<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/NCT03796273</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00054587</org_study_id>
    <secondary_id>NCI-2018-03087</secondary_id>
    <secondary_id>CCCWFU 91118</secondary_id>
    <secondary_id>P30CA012197</secondary_id>
    <nct_id>NCT03796273</nct_id>
  </id_info>
  <brief_title>Ketoconazole Before Surgery in Treating Patients With Recurrent Glioma or Breast Cancer Brain Metastases</brief_title>
  <official_title>tGLI1 as a Therapeutic Target in Brain Metastases: A Window of Opportunity Study in Breast Cancer Brain Metastases and Primary Gliomas</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Wake Forest University Health Sciences</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Wake Forest University Health Sciences</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This trial studies the side effects and how well ketoconazole works before surgery in&#xD;
      treating patients with glioma that has come back or breast cancer that has spread to the&#xD;
      brain. Ketoconazole is an antifungal drug that may be able to block a protein, tGLI1 and may&#xD;
      help to treat brain tumors.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To determine if ketoconazole alters the tGLI1 activation signature (tGAS) which is&#xD;
      consisted of eight validated tGLI1 regulated genes (CD24, CD44, VEGF-A, VEGF-C, VEGFR2, TEM7,&#xD;
      OCT-4. and heparanase) in tGLI1 expressing brain biospecimens.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To determine if pre-treatment with ketoconazole, an inhibitor of the tGLI1 pathway in&#xD;
      tissue culture and animal models, reduces circulating tGLI1 associated exosomal miRNA&#xD;
      expression (miR1290 and miR1246) in brain tumor patients.&#xD;
&#xD;
      II. To describe the safety of ketoconazole when administered peri-operatively to patients&#xD;
      with primary and secondary brain tumors.&#xD;
&#xD;
      III. To measure the blood brain penetrance of ketoconazole in serum relative to enhancing&#xD;
      brain tissue.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. To measure blood brain penetration of ketoconazole in serum relative to cerebrospinal&#xD;
      fluid (CSF) and serum relative to non-enhancing brain tissue (exploratory recurrent glioma&#xD;
      patients only).&#xD;
&#xD;
      II. To compare tGLI1 expression and pathway modulation with ketoconazole pre-treatment in&#xD;
      patients with recurrent gliomas relative to breast cancer brain metastases (BCBM).&#xD;
&#xD;
      III. To determine the overall survival and toxicity outcomes for patients that continue&#xD;
      ketoconazole after surgery, at the discretion of the treating physician.&#xD;
&#xD;
      OUTLINE: Patients are randomized to 1 of 2 arms.&#xD;
&#xD;
      ARM I: Patients receive ketoconazole orally (PO) once daily (QD) on days 1-4 before standard&#xD;
      surgery in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      ARM II: Patients undergo standard surgery.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30 days.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">March 13, 2019</start_date>
  <completion_date type="Anticipated">November 2023</completion_date>
  <primary_completion_date type="Anticipated">October 2023</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>tGLI1 activation signature 8 (t-GAS 8)</measure>
    <time_frame>Up to 30 days after surgery</time_frame>
    <description>The primary outcome of this study is modulation of the tGLI1 pathway as assessed by the tGLI1 activation signature 8 (t-GAS 8) [29, 40]. t-GAS 8 consists of eight validated tGLI1 regulated genes (CD24, CD44, VEGF-A, VEGF-C, VEGFR2, TEM7, OCT-4. and heparanase) and is measured using qPCR in patients whose brain tissue expresses tGLI1 (by IHC). The distribution of the tGAS will be examined and transformed to approximate the conditional normality assumption if necessary. Analysis of variance (ANOVA) methods will be used to determine the effects of different factors of interest (e.g., treatment or tumor type) on the outcomes measured.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>tGLI1 pathway activation</measure>
    <time_frame>Up to 30 days after surgery</time_frame>
    <description>tGLI1 pathway activation will be compared between treatment groups using ANOVA as described for the analysis of primary objective.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events (AEs)</measure>
    <time_frame>Up to 30 days after surgery</time_frame>
    <description>The safety of ketoconazole will be defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0 criteria and determined by adverse event proportions. The adverse event proportions will be compared between treatment groups using chi-squared tests. If feasible, a logistic regression model will be used to detect whether the adverse event proportion is higher in the treatment group after adjusting for the tumor type.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood brain penetrance of ketoconazole in serum relative to enhancing brain tissue</measure>
    <time_frame>Up to 30 days after surgery</time_frame>
    <description>The analysis will be the same as that for the analysis of primary objective.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Serum ketoconazole concentrations in Cerebrospinal Fluid (CSF)</measure>
    <time_frame>Up to 30 days after surgery</time_frame>
    <description>Measured using mass spectroscopy. The analysis will be the same as that for the analysis of primary objective. If the sample size is too small, the nonparametric approach will be considered as the primary analysis.</description>
  </other_outcome>
  <other_outcome>
    <measure>Serum ketoconazole concentrations in enhancing brain tissue</measure>
    <time_frame>Up to 30 days after surgery</time_frame>
    <description>Measured using mass spectroscopy. The analysis will be the same as that for the analysis of primary objective. If the sample size is too small, the nonparametric approach will be considered as the primary analysis.</description>
  </other_outcome>
  <other_outcome>
    <measure>Serum ketoconzcole concentrations in unenhancing brain tissue</measure>
    <time_frame>Up to 30 days after surgery</time_frame>
    <description>Measured using mass spectroscopy. The analysis will be the same as that for the analysis of primary objective. If the sample size is too small, the nonparametric approach will be considered as the primary analysis.</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes in tGLI1 signaling pathway</measure>
    <time_frame>Baseline up to 30 days after surgery</time_frame>
    <description>Will be calculated and compared between treatment groups. Ideally analysis of covariance should be done. However, due to the small sample size, ANOVA as described for the primary analysis approach or the 2-sample t test will be used. If needed, non-parametric approaches will be used instead.</description>
  </other_outcome>
  <other_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>From the date of the starting ketoconazole to the date of death from any cause, assessed up to 30 days after ketoconazole treatment completion</time_frame>
    <description>The Kaplan-Meier method will be used to estimate OS probability and median time of survival along with the 95% confidence interval.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">19</enrollment>
  <condition>Anatomic Stage IV Breast Cancer AJCC v8</condition>
  <condition>Astrocytoma</condition>
  <condition>Breast Carcinoma Metastatic in the Brain</condition>
  <condition>Glioma</condition>
  <condition>Invasive Breast Carcinoma</condition>
  <condition>Oligodendroglioma</condition>
  <condition>Prognostic Stage IV Breast Cancer AJCC v8</condition>
  <condition>Recurrent Glioma</condition>
  <arm_group>
    <arm_group_label>Arm I (ketoconazole)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive ketoconazole PO QD on days 1-4 before standard surgery in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm II (standard surgery)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients undergo standard surgery.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Best Practice</intervention_name>
    <description>Undergo standard surgery</description>
    <arm_group_label>Arm I (ketoconazole)</arm_group_label>
    <arm_group_label>Arm II (standard surgery)</arm_group_label>
    <other_name>standard of care</other_name>
    <other_name>standard therapy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ketoconazole</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Arm I (ketoconazole)</arm_group_label>
    <other_name>Fungarest</other_name>
    <other_name>Fungoral</other_name>
    <other_name>Ketoderm</other_name>
    <other_name>Ketoisdin</other_name>
    <other_name>Nizoral</other_name>
    <other_name>Orifungal M</other_name>
    <other_name>Panfungol</other_name>
    <other_name>R-41400</other_name>
    <other_name>Xolegel</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects must have a history of:&#xD;
&#xD;
               -  Histologically confirmed primary breast cancer including primary invasive and&#xD;
                  metastatic breast cancers with imaging findings consistent with brain metastasis.&#xD;
                  In the event that a patient presents with an initial diagnosis of metastatic&#xD;
                  breast cancer with imaging findings of a new brain metastases and unequivocal&#xD;
                  imaging findings of a primary breast cancer, consideration for study enrollment&#xD;
                  requires approval from the study chair (primary cohort)&#xD;
&#xD;
        OR&#xD;
&#xD;
          -  Histologically confirmed primary glioma including astrocytoma or oligodendroglioma of&#xD;
             any World Health Organization grade with imaging findings consistent with recurrent or&#xD;
             progressive disease (exploratory cohort). Patients with ependymoma will not be&#xD;
             included.&#xD;
&#xD;
               -  Subjects must be undergoing surgical resection for clinical purposes with&#xD;
                  anticipated resection of at least 300 mg of tissue.&#xD;
&#xD;
               -  Patients with any prior number of radiation (including brain radiation),&#xD;
                  chemotherapy, or surgical interventions will be eligible for this protocol.&#xD;
&#xD;
               -  The effects of ketoconazole on the developing human fetus are unknown. For this&#xD;
                  reason, women of child-bearing potential and men must agree to use adequate&#xD;
                  contraception (hormonal or barrier method of birth control; abstinence) prior to&#xD;
                  study entry and for the duration of study participation. Should a woman become&#xD;
                  pregnant or suspect she is pregnant while participating in this study, she should&#xD;
                  inform her treating physician immediately.&#xD;
&#xD;
               -  Ability to understand and the willingness to sign an Institutional Review Board&#xD;
                  (IRB)-approved informed consent document (either directly or via a legally&#xD;
                  authorized representative).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subjects with contraindication to ketoconazole including:&#xD;
&#xD;
               -  Prior allergic reaction or intolerance of ketoconazole&#xD;
&#xD;
               -  Known active hepatitis&#xD;
&#xD;
               -  QTc prolongation (based on electrocardiography [EKG] obtained within 21 days of&#xD;
                  enrollment, with a threshold of &gt;450 ms in males and &gt;470 ms in female)&#xD;
&#xD;
               -  Known liver cirrhosis will be excluded from enrollment&#xD;
&#xD;
               -  Positive serum pregnancy test within 21 days of enrollment&#xD;
&#xD;
          -  Subjects currently taking medications that are included in the contraindicated&#xD;
             concurrent medications section of the Food and Drug Administration (FDA) approved&#xD;
             indications for ketoconazole will be required to complete a seven day wash out period&#xD;
             prior to consideration for enrollment.&#xD;
&#xD;
          -  Subjects for whom collection of blood, or tissue samples is unsafe or clinically&#xD;
             inadvisable.&#xD;
&#xD;
          -  Pregnant women are excluded from this study because ketoconazole is a Class B agent&#xD;
             with the potential for teratogenic or abortifacient effects. Because there is an&#xD;
             unknown but potential risk for adverse events in nursing infants secondary to&#xD;
             treatment of the mother with ketoconazole, breastfeeding should be discontinued if the&#xD;
             mother is treated with ketoconazole.&#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>Roy Strowd</last_name>
    <role>Principal Investigator</role>
    <affiliation>Wake Forest University Health Sciences</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Wake Forest University Health Sciences</name>
      <address>
        <city>Winston-Salem</city>
        <state>North Carolina</state>
        <zip>27157</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Roy E. Strowd</last_name>
      <phone>336-716-7422</phone>
      <email>rstrowd@wakehealth.edu</email>
    </contact>
    <investigator>
      <last_name>Roy E. Strowd</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>December 26, 2018</study_first_submitted>
  <study_first_submitted_qc>January 3, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 8, 2019</study_first_posted>
  <last_update_submitted>August 9, 2023</last_update_submitted>
  <last_update_submitted_qc>August 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Glioma</mesh_term>
    <mesh_term>Brain Neoplasms</mesh_term>
    <mesh_term>Astrocytoma</mesh_term>
    <mesh_term>Oligodendroglioma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ketoconazole</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03796273
org study id: IRB00054587
secondary id: NCI-2018-03087
secondary id: CCCWFU 91118
secondary id: P30CA012197
nct id: NCT03796273
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This trial studies the side effects and how well ketoconazole works before surgery in
      treating patients with glioma that has come back or breast cancer that has spread to the
      brain. Ketoconazole is an antifungal drug that may be able to block a protein, tGLI1 and may
      help to treat brain tumors.
PRIMARY OBJECTIVES:

      I. To determine if ketoconazole alters the tGLI1 activation signature (tGAS) which is
      consisted of eight validated tGLI1 regulated genes (CD24, CD44, VEGF-A, VEGF-C, VEGFR2, TEM7,
      OCT-4. and heparanase) in tGLI1 expressing brain biospecimens.

      SECONDARY OBJECTIVES:

      I. To determine if pre-treatment with ketoconazole, an inhibitor of the tGLI1 pathway in
      tissue culture and animal models, reduces circulating tGLI1 associated exosomal miRNA
      expression (miR1290 and miR1246) in brain tumor patients.

      II. To describe the safety of ketoconazole when administered peri-operatively to patients
      with primary and secondary brain tumors.

      III. To measure the blood brain penetrance of ketoconazole in serum relative to enhancing
      brain tissue.

      EXPLORATORY OBJECTIVES:

      I. To measure blood brain penetration of ketoconazole in serum relative to cerebrospinal
      fluid (CSF) and serum relative to non-enhancing brain tissue (exploratory recurrent glioma
      patients only).

      II. To compare tGLI1 expression and pathway modulation with ketoconazole pre-treatment in
      patients with recurrent gliomas relative to breast cancer brain metastases (BCBM).

      III. To determine the overall survival and toxicity outcomes for patients that continue
      ketoconazole after surgery, at the discretion of the treating physician.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive ketoconazole orally (PO) once daily (QD) on days 1-4 before standard
      surgery in the absence of disease progression or unacceptable toxicity.

      ARM II: Patients undergo standard surgery.

      After completion of study treatment, patients are followed up at 30 days.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: tGLI1 activation signature 8 (t-GAS 8)
time frame: Up to 30 days after surgery
description: The primary outcome of this study is modulation of the tGLI1 pathway as assessed by the tGLI1 activation signature 8 (t-GAS 8) [29, 40]. t-GAS 8 consists of eight validated tGLI1 regulated genes (CD24, CD44, VEGF-A, VEGF-C, VEGFR2, TEM7, OCT-4. and heparanase) and is measured using qPCR in patients whose brain tissue expresses tGLI1 (by IHC). The distribution of the tGAS will be examined and transformed to approximate the conditional normality assumption if necessary. Analysis of variance (ANOVA) methods will be used to determine the effects of different factors of interest (e.g., treatment or tumor type) on the outcomes measured.
measure: tGLI1 pathway activation
time frame: Up to 30 days after surgery
description: tGLI1 pathway activation will be compared between treatment groups using ANOVA as described for the analysis of primary objective.
measure: Incidence of adverse events (AEs)
time frame: Up to 30 days after surgery
description: The safety of ketoconazole will be defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0 criteria and determined by adverse event proportions. The adverse event proportions will be compared between treatment groups using chi-squared tests. If feasible, a logistic regression model will be used to detect whether the adverse event proportion is higher in the treatment group after adjusting for the tumor type.
measure: Blood brain penetrance of ketoconazole in serum relative to enhancing brain tissue
time frame: Up to 30 days after surgery
description: The analysis will be the same as that for the analysis of primary objective.
measure: Serum ketoconazole concentrations in Cerebrospinal Fluid (CSF)
time frame: Up to 30 days after surgery
description: Measured using mass spectroscopy. The analysis will be the same as that for the analysis of primary objective. If the sample size is too small, the nonparametric approach will be considered as the primary analysis.
measure: Serum ketoconazole concentrations in enhancing brain tissue
time frame: Up to 30 days after surgery
description: Measured using mass spectroscopy. The analysis will be the same as that for the analysis of primary objective. If the sample size is too small, the nonparametric approach will be considered as the primary analysis.
measure: Serum ketoconzcole concentrations in unenhancing brain tissue
time frame: Up to 30 days after surgery
description: Measured using mass spectroscopy. The analysis will be the same as that for the analysis of primary objective. If the sample size is too small, the nonparametric approach will be considered as the primary analysis.
measure: Changes in tGLI1 signaling pathway
time frame: Baseline up to 30 days after surgery
description: Will be calculated and compared between treatment groups. Ideally analysis of covariance should be done. However, due to the small sample size, ANOVA as described for the primary analysis approach or the 2-sample t test will be used. If needed, non-parametric approaches will be used instead.
measure: Overall survival (OS)
time frame: From the date of the starting ketoconazole to the date of death from any cause, assessed up to 30 days after ketoconazole treatment completion
description: The Kaplan-Meier method will be used to estimate OS probability and median time of survival along with the 95% confidence interval.
arm group label: Arm I (ketoconazole)
arm group type: Experimental
description: Patients receive ketoconazole PO QD on days 1-4 before standard surgery in the absence of disease progression or unacceptable toxicity.
arm group label: Arm II (standard surgery)
arm group type: Active Comparator
description: Patients undergo standard surgery.
intervention type: Other
intervention name: Best Practice
description: Undergo standard surgery
arm group label: Arm I (ketoconazole)
arm group label: Arm II (standard surgery)
other name: standard of care
other name: standard therapy
intervention type: Drug
intervention name: Ketoconazole
description: Given PO
arm group label: Arm I (ketoconazole)
other name: Fungarest
other name: Fungoral
other name: Ketoderm
other name: Ketoisdin
other name: Nizoral
other name: Orifungal M
other name: Panfungol
other name: R-41400
other name: Xolegel
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Roy Strowd
role: Principal Investigator
affiliation: Wake Forest University Health Sciences
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Breast Neoplasms
mesh term: Glioma
mesh term: Brain Neoplasms
mesh term: Astrocytoma
mesh term: Oligodendroglioma
mesh term: Ketoconazole