Azoles Targeting Recurrent High Grade Gliomas

NCT03763396 | Not Yet Recruiting Early Phase 1

• 1 other identifier: 18-5097
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Brain Tumor, Recurrent; Cancer, Advanced; Glioma of Brain

Keywords

recurrent high grade glioma, posaconazole, ketoconazole, hexokinase 2 (HK2)

Outcome Measures

Primary Outcomes (2)

• Intratumoral concentrations of KCZ or PCZ

  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

  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)

• Assess Hexokinase 2 activity

  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

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

  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

• assess the biological effects of KCZ or PCZ on tumor proliferation

  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

• assess biological effects of KCZ or PCZ on tumor cell death

  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

• assess biological effects of KCZ or PCZ on tumor angiogenesis

  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

Study Arms (4)

Ketoconazole (KCZ) Single Dose Group

EXPERIMENTAL

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

Drug: Ketoconazole (KCZ)

Ketoconazole (KCZ) Repeated Dose Group

EXPERIMENTAL

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

Drug: Ketoconazole (KCZ)

Posaconazole (PCZ) Single Dose group

EXPERIMENTAL

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

Drug: Posaconazole (PCZ)

Posaconazole (PCZ) Repeated Dose group

EXPERIMENTAL

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.

Drug: Posaconazole (PCZ)

Interventions

Ketoconazole (KCZ) DRUG

Oral Tablet

Ketoconazole (KCZ) Repeated Dose Group; Ketoconazole (KCZ) Single Dose Group

Posaconazole (PCZ) DRUG

Delayed Release Oral Tablet

Posaconazole (PCZ) Repeated Dose group; Posaconazole (PCZ) Single Dose group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• \. 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.

Sponsors & Collaborators

• University Health Network, Toronto: lead

Study Sites (1)

Toronto Western Hospital

Toronto, Ontario, M5T 2S8, Canada

Location

MeSH Terms

Conditions

Brain Neoplasms; Neoplasms; Glioma

Interventions

Ketoconazole; posaconazole

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Gelareh Zadeh, MD, PhD

  University Health Network/Toronto Western Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 13, 2018
• First Posted: December 4, 2018
• Study Start: June 1, 2024
• Primary Completion: June 1, 2025
• Study Completion (Estimated): June 1, 2027
• Last Updated: March 8, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)