Azoles Targeting Recurrent High Grade Gliomas
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ClinicalTrials.gov Identifier: NCT03763396 |
Recruitment Status :
Active, not recruiting
First Posted : December 4, 2018
Last Update Posted : April 1, 2021
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Condition or disease | Intervention/treatment | Phase |
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Brain Tumor, Recurrent Cancer, Advanced Glioma of Brain | Drug: Ketoconazole (KCZ) Drug: Posaconazole (PCZ) | Early Phase 1 |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 30 participants |
Allocation: | Non-Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Other |
Official Title: | A Phase 0 Clinical Trial of Two Candidate Azoles (Ketoconazole and Posaconazole) for Patients With Recurrent High Grade Glioma |
Actual Study Start Date : | August 1, 2019 |
Estimated Primary Completion Date : | August 2022 |
Estimated Study Completion Date : | August 2022 |

Arm | Intervention/treatment |
---|---|
Experimental: Ketoconazole (KCZ) Single Dose Group
Single dose 400mg oral tablets 4-24 hours prior to surgery
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Drug: Ketoconazole (KCZ)
Oral Tablet |
Experimental: Ketoconazole (KCZ) Repeated Dose Group
400mg oral tablets twice a day (BID) for 2-5 days prior to surgery
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Drug: Ketoconazole (KCZ)
Oral Tablet |
Experimental: Posaconazole (PCZ) Single Dose group
Single dose 300 mg delayed release oral tablets 4-24 hours prior to surgery
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Drug: Posaconazole (PCZ)
Delayed Release Oral Tablet |
Experimental: Posaconazole (PCZ) Repeated Dose group
300 mg delayed release oral tablets twice a day (BID) for day 1; every day thereafter is a single dose of 300 mg delayed release oral tablets. Total treatment time is 7-10 days prior to surgery.
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Drug: Posaconazole (PCZ)
Delayed Release Oral Tablet |
- Intratumoral concentrations of KCZ or PCZ [ Time Frame: Following either single dose regimen(4-24hours prior to surgery) or repeated dose regimen of KCZ( for 2-5 days) or PCZ( for 7-10 days) ]
- Plasma concentrations of KCZ or PCZ [ Time Frame: Following either single dose regimen(4-24hours prior to surgery) or repeated dose regimen of KCZ(for 2-5 days) or PCZ(for 7-10 days) ]
- Assess Hexokinase 2 activity [ Time Frame: Following either single dose regimen(4-24hours prior to surgery) or repeated dose regimen of KCZ(for 2-5 days) or PCZ(for 7-10 days) compared to archive tumor tissue from baseline ]enzyme activity measured using optical absorbance with a spectrophotometer
- Assess the biological effects of KCZ or PCZ on metabolites within the glycolytic pathway [ Time Frame: Following either single dose regimen(4-24hours prior to surgery) or repeated dose regimen of KCZ(for 2-5 days) or PCZ(for 7-10 days) compared to archive tumor tissue from baseline ]quantify presence/absence of metabolites using mass spectrometry
- assess the biological effects of KCZ or PCZ on tumor proliferation [ Time Frame: Following either single dose regimen(4-24hours prior to surgery) or repeated dose regimen of KCZ(for 2-5 days) or PCZ(for 7-10 days) compared to archive tumor tissue from baseline ]measured using ki-67 proliferation index
- assess biological effects of KCZ or PCZ on tumor cell death [ Time Frame: Following either single dose regimen(4-24hours prior to surgery) or repeated dose regimen of KCZ(for 2-5 days) or PCZ(for 7-10 days) compared to archive tumor tissue from baseline ]measured using TUNEL staining
- assess biological effects of KCZ or PCZ on tumor angiogenesis [ Time Frame: Following either single dose regimen(4-24hours prior to surgery) or repeated dose regimen of KCZ(for 2-5 days) or PCZ(for 7-10 days) compared to archive tumor tissue from baseline ]measured using VEGF/CD-31 immunohistochemistry

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Age ≥18 years
- Evidence of recurrent HGG that in the opinion of the treating team does not represent pseudoprogression and 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, GGT, bilirubin within 1.5x institutional upper limit of normal
- Potassium, calcium, and magnesium within normal limits (PCZ cohort)
- Adequate renal function defined as eGFR levels within 1.5x the institutional upper limit of normal (only for KCZ cohort)
- Ability to swallow medication
- 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.
- 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:
- 1. Patients may not be receiving any other investigational agents while on study
- Patients who have known allergy to KCZ, PCZ, or other azoles
- 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
- Patients with a history of acute or chronic hepatitis
- Patients with liver enzymes (ALT, AST, ALP, GGT, Bilirubin) >1.5x above normal range for the laboratory performing the test
- ECG with QT > 450 msec (PCZ cohort)
- Patients taking drugs known to prolong the QT interval (PCZ cohort)
- Patients who are taking metronidazole and cannot be safely moved to a different antibiotic greater than 7 days prior to starting KCZ therapy
- Patients who have taken any azoles within the last 3 months
- 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)
- Uncontrolled intercurrent illness such as chronic hepatitis, acute hepatitis, or psychiatric illness/social situation that would limit compliance with study requirements
- Patients with a history of Addison's disease or other forms of adrenal insufficiency
- Patient with little or no stomach acid production (achlorhydria) are excluded from the KCZ cohort
- 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 KCZ or PCZ, such as isoniazid, nevirapine, rifamycins (such as rifabutin, rifampin), St. John's wort, among others (see section 5.3 for full details).
- Patients who are currently taking medications for which the metabolism may be affected by KCZ or PCZ, 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)

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): NCT03763396
Canada, Ontario | |
Toronto Western Hospital | |
Toronto, Ontario, Canada, M5T 2S8 |
Principal Investigator: | Gelareh Zadeh, MD, PhD | University Health Network/Toronto Western Hospital |
Responsible Party: | University Health Network, Toronto |
ClinicalTrials.gov Identifier: | NCT03763396 |
Other Study ID Numbers: |
18-5097 |
First Posted: | December 4, 2018 Key Record Dates |
Last Update Posted: | April 1, 2021 |
Last Verified: | March 2021 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Studies a U.S. FDA-regulated Drug Product: | No |
Studies a U.S. FDA-regulated Device Product: | No |
recurrent high grade glioma, posaconazole, ketoconazole, hexokinase 2 (HK2) |
Glioma Brain Neoplasms Recurrence Disease Attributes Pathologic Processes Neoplasms, Neuroepithelial Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Neoplasms, Glandular and Epithelial Neoplasms, Nerve Tissue Central Nervous System Neoplasms Nervous System Neoplasms Neoplasms by Site |
Brain Diseases Central Nervous System Diseases Nervous System Diseases Ketoconazole Posaconazole Antifungal Agents Anti-Infective Agents 14-alpha Demethylase Inhibitors Cytochrome P-450 Enzyme Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Steroid Synthesis Inhibitors Hormone Antagonists Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs |