Ketoconazole for Brain Cancer

Overseen By Micaiah D Grien, BS

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Milton S. Hershey Medical Center

Must not be taking: Anticonvulsants, Rifamycins, Benzodiazepines, others

Disqualifiers: Hepatitis, Addison's disease, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 12 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether ketoconazole, a drug currently used to treat fungal infections, can effectively penetrate and impact brain tumors. The goal is to determine if it can stop tumor cells from dividing. It targets individuals with high-grade gliomas (a type of brain tumor) who are scheduled for surgery. Participants must be able to swallow pills and adhere to a treatment plan. The study aims to assess whether ketoconazole could become a promising new treatment option for brain cancer. As an Early Phase 1 trial, this research focuses on understanding how ketoconazole works in people, offering participants a chance to contribute to groundbreaking cancer treatment research.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications that interact with ketoconazole, such as some antibiotics, anti-seizure drugs, and medications for erectile dysfunction or pulmonary hypertension. If you are on these medications, you may need to switch to alternatives or stop them before joining the trial.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications that interact with ketoconazole, such as some antibiotics, anti-convulsants, and medications that affect its metabolism. If you are on these medications, you may need to switch to alternatives or stop them before starting the trial.

Is there any evidence suggesting that ketoconazole is likely to be safe for humans?

Research has shown that ketoconazole is already FDA-approved for treating fungal infections, indicating its safety is well understood. Many people have used ketoconazole for these infections, so doctors are familiar with its side effects, such as nausea and skin rash.

Studies have found that ketoconazole can pass through the protective barrier around the brain, suggesting it can reach brain tumors. In research with mice, ketoconazole was effective against certain brain tumors.

Although this trial is in the early stages, the existing approval of ketoconazole for other uses offers some reassurance about its safety. However, since this is a new use of the drug, researchers are closely monitoring for any new side effects related to treating brain tumors. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for brain cancer, which often include surgery, radiation, and chemotherapy, ketoconazole is being explored for its ability to inhibit enzymes involved in steroid production, potentially affecting tumor growth. Researchers are excited about ketoconazole because it offers a novel approach by targeting the hormonal environment that may influence brain cancer progression. Additionally, ketoconazole is an oral medication, which could make it easier to administer compared to treatments requiring hospital visits. This unique mechanism and delivery method set ketoconazole apart from traditional brain cancer therapies and fuel researchers' interest in its potential benefits.

What evidence suggests that ketoconazole might be an effective treatment for brain cancer?

Research has shown that ketoconazole, the treatment under study in this trial, has potential for treating brain tumors. In lab tests, it slowed the growth of tumor cells. Studies with mice found that ketoconazole increased survival rates and reduced tumor activity. These results suggest that ketoconazole might reach the brain and target tumor cells. While these findings are promising, more research is needed to confirm its effects in humans. ^{1 2 5 6 7}

Who Is on the Research Team?

Alireza Mansouri

Principal Investigator

Milton S. Hershey Medical Center

Are You a Good Fit for This Trial?

Adults with high-grade gliomas needing surgery can join this trial if they're in good enough health, can swallow pills, and have a life expectancy over 12 weeks. They must agree to use birth control and be able to follow the study plan. People who've had bad reactions to similar drugs, are pregnant or breastfeeding, have certain illnesses like hepatitis or psychiatric conditions that could affect participation, or take specific medications that interact with ketoconazole cannot participate.

Inclusion Criteria

I can take care of myself and am up and about more than half of my waking hours.

You are expected to live for at least 12 more weeks.

My liver tests (ALT, AST, ALP) are within normal range.

Exclusion Criteria

You are allergic to ketoconazole or similar medications called azoles.

I have a history of hepatitis.

I cannot switch from metronidazole to another antibiotic 7 days before starting ketoconazole.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants will take 400 mg of ketoconazole by mouth twice a day until the day of biopsy or surgery, with the last dose taken the morning after surgery.

12 days

1 visit (in-person) for biopsy or surgery

Pharmacokinetics Assessment

Continuous measurement of drug concentration in brain tissue using microdialysis catheters over a 24-hour period post-surgery.

24 hours

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of adverse events and pharmacodynamic effects.

14 days +/- 7 days post-op

Multiple visits (in-person) for follow-up assessments

What Are the Treatments Tested in This Trial?

Interventions

• Ketoconazole

Trial Overview The trial is testing whether ketoconazole, a drug normally used for fungal infections, can reach brain tumors in sufficient amounts to stop tumor growth. The goal is to see if it's effective against brain cancer cells and should be researched further as a treatment option.

How Is the Trial Designed?

Group I: Ketoconazole Experimental Treatment 1 Intervention

Participants will be taking 400 mg of the study drug (two 200 mg tablets) by mouth twice 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) and in the evening after their biopsy or surgery (after 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.

Who Is Running the Clinical Trial?

Milton S. Hershey Medical Center

Lead Sponsor

Trials

515

Recruited

2,873,000+

Published Research Related to This Trial

Ketoconazole (KTZ) was successfully used as a monotherapy for two patients with cryptococcosis of the CNS who either did not respond to or could not tolerate standard treatments, showing its potential efficacy in difficult cases.

While KTZ was well-tolerated with minimal side effects during the six-month treatment, one patient experienced a relapse of the infection after therapy was stopped, indicating the need for ongoing monitoring after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketoconazole in the treatment of cryptococcosis of the central nervous system. Trevisol-Bittencourt, PC., Sander, JW., Silvado, CS., et al.[2019]

A study involving 24 healthy males showed that ketoconazole is rapidly absorbed, with peak plasma concentrations reached within 1 to 1.7 hours after administration, depending on the formulation (tablet, suspension, or solution).

The pharmacokinetics of ketoconazole demonstrated dose-dependent behavior, where higher doses led to a decrease in oral clearance and a more than proportional increase in drug concentration, suggesting that hepatic metabolism may become saturated at higher doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and dose proportionality of ketoconazole in normal volunteers. Huang, YC., Colaizzi, JL., Bierman, RH., et al.[2021]

In a study using BALB/c mice with cryptococcal meningitis, oral ketoconazole therapy significantly prolonged survival, although most mice still eventually succumbed to the infection.

Ketoconazole effectively reduced cryptococcal counts in the liver but had limited impact on the brain, indicating that while it may have potential as a treatment for cryptococcal meningitis, its efficacy in the central nervous system is limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketoconazole therapy of murine cryptococcal meningitis. Craven, PC., Graybill, JR., Jorgensen, JH.[2013]

Ketoconazole demonstrated significant cytotoxic effects against various cancer cell lines, with the ability to inhibit 90% of colony growth at specific concentrations, indicating its potential as a treatment option.

The effective concentration of 10 micrograms/ml achievable in humans suggests that ketoconazole warrants further clinical evaluation for its use in treating human malignancies, particularly in breast and pancreatic cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytotoxicity of ketoconazole in malignant cell lines. Rochlitz, CF., Damon, LE., Russi, MB., et al.[2019]

Ketoconazole is an effective oral antifungal agent that works by impairing the synthesis of ergosterol in fungal cell membranes, making it suitable for treating various fungal infections like candidiasis and histoplasmosis.

While ketoconazole shows promise, particularly in conditions not yet FDA-approved, its common side effects include nausea and transient liver enzyme elevations, and more extensive comparative studies are needed to fully evaluate its long-term safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of ketoconazole. Sohn, CA.[2013]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11888219/

Targeting tGLI1, a novel mediator of tumor therapeutic ... Targeting tGLI1, a novel mediator of tumor therapeutic resistance, using Ketoconazole sensitizes glioblastoma to CDK4/6 therapy and chemoradiation.

2. centerwatch.com centerwatch.com/clinical-trials/listings/NCT04869449/neuro-pharmacological-properties-of-repurposed-ketoconazole-in-glioblastomas

Neuro-pharmacological Properties of Repurposed ... Ketoconazole and posaconazole have shown efficacy in reducing tumor cell proliferation in in-vitro studies.

3. medicalupdate.pennstatehealth.org medicalupdate.pennstatehealth.org/neurology-neurosurgery/glioma-tumor-cell-growth/

Study will test effectiveness of two antifungal medications in ... It is now essential to show that these drugs can cross the blood-brain barrier and recapitulate in humans the effect on tumor cells that we have seen in mice.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8103287/

Ketoconazole and Posaconazole Selectively Target HK2 ... Treatment of mice bearing GBM with ketoconazole and posaconazole increased their survival, reduced tumor cell proliferation, and decreased tumor metabolism. In ...

5. aacrjournals.org aacrjournals.org/clincancerres/article-abstract/25/2/844/125338

Ketoconazole and Posaconazole Selectively Target HK2 ... Treatment of mice bearing GBM with ketoconazole and posaconazole increased their survival, reduced tumor cell proliferation, and decreased tumor metabolism.

6. ctv.veeva.com ctv.veeva.com/study/neuro-pharmacological-study-of-ketoconazole-for-high-grade-gliomas

Neuro-pharmacological Properties of Repurposed ... This research is being done to find out if the study drug (ketoconazole) can enter brain tumors at a high enough amount to stop the tumor ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04825275

Study Details | NCT04825275 | Neuro-pharmacological ... Both ketoconazole and posaconazole are FDA-approved anti-fungal agents with a well-established side effect and safety profile. Ketoconazole and posaconazole ...