Ketoconazole + Posaconazole for Recurrent Brain Cancer

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: University Health Network, Toronto

Must not be taking: Azoles, Metronidazole, Anticonvulsants, others

Disqualifiers: Hepatitis, Adrenal insufficiency, others

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

Compensation: Varies

Number of Visits: 2

Duration: 1-10 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two drugs, ketoconazole and posaconazole (an antifungal medication), to determine their effectiveness in treating recurring high-grade gliomas, an aggressive brain cancer. Researchers believe these drugs affect how cancer cells use glucose, potentially slowing tumor growth. Participants will receive one of these drugs before surgery, and researchers will assess how much of the drug reaches the brain and its effects on the tumor. Individuals with recurring high-grade gliomas requiring surgery might be suitable for this study. As an Early Phase 1 trial, this research aims to understand how these treatments work in people, offering participants a chance to contribute to groundbreaking cancer research.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications that interact with the study drugs, such as some anti-seizure medications, certain antibiotics, and drugs that affect heart rhythm. If you're on any of these, you may need to switch to alternatives before joining the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that both ketoconazole and posaconazole have potential for treating brain tumors. Studies found that these drugs can slow tumor growth by affecting how tumors use glucose, a sugar that cancer cells often need to grow.

For ketoconazole, earlier research in mice and lab settings suggested it might help target brain tumors. However, this is an early test in humans, so detailed safety information remains limited. It is important to note that ketoconazole is already FDA-approved for treating fungal infections, indicating it has been tested for safety in other conditions.

Posaconazole has also shown promise in lab settings for slowing tumor growth. Like ketoconazole, it is an antifungal drug with FDA approval for other uses, meaning its safety is somewhat understood, though not specifically for brain cancer treatment.

Since this is an early-phase trial, the main goal is to determine how safe these drugs are for patients with brain cancer. While some safety evidence exists from their use in other conditions, this trial will provide more specific insights for people with high-grade gliomas. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using ketoconazole and posaconazole for recurrent brain cancer because these antifungal drugs could offer a new approach to treatment. Unlike the typical chemotherapy and radiation therapies, which target rapidly dividing cells, these drugs inhibit certain enzymes that may be critical in tumor growth. Ketoconazole and posaconazole are already known for their safety in treating fungal infections, which might translate into fewer side effects when repurposed for cancer therapy. The potential to administer these drugs orally, either as a single dose or over several days, offers flexibility and convenience compared to traditional treatments, which often require hospital visits. This unique mechanism and delivery method could open new avenues for managing difficult-to-treat brain cancers.

What evidence suggests that this trial's treatments could be effective for recurrent brain cancer?

Research suggests that the drugs ketoconazole and posaconazole might help treat high-grade gliomas, a type of aggressive brain cancer. In lab tests, both drugs have slowed the growth of these tumors. In this trial, participants will receive either ketoconazole or posaconazole. Ketoconazole has reduced tumor cell growth and proved helpful when other treatments stop working. Posaconazole, on the other hand, has shrunk tumors and boosted the body's immune response to cancer. These drugs likely work by interfering with how cancer cells use sugar, which they need to grow. While these findings are promising, more research is needed to determine their effectiveness in people. ^{2 3 4 5 6}

Who Is on the Research Team?

Gelareh Zadeh, MD, PhD

Principal Investigator

University Health Network/Toronto Western Hospital

Are You a Good Fit for This Trial?

Adults over 18 with recurrent high-grade gliomas (a type of aggressive brain cancer) who need surgery can join. They should be relatively stable (KPS ≥ 60%, ECOG ≤ 2), expected to live more than 12 weeks, and have good liver and kidney function. Women and men must use birth control during the study.

Inclusion Criteria

Life expectancy greater than 12 weeks

Potassium, calcium, and magnesium within normal limits (PCZ cohort)

My kidney function is within the normal range required.

Exclusion Criteria

I have not taken azole medications in the last 3 months.

Patients may not be receiving any other investigational agents while on study

Patients who have known allergy to KCZ, PCZ, or other azoles

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either a single dose or repeated doses of ketoconazole or posaconazole before surgery

1-10 days

1 visit (in-person) for surgery

Surgery

Surgery is performed to measure drug concentration in the brain and assess biological effects on the tumor

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ketoconazole
• Posaconazole

Trial Overview The trial is testing Ketoconazole (KCZ) and Posaconazole (PCZ), two drugs that may interfere with the tumor's glucose use, potentially slowing its growth. Participants will receive doses before their scheduled surgeries where drug levels in the brain and effects on the tumor will be assessed.

How Is the Trial Designed?

Group I: Posaconazole (PCZ) Single Dose group Experimental Treatment 1 Intervention

Single dose 300 mg delayed release oral tablets 4-24 hours prior to surgery

Group II: Posaconazole (PCZ) Repeated Dose group Experimental Treatment 1 Intervention

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.

Group III: Ketoconazole (KCZ) Single Dose Group Experimental Treatment 1 Intervention

Single dose 400mg oral tablets 4-24 hours prior to surgery

Group IV: Ketoconazole (KCZ) Repeated Dose Group Experimental Treatment 1 Intervention

400mg oral tablets twice a day (BID) for 2-5 days prior to surgery

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Published Research Related to This Trial

Patupilone, a chemotherapy drug, showed a progression-free survival rate of 36% in patients with non-small cell lung cancer (NSCLC) and brain metastases, indicating its potential efficacy in this challenging population.

The treatment was associated with significant adverse events, including diarrhea (24%) and pulmonary embolisms (8%), leading to all patients discontinuing the drug, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase 2 study of patupilone for recurrent or progressive brain metastases from non-small cell lung cancer. Nayak, L., DeAngelis, LM., Robins, HI., et al.[2018]

Oral targeted agents, including BRAF inhibitors and various receptor inhibitors, show potential in treating brain metastases, but there is a lack of comprehensive data on their effectiveness in this specific area.

Many patients with brain metastases are excluded from clinical trials, leading to a significant gap in research and documentation of the intracranial activity of these therapies, highlighting the need for more focused investigations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Targeted Therapies and Central Nervous System (CNS) Metastases. Gabay, MP., Wirth, SM., Stachnik, JM., et al.[2022]

Citations

1. 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 ...

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. 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.

4. mdpi.com mdpi.com/2072-6694/14/17/4256

An FDA-Approved Antifungal, Ketoconazole, and Its Novel ... Ex vivo imaging of the resected samples showed that KCZ reduced the frequency of brain and bone metastases by 45% and 11%, respectively (Figure 3c). Furthermore ...

5. 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.

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2018-03087

Ketoconazole before Surgery in Treating Patients with ... This early phase I trial studies the side effects and how well ketoconazole works before surgery in treating patients with glioma that has come back (recurrent) ...