Azoles Targeting Recurrent High Grade Gliomas

• ClinicalTrials.gov Identifier: NCT03763396
• Recruitment Status: Recruiting
• First Posted: December 4, 2018
• Last Update Posted: December 12, 2019
• Sponsor: University Health Network, Toronto
• Information provided by (Responsible Party): University Health Network, Toronto

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Brain Tumor, Recurrent; Cancer, Advanced; Glioma of Brain	Drug: Ketoconazole (KCZ); Drug: Posaconazole (PCZ)	Early Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Phase 0 Clinical Trial of Two Candidate Azoles (Ketoconazole and Posaconazole) for Patients With Recurrent High Grade Glioma
• Actual Study Start Date: August 1, 2019
• Estimated Primary Completion Date: August 2022
• Estimated Study Completion Date: August 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ketoconazole (KCZ) Single Dose Group; Single dose 400mg oral tablets 4-24 hours prior to surgery	Drug: Ketoconazole (KCZ); Oral Tablet
Experimental: Ketoconazole (KCZ) Repeated Dose Group; 400mg oral tablets twice a day (BID) for 2-5 days prior to surgery	Drug: Ketoconazole (KCZ); Oral Tablet
Experimental: Posaconazole (PCZ) Single Dose group; Single dose 300 mg delayed release oral tablets 4-24 hours prior to surgery	Drug: Posaconazole (PCZ); Delayed Release Oral Tablet
Experimental: Posaconazole (PCZ) Repeated Dose group; 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); Delayed Release Oral Tablet

Outcome Measures

Primary Outcome Measures :

1. 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) ]
2. Plasma 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) ]

Secondary Outcome Measures :

1. Assess Hexokinase 2 activity [ 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) compared to archive tumor tissue from baseline ]
   enzyme activity measured using optical absorbance with a spectrophotometer
2. Assess the biological effects of KCZ or PCZ on metabolites within the glycolytic pathway [ 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) compared to archive tumor tissue from baseline ]
   quantify presence/absence of metabolites using mass spectrometry
3. assess the biological effects of KCZ or PCZ on tumor proliferation [ 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) compared to archive tumor tissue from baseline ]
   measured using ki-67 proliferation index
4. assess biological effects of KCZ or PCZ on tumor cell death [ 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) compared to archive tumor tissue from baseline ]
   measured using TUNEL staining
5. assess biological effects of KCZ or PCZ on tumor angiogenesis [ 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) compared to archive tumor tissue from baseline ]
   measured using VEGF/CD-31 immunohistochemistry

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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)
• 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)

Contacts and Locations

Locations

Canada, Ontario

Toronto Western Hospital; Recruiting

Toronto, Ontario, Canada, M5T 2S8

Contact: Clinical Research Analyst 416-603-5800 ext 5578 eric.monsalves@uhnresearch.ca

Principal Investigator: Gelareh Zadeh, MD, PhD

Sub-Investigator: Alireza Mansouri, MD, MSc

Sponsors and Collaborators

University Health Network, Toronto

Investigators

• Principal Investigator: Gelareh Zadeh, MD, PhD; University Health Network/Toronto Western Hospital

More Information

• Responsible Party: University Health Network, Toronto
• ClinicalTrials.gov Identifier: NCT03763396
• Other Study ID Numbers: 18-5097
• First Posted: December 4, 2018
• Last Update Posted: December 12, 2019
• Last Verified: December 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University Health Network, Toronto:

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

Additional relevant MeSH terms:

Glioma; Brain Neoplasms; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Ketoconazole; Posaconazole; Antifungal Agents; Anti-Infective Agents; 14-alpha Demethylase Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Steroid Synthesis Inhibitors; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Cytochrome P-450 CYP3A Inhibitors; Trypanocidal Agents; Antiprotozoal Agents