Neuro-pharmacological Study of Posaconazole for High-grade Gliomas: A Phase 0 Clinical Trial
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|ClinicalTrials.gov Identifier: NCT04825275|
Recruitment Status : Not yet recruiting
First Posted : April 1, 2021
Last Update Posted : September 14, 2021
|Condition or disease||Intervention/treatment||Phase|
|Glioblastoma Glioblastoma Multiforme Glioblastoma Multiforme of Brain Glioblastoma Multiforme, Adult||Drug: Posaconazole Pill||Early Phase 1|
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 (Clinical Trial)|
|Estimated Enrollment :||10 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Neuro-pharmacological Study of Posaconazole for High-grade Gliomas: A Phase 0 Clinical Trial|
|Estimated Study Start Date :||October 2021|
|Estimated Primary Completion Date :||May 2023|
|Estimated Study Completion Date :||May 2023|
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 Name: Noxafil
No Intervention: Control
Participants will not undergo any intervention.
- Establish the neuro-pharmacokinetic profile of posaconazole, using microdialysis catheters [ Time Frame: Collected over a 24-hour period after surgery (biopsy or resection) ]Assessment of the concentration versus time curves of drug in the dialysate fluid
- Evaluate tolerability of preoperative steady-state dosing of Posaconazole [ Time Frame: from Baseline to Visit 7 (14 days +/- 7 days post-op) ]Measured through the Grade and Frequency of adverse events, based on the CTCAE v5.0 criteria
- Evaluate posaconazole effect on Hexokinase 2 activity within tumor tissue [ Time Frame: Within 24 hours after biopsy or tumor resection ]Measured using a hexokinase assay on tumor tissue
- Evaluate posaconazole on tumor proliferation in tumor tissue [ Time Frame: Within 24 hours after biopsy or tumor resection ]Measured using Ki-67 proliferation index
- Evaluate posaconazole on cell death in tumor tissue [ Time Frame: Within 24 hours after biopsy or tumor resection ]Measured using TUNEL staining
- Evaluate posaconazole angiogenesis in tumor tissue [ Time Frame: Within 24 hours after biopsy or tumor resection ]Based on expression of VEGF
- Correlation of posaconazole pharmacokinetic profile with that of lactate using MDC [ Time Frame: Over the same 24-hour period used to measure the concentration of drug ]Assessed based on the concentration versus time profile of lactate in the dialysate fluid
- Correlation of posaconazole pharmacokinetic profile with that of pyruvate using MDC [ Time Frame: Over the same 24-hour period used to measure the concentration of drug ]Assessed based on the concentration versus time profile of pyruvate in the dialysate fluid
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04825275
|Contact: Kirsten Shuler, MSc||717-531-0003 Ext. firstname.lastname@example.org|
|Contact: John M Graybealemail@example.com|
|United States, Pennsylvania|
|Penn State Milton S Hershey Medical Center|
|Hershey, Pennsylvania, United States, 17033|
|Contact: Alireza M Mansouri 437-215-1000 firstname.lastname@example.org|
|Principal Investigator:||Alireza Mansouri, MD||Milton S. Hershey Medical Center|