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

Trial Summary

What is the purpose of this trial?

This trial is testing posaconazole, a drug usually used for fungal infections, to see if it can help treat brain tumors by stopping the tumor cells from growing. The study focuses on patients with limited treatment options for their brain tumors.

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.

How does the drug ketoconazole differ from other treatments for brain cancer?

Ketoconazole is unique because it is an antifungal drug that has shown potential in treating certain cancers by inhibiting cell growth, although it is not a standard treatment for brain cancer. It works by blocking the synthesis of ergosterol, a key component of fungal cell membranes, and has been used in other conditions like prostate and breast cancer. ^{1 2 3 4 5}

How does the drug ketoconazole differ from other treatments for brain cancer?

Ketoconazole is unique because it is an antifungal drug that has shown potential in treating certain cancers due to its ability to inhibit cell growth, which is different from traditional chemotherapy drugs. It is taken orally, which can be more convenient compared to some cancer treatments that require intravenous administration. ^{1 2 3 4 5}

Research Team

Alireza Mansouri

Principal Investigator

Milton S. Hershey Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 (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]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Cytotoxicity of ketoconazole in malignant cell lines. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and dose proportionality of ketoconazole in normal volunteers. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Evaluation of ketoconazole. [2013]

4. United States pubmed.ncbi.nlm.nih.gov

Ketoconazole therapy of murine cryptococcal meningitis. [2013]

5. Germany pubmed.ncbi.nlm.nih.gov

Ketoconazole in the treatment of cryptococcosis of the central nervous system. [2019]