in the function of brain capillary vessel, water, inorganic ions and small organic molecules freely diffuse across the membrane of the probe, whereas proteins and protein bound compounds are impermeable. Additionally, lipophilic compounds are poorly recovered. Therefore, assessment of pharmacokinetics of drug using MDC provides valuable insight relevant to its anti-neoplastic properties.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S Hershey Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥18 years
• Evidence of primary or recurrent HGG that in the opinion of the treating team would require surgical resection
• Karnofsky Performance Score (KPS) ≥ 60%
• ECOG ≤ 2
• Life expectancy greater than 12 weeks
• Adequate liver function defined as ALT, AST, ALP within 1.5x institutional upper limit of normal (for study drug arm only)
• Ability to swallow medication (for study drug arm only)
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation (for study drug arm only)
• Ability to understand and willingness to sign a written informed consent document
• Be able to comply with treatment plan, study procedures and follow-up examinations

Exclusion Criteria:

• Patients may not be receiving any other investigational agents while on study
• Patients who have known allergy to posaconazole or other azoles (for study drug arm only)
• Patients who have previously had a severe side effect, such as agranulocytosis and neutropenia, in conjunction with previous azole class drugs for a parasitic infection (for study drug arm only)
• Patients with a history of acute or chronic hepatitis (for study drug arm only)
• Patients with liver enzymes (ALT, AST, ALP) >1.5x above normal range for the laboratory performing the test (for study drug arm only)
• Patients who are taking metronidazole and cannot be safely moved to a different antibiotic greater than 7 days prior to starting posaconazole therapy (for study drug arm only)
• Patients who are taking any anti-convulsant medication that interferes with the cytochrome P450 pathway (e.g. phenytoin, phenobarbital, carbamazepine, etc.) and who cannot be switched to alternative medications such as keppra (levetiracetam) (for study drug arm only)
• Uncontrolled intercurrent illness such as chronic hepatitis, acute hepatitis, or psychiatric illness/social situation that would limit compliance with study requirements (for study drug arm only)
• Patients with a history of Addison's disease or other forms of adrenal insufficiency (for study drug arm only)
• Patient with little or no stomach acid production (achlorhydria) (for study drug arm only)
• Pregnant and breast feeding women)
• Patients with a history of any medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risks associated with the study participation or investigational product administration or may interfere with the interpretation of the results.
• Patients who are not available for follow-up assessments or unable to comply with study requirements.
• Patients who are currently taking medications that induce the metabolism of posaconazole, such as isoniazid, nevirapine, rifamycins (such as rifabutin, rifampin), or St. John's wort and cannot be safely discontinued off of them for the duration of the trial (for study drug arm only).
• Patients who are currently taking medications for which the metabolism may be affected by posaconazole, which include but are not limited to: benzodiazepines (such as alprazolam, midazolam, triazolam), domperidone, eletriptan, eplerenone, ergot drugs (such as ergotamine), nisoldipine, drugs used to treat erectile dysfunction-ED or pulmonary hypertension (such as sildenafil, tadalafil), some drugs used to treat seizures (such as carbamazepine, phenytoin), some statin drugs (such as atorvastatin, lovastatin, simvastatin) (for study drug arm only).
• Patients who are non-English speakers
• Patients who are not capable of understanding the consent form and would need a legally authorized representative.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Posaconazole; Participants will be taking 300 mg of the study drug (three 100 mg tablets) by mouth twice a day the first day and then 300 mg once a day until the day of biopsy or surgery. On the day of biopsy or surgery, participants will take their medication the morning of their biopsy or surgery (before the operation). Participants will then take the last dose of the medication in the morning of the day after their biopsy or surgery. Participants will be given 12 days' worth of the study drug (pills) and verbally instructed how and when to take them.	Drug: Posaconazole Pill; 300 mg (three 100 mg tablets) orally; Other Names: Noxafil
No Intervention: Control; Participants will not undergo any intervention.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Posaconazole Concentration in Cerebrospinal Fluid Using Microdialysis Catheters	Assessment of the concentration of drug in the dialysate fluid.	Collected over a 24-hour period after surgery (biopsy or resection)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Able to Tolerate Preoperative Steady-state Dosing of Posaconazole	Measured through the Grade and Frequency of adverse events, based on the CTCAE v5.0 criteria	from Baseline to Visit 7 (14 days +/- 7 days post-op)
Posaconazole Effect on Hexokinase 2 Concentration Within Tumor Tissue	Measured using a hexokinase-2 ELISA with a range of 1.56 ng/mL - 100 ng/mL on tumor tissue.	Within 24 hours after biopsy or tumor resection
Posaconazole Effect on Tumor Proliferation in Tumor Tissue	Measured using Ki-67 proliferation index with of a range of 0% proliferation (no proliferation) to 100% (high proliferation). Ki-67 is a marker found in actively dividing cells. A higher Ki-67 value may signify a more aggressive tumor. Ki-67 is routinely measured during pathology analysis of tumor samples.	Within 24 hours after biopsy or tumor resection
Posaconazole Effect on Cell Death in Tumor Tissue	Measured using a BCL-2 ELISA with a range of 0.156 ng/mL to 10 ng/mL.	Within 24 hours after biopsy or tumor resection
Posaconazole Effect on Angiogenesis in Tumor Tissue	Measured using a CD31 ELISA with a range of 31.2 pg/mL to 2000 pg/mL.	Within 24 hours after biopsy or tumor resection
Correlation of Neuro-pharmacokinetic Profile of Posaconazole With Lactate Concentration	The concentration vs. time profile of posaconazole will be correlated with the concentration vs. time profile of lactate in the cerebrospinal fluid.	Collected over a 24-hour period after surgery (biopsy or resection)
Correlation of Neuro-pharmacokinetic Profile of Posaconazole With Pyruvate Concentration	The concentration vs. time profile of posaconazole will be correlated with the concentration vs. time profile of pyruvate in the cerebrospinal fluid.	Collected over a 24-hour period after surgery (biopsy or resection)

Collaborators and Investigators

• Sponsor: Milton S. Hershey Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Alireza Mansouri, MD, Milton S. Hershey Medical Center

Publications and helpful links

General Publications

• Bhanja D, Neighbors J, Connor J, Zadeh G, Mansouri A. Neuropharmacological Study of Posaconazole for Glioblastoma: A Phase 0 Clinical Trial Protocol. Neurosurgery. 2022 Oct 1;91(4):658-665. doi: 10.1227/neu.0000000000002071. Epub 2022 Jul 25.

Study record dates

Study Major Dates

• Study Start (Actual): May 13, 2022
• Primary Completion (Actual): November 6, 2024
• Study Completion (Actual): November 6, 2024

Study Registration Dates

• First Submitted: March 25, 2021
• First Submitted That Met QC Criteria: March 27, 2021
• First Posted (Actual): April 1, 2021

Study Record Updates

• Last Update Posted (Actual): January 23, 2026
• Last Update Submitted That Met QC Criteria: January 5, 2026
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Glioblastoma Multiforme; GBM; Posaconazole; Glioblastoma; Brain cancer; Anti-fungal agents
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Central Nervous System Neoplasms; Glioblastoma; Brain Neoplasms; Anti-Infective Agents; Antifungal Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Enzyme Inhibitors; Steroid Synthesis Inhibitors; Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; 14-alpha Demethylase Inhibitors; Trypanocidal Agents; posaconazole
• Other Study ID Numbers: STUDY00015948; 1R03CA255992-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No