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Brain Tumor, RecurrentEarly Phase 1NCT03763396

Azoles Targeting Recurrent High Grade Gliomas

A Early Phase 1 study testing Ketoconazole (KCZ) and Posaconazole (PCZ) in people with Brain Tumor, Recurrent and Cancer, Advanced, run by University Health Network, Toronto at 1 site in Canada.

Not yet recruiting

Opening soon. The study is approved but enrolment has not started yet. Sites may already take enquiries.

Sites and contacts
Official record
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Trial summary

High-grade gliomas are the most common and aggressive type of brain cancer. Scientists don't fully understand how they grow and spread, and treatments haven't improved much in recent years. However, it's been discovered that these cancers rely heavily on using glucose to maintain their cancerous traits. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Ketoconazole (KCZ) and Posaconazole (PCZ)
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
30 participants
Where
1 siteCanada
Study dates
1 Jun 2024to Jun 2027
Phase
Early Phase 1
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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)
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  • 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)

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Canada1 site

  • Toronto Western Hospital

    Toronto, Ontario, M5T 2S8

    Clinical Research ccordinator, 416-603-5800 ext. 5578, ttung@uhnres.utoronto.ca

    Gelareh Zadeh, MD, PhD

Other trials in Canada

About this study

Official title: A Phase 0 Clinical Trial of Two Candidate Azoles (Ketoconazole and Posaconazole) for Patients With Recurrent High Grade Glioma

High-grade gliomas are the most common and aggressive type of brain cancer. Scientists don't fully understand how they grow and spread, and treatments haven't improved much in recent years. However, it's been discovered that these cancers rely heavily on using glucose to maintain their cancerous traits. In lab tests, drugs from the azole class, which target a key step in glucose metabolism, have shown promise in reducing tumor growth in these cancers. Researchers now want to test two of these drugs, ketoconazole and posaconazole, in patients with recurring high-grade gliomas. A small group of these patients will receive either one or several doses of these drugs before undergoing surgery. During the surgery, doctors will measure how much of the drug is present in the brain. They will also study how the drug affects the tumor, particularly its ability to process glucose. This research aims to provide initial insights into how these drugs work in patients with this type of brain cancer, which could guide future research and treatment strategies.

Read the detailed description

High grade gliomas (WHO grade III and IV)(HGG) are the most common malignant, and aggressive brain tumour in humans. Current understanding of the mechanisms contributing to their growth and progression remain limited. Furthermore, treatment options have not advanced in recent decades. Recently, it has become evident that these tumours are dependent on glucose metabolism to maintain oncogenic properties. From a preclinical standpoint, targeting hexokinase 2 (HK2), the first committed step of glucose metabolism, with azole class drugs has been shown to display favourable anti-tumour effects in both in vitro and in vivo HGG models. We would like to translate these preclinical findings into the clinical setting by implementing a proof-of biological concept study with two azole drugs: ketoconazole (KCZ) and posaconazole (PCZ). A small cohort of recurrent HGG patients will receive either a single-, or repeated, steady state dose of either KCZ or PCZ and will then go for surgery where drug concentrations will be measured intraoperatively. Study drug selection and dosing details will be selected based on urgency of surgery and patient clinical characteristics Downstream biological effects of drug on tumour tissue, including HK2 activity, will also be assessed. This study will provide a preliminary understanding of azole drug activity in recurrent HGG patients and will help inform future studies of azole drug efficacy in this patient population

Being tested
Ketoconazole (KCZ), Posaconazole (PCZ)
Keywords
recurrent high grade glioma, posaconazole, ketoconazole, hexokinase 2 (HK2)
Medical subject headings
Brain Neoplasms, Neoplasms, Glioma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Ketoconazole (KCZ)Drug

    Oral Tablet

  • Posaconazole (PCZ)Drug

    Delayed Release Oral Tablet

Study groups in NCT03763396
Study groupRoleWhat they receive
Ketoconazole (KCZ) Single Dose GroupExperimentalSingle dose 400mg oral tablets 4-24 hours prior to surgery
Receives: Drug: Ketoconazole (KCZ)
Ketoconazole (KCZ) Repeated Dose GroupExperimental400mg oral tablets twice a day (BID) for 2-5 days prior to surgery
Receives: Drug: Ketoconazole (KCZ)
Posaconazole (PCZ) Single Dose groupExperimentalSingle dose 300 mg delayed release oral tablets 4-24 hours prior to surgery
Receives: Drug: Posaconazole (PCZ)
Posaconazole (PCZ) Repeated Dose groupExperimental300 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.
Receives: Drug: Posaconazole (PCZ)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Intratumoral concentrations of KCZ or PCZ

    Measured: 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)

  2. Plasma concentrations of KCZ or PCZ

    Measured: 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)

Secondary outcomes (5)

  1. Assess Hexokinase 2 activity

    enzyme activity measured using optical absorbance with a spectrophotometer

    Measured: 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

  2. Assess the biological effects of KCZ or PCZ on metabolites within the glycolytic pathway

    quantify presence/absence of metabolites using mass spectrometry

    Measured: 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

  3. assess the biological effects of KCZ or PCZ on tumor proliferation

    measured using ki-67 proliferation index

    Measured: 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

  4. assess biological effects of KCZ or PCZ on tumor cell death

    measured using TUNEL staining

    Measured: 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

  5. assess biological effects of KCZ or PCZ on tumor angiogenesis

    measured using VEGF/CD-31 immunohistochemistry

    Measured: 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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Dec 2018
  2. Study start1 Jun 2024 (estimated)
  3. Primary completionJun 2025 (estimated)
  4. Study completionJun 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Early Phase 1
Primary purpose
Other
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
30 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03763396
Sponsor's protocol ID
18-5097
Status last verified
Mar 2024
First submitted
13 Nov 2018
Last updated
8 Mar 2024
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Early Phase 1 study testing Ketoconazole (KCZ) and Posaconazole (PCZ) in people with Brain Tumor, Recurrent and Cancer, Advanced, run by University Health Network, Toronto at 1 site in Canada.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 12 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: opening soon, as of the sponsor's last update on 8 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03763396.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Mar 2024.

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