<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03763396</url>
  </required_header>
  <id_info>
    <org_study_id>18-5097</org_study_id>
    <nct_id>NCT03763396</nct_id>
  </id_info>
  <brief_title>Azoles Targeting Recurrent High Grade Gliomas</brief_title>
  <official_title>A Phase 0 Clinical Trial of Two Candidate Azoles (Ketoconazole and Posaconazole) for Patients With Recurrent High Grade Glioma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Health Network, Toronto</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Health Network, Toronto</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      High grade gliomas (WHO grade III and IV)(HGG) are the most common malignant, and aggressive&#xD;
      brain tumour in humans. Current understanding of the mechanisms contributing to their growth&#xD;
      and progression remain limited. Furthermore, treatment options have not advanced in recent&#xD;
      decades. Recently, it has become evident that these tumours are dependent on glucose&#xD;
      metabolism to maintain oncogenic properties. From a preclinical standpoint, targeting&#xD;
      hexokinase 2 (HK2), the first committed step of glucose metabolism, with azole class drugs&#xD;
      has been shown to display favourable anti-tumour effects in both in vitro and in vivo HGG&#xD;
      models. We would like to translate these preclinical findings into the clinical setting by&#xD;
      implementing a proof-of biological concept study with two azole drugs: ketoconazole (KCZ) and&#xD;
      posaconazole (PCZ). A small cohort of recurrent HGG patients will receive either a single-,&#xD;
      or repeated, steady state dose of either KCZ or PCZ and will then go for surgery where drug&#xD;
      concentrations will be measured intraoperatively. Study drug selection and dosing details&#xD;
      will be selected based on urgency of surgery and patient clinical characteristics Downstream&#xD;
      biological effects of drug on tumour tissue, including HK2 activity, will also be assessed.&#xD;
      This study will provide a preliminary understanding of azole drug activity in recurrent HGG&#xD;
      patients and will help inform future studies of azole drug efficacy in this patient&#xD;
      population&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">August 1, 2019</start_date>
  <completion_date type="Anticipated">August 2022</completion_date>
  <primary_completion_date type="Anticipated">August 2022</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Intratumoral concentrations of KCZ or PCZ</measure>
    <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)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Plasma concentrations of KCZ or PCZ</measure>
    <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)</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Assess Hexokinase 2 activity</measure>
    <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</time_frame>
    <description>enzyme activity measured using optical absorbance with a spectrophotometer</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess the biological effects of KCZ or PCZ on metabolites within the glycolytic pathway</measure>
    <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</time_frame>
    <description>quantify presence/absence of metabolites using mass spectrometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>assess the biological effects of KCZ or PCZ on tumor proliferation</measure>
    <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</time_frame>
    <description>measured using ki-67 proliferation index</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>assess biological effects of KCZ or PCZ on tumor cell death</measure>
    <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</time_frame>
    <description>measured using TUNEL staining</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>assess biological effects of KCZ or PCZ on tumor angiogenesis</measure>
    <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</time_frame>
    <description>measured using VEGF/CD-31 immunohistochemistry</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Brain Tumor, Recurrent</condition>
  <condition>Cancer, Advanced</condition>
  <condition>Glioma of Brain</condition>
  <arm_group>
    <arm_group_label>Ketoconazole (KCZ) Single Dose Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single dose 400mg oral tablets 4-24 hours prior to surgery</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ketoconazole (KCZ) Repeated Dose Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>400mg oral tablets twice a day (BID) for 2-5 days prior to surgery</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Posaconazole (PCZ) Single Dose group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single dose 300 mg delayed release oral tablets 4-24 hours prior to surgery</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Posaconazole (PCZ) Repeated Dose group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ketoconazole (KCZ)</intervention_name>
    <description>Oral Tablet</description>
    <arm_group_label>Ketoconazole (KCZ) Repeated Dose Group</arm_group_label>
    <arm_group_label>Ketoconazole (KCZ) Single Dose Group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Posaconazole (PCZ)</intervention_name>
    <description>Delayed Release Oral Tablet</description>
    <arm_group_label>Posaconazole (PCZ) Repeated Dose group</arm_group_label>
    <arm_group_label>Posaconazole (PCZ) Single Dose group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥18 years&#xD;
&#xD;
          -  Evidence of recurrent HGG that in the opinion of the treating team does not represent&#xD;
             pseudoprogression and would require surgical resection&#xD;
&#xD;
          -  Karnofsky Performance Score (KPS) ≥ 60%&#xD;
&#xD;
          -  ECOG ≤ 2&#xD;
&#xD;
          -  Life expectancy greater than 12 weeks&#xD;
&#xD;
          -  Adequate liver function defined as ALT, AST, ALP, GGT, bilirubin within 1.5x&#xD;
             institutional upper limit of normal&#xD;
&#xD;
          -  Potassium, calcium, and magnesium within normal limits (PCZ cohort)&#xD;
&#xD;
          -  Adequate renal function defined as eGFR levels within 1.5x the institutional upper&#xD;
             limit of normal (only for KCZ cohort)&#xD;
&#xD;
          -  Ability to swallow medication&#xD;
&#xD;
          -  Women of child-bearing potential and men must agree to use adequate contraception&#xD;
             (hormonal or barrier method of birth control; abstinence) for the duration of study&#xD;
             participation.&#xD;
&#xD;
          -  Ability to understand and willingness to sign a written informed consent document&#xD;
&#xD;
          -  Be able to comply with treatment plan, study procedures and follow-up examinations&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  1. Patients may not be receiving any other investigational agents while on study&#xD;
&#xD;
          -  Patients who have known allergy to KCZ, PCZ, or other azoles&#xD;
&#xD;
          -  Patients who have previously had a severe side effect, such as agranulocytosis and&#xD;
             neutropenia, in conjunction with previous azole class drugs for a parasitic infection&#xD;
&#xD;
          -  Patients with a history of acute or chronic hepatitis&#xD;
&#xD;
          -  Patients with liver enzymes (ALT, AST, ALP, GGT, Bilirubin) &gt;1.5x above normal range&#xD;
             for the laboratory performing the test&#xD;
&#xD;
          -  ECG with QT &gt; 450 msec (PCZ cohort)&#xD;
&#xD;
          -  Patients taking drugs known to prolong the QT interval (PCZ cohort)&#xD;
&#xD;
          -  Patients who are taking metronidazole and cannot be safely moved to a different&#xD;
             antibiotic greater than 7 days prior to starting KCZ therapy&#xD;
&#xD;
          -  Patients who have taken any azoles within the last 3 months&#xD;
&#xD;
          -  Patients who are taking any anti-convulsant medication that interferes with the&#xD;
             cytochrome P450 pathway (e.g. phenytoin, phenobarbital, carbamazepine, etc.) and who&#xD;
             cannot be switched to alternative medications such as keppra (levetiracetam)&#xD;
&#xD;
          -  Uncontrolled intercurrent illness such as chronic hepatitis, acute hepatitis, or&#xD;
             psychiatric illness/social situation that would limit compliance with study&#xD;
             requirements&#xD;
&#xD;
          -  Patients with a history of Addison's disease or other forms of adrenal insufficiency&#xD;
&#xD;
          -  Patient with little or no stomach acid production (achlorhydria) are excluded from the&#xD;
             KCZ cohort&#xD;
&#xD;
          -  Pregnant and breast feeding women&#xD;
&#xD;
          -  Patients with a history of any medical or psychiatric condition or laboratory&#xD;
             abnormality that in the opinion of the investigator may increase the risks associated&#xD;
             with the study participation or investigational product administration or may&#xD;
             interfere with the interpretation of the results.&#xD;
&#xD;
          -  Patients who are not available for follow-up assessments or unable to comply with&#xD;
             study requirements.&#xD;
&#xD;
          -  Patients who are currently taking medications that induce the metabolism of KCZ or&#xD;
             PCZ, such as isoniazid, nevirapine, rifamycins (such as rifabutin, rifampin), St.&#xD;
             John's wort, among others (see section 5.3 for full details).&#xD;
&#xD;
          -  Patients who are currently taking medications for which the metabolism may be affected&#xD;
             by KCZ or PCZ, which include but are not limited to: benzodiazepines (such as&#xD;
             alprazolam, midazolam, triazolam), domperidone, eletriptan, eplerenone, ergot drugs&#xD;
             (such as ergotamine), nisoldipine, drugs used to treat erectile dysfunction-ED or&#xD;
             pulmonary hypertension (such as sildenafil, tadalafil), some drugs used to treat&#xD;
             seizures (such as carbamazepine, phenytoin), some statin drugs (such as atorvastatin,&#xD;
             lovastatin, simvastatin)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Gelareh Zadeh, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Health Network/Toronto Western Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Toronto Western Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5T 2S8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>November 13, 2018</study_first_submitted>
  <study_first_submitted_qc>November 30, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 4, 2018</study_first_posted>
  <last_update_submitted>March 30, 2021</last_update_submitted>
  <last_update_submitted_qc>March 30, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 1, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>recurrent high grade glioma, posaconazole, ketoconazole, hexokinase 2 (HK2)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioma</mesh_term>
    <mesh_term>Brain Neoplasms</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ketoconazole</mesh_term>
    <mesh_term>Posaconazole</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03763396
org study id: 18-5097
nct id: NCT03763396
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: None (Open Label)
measure: 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)
measure: 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)
measure: 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
description: enzyme activity measured using optical absorbance with a spectrophotometer
measure: 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
description: quantify presence/absence of metabolites using mass spectrometry
measure: 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
description: measured using ki-67 proliferation index
measure: 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
description: measured using TUNEL staining
measure: 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
description: measured using VEGF/CD-31 immunohistochemistry
arm group label: Ketoconazole (KCZ) Single Dose Group
arm group type: Experimental
description: Single dose 400mg oral tablets 4-24 hours prior to surgery
arm group label: Ketoconazole (KCZ) Repeated Dose Group
arm group type: Experimental
description: 400mg oral tablets twice a day (BID) for 2-5 days prior to surgery
arm group label: Posaconazole (PCZ) Single Dose group
arm group type: Experimental
description: Single dose 300 mg delayed release oral tablets 4-24 hours prior to surgery
arm group label: Posaconazole (PCZ) Repeated Dose group
arm group type: Experimental
description: 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.
intervention type: Drug
intervention name: Ketoconazole (KCZ)
description: Oral Tablet
arm group label: Ketoconazole (KCZ) Repeated Dose Group
arm group label: Ketoconazole (KCZ) Single Dose Group
intervention type: Drug
intervention name: Posaconazole (PCZ)
description: Delayed Release Oral Tablet
arm group label: Posaconazole (PCZ) Repeated Dose group
arm group label: Posaconazole (PCZ) Single Dose group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Gelareh Zadeh, MD, PhD
role: Principal Investigator
affiliation: University Health Network/Toronto Western Hospital
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Glioma
mesh term: Brain Neoplasms
mesh term: Recurrence
mesh term: Ketoconazole
mesh term: Posaconazole
sharing ipd: No