<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/NCT01729260</url>
  </required_header>
  <id_info>
    <org_study_id>J1194</org_study_id>
    <secondary_id>NA_00049848</secondary_id>
    <nct_id>NCT01729260</nct_id>
  </id_info>
  <brief_title>Mebendazole in Newly Diagnosed High-Grade Glioma Patients Receiving Temozolomide</brief_title>
  <acronym>Mebendazole</acronym>
  <official_title>Phase I Study of Mebendazole in Newly Diagnosed High-Grade Glioma Patients Receiving Temozolomide</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Accelerate Brain Cancer Cure</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to find the highest dose of mebendazole (MBZ) that can be safely&#xD;
      given to people with malignant brain tumors in combination with the current standard of care&#xD;
      (temozolomide) without causing severe side effects. We also want to find out if MBZ can slow&#xD;
      the growth of the brain tumor. The study doctors have found that MBZ is effective against&#xD;
      malignant brain tumors in the laboratory and animal models of brain tumors.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Glioblastoma (GBM) is the most common and aggressive brain cancer, and despite significant&#xD;
      advances in treatment the majority of patients die within two years of diagnosis. During&#xD;
      routine animal studies we serendipitously observed that fenbendazole, a benzimidazole&#xD;
      antihelminthic used for pinworms, prevented tumor engraftment. Subsequent in vitro and in&#xD;
      vivo experiments with benzimidazoles identified mebendazole as the drug having the best&#xD;
      results in preclinical testing 1. In GBM cell lines, mebendazole displayed cytotoxicity with&#xD;
      IC50s ranging from 0.1-0.3 μM. Mebendazole disrupted microtubule formation in GBM cells and&#xD;
      it's in vitro activity was correlated with reduced tubulin polymerization. In two orthotopic&#xD;
      mouse glioma models, one syngeneic and one xenograft, mebendazole significantly extended&#xD;
      average survival up to 63% compared to untreated controls 1.&#xD;
&#xD;
      Mebendazole is an FDA approved antiparasitic agent with a well-established side effect and&#xD;
      safety record and was effective in our animal models in dosing schedules that are documented&#xD;
      as safe in humans. Therefore, mebendazole is a possible anti-cancer therapeutic with&#xD;
      pre-clinical safety and efficacy and provides a promising opportunity for a clinical trial in&#xD;
      patients with malignant gliomas.&#xD;
&#xD;
      In addition, a recently published case report case report from the University of Michigan&#xD;
      documented successful long term control in metastatic adrenocortical adenocarcinoma using&#xD;
      mebendazole 2. Mebendazole was well tolerated at 200 mg/day and used as the sole treatment&#xD;
      after the patient failed other chemotherapies.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 4, 2013</start_date>
  <completion_date type="Actual">April 16, 2021</completion_date>
  <primary_completion_date type="Actual">September 2016</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>maximum tolerated dose (MTD) of mebendazole</measure>
    <time_frame>8 months</time_frame>
    <description>To determine the maximum tolerated dose (MTD) of mebendazole in combination with temozolomide (TMZ) given after surgery and the standard radiation and TMZ treatment in patients with newly diagnosed malignant gliomas.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>10 years</time_frame>
    <description>Overall survival in years.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Newly Diagnosed High-Grade Glioma</condition>
  <arm_group>
    <arm_group_label>Mebendazole</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All study participants will receive study drug; Mebendazole.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Mebendazole</intervention_name>
    <description>The mebendazole will be given by mouth three times every day on a 28 day cycle. it's in the form of 500 mg chewable tablets, to be taken with meals.</description>
    <arm_group_label>Mebendazole</arm_group_label>
    <other_name>Brand name: Vermox</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients must have histologically confirmed newly diagnosed high-grade glioma(WHO&#xD;
             Grade III or IV)&#xD;
&#xD;
          2. Age ≥18 years&#xD;
&#xD;
          3. Karnofsky Performance Score (KPS) ≥ 60%&#xD;
&#xD;
          4. Life expectancy greater than 12 weeks&#xD;
&#xD;
          5. Patients must have adequate organ and marrow function&#xD;
&#xD;
          6. Completed &gt;80% of the prescribed radiation therapy and concurrent temozolomide&#xD;
             according to the Stupp regimen without grade 3 or 4 hematologic toxicity&#xD;
&#xD;
          7. Patients may have received Gliadel during surgery&#xD;
&#xD;
          8. Ability to swallow pills and keep medication record&#xD;
&#xD;
          9. 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;
         10. Ability to understand and willingness to sign a written informed consent document&#xD;
&#xD;
         11. Be able to comply with treatment plan, study procedures and follow-up examinations&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients must not have received prior therapy other than standard chemoradiation&#xD;
             according to Stupp et al and Gliadel.&#xD;
&#xD;
          2. Patients may not be receiving any other investigational agents while on study&#xD;
&#xD;
          3. Patients who have known allergy to mebendazole or benzimidazole&#xD;
&#xD;
          4. Patients who have previously had a severe side effect, such as agranulocytosis and&#xD;
             neutropenia, in conjunction with previous mebendazole or benzimidazole class drug for&#xD;
             a parasitic infection&#xD;
&#xD;
          5. Patients who are taking metronidazole and cannot be safely moved to a different&#xD;
             antibiotic greater than 7 days prior to starting mebendazole therapy&#xD;
&#xD;
          6. Patients who have taken any benzimidazole (ABZ, flubendazole, thiabendazole,&#xD;
             fenbendazole, triclabendazole, etc.) within the last 3 months&#xD;
&#xD;
          7. Patients who are taking any anti-convulsant medication that interferes with the&#xD;
             cytochrome P450 pathway (e.g. phenytoin, phenobarbital, carbamazepine, etc.)&#xD;
&#xD;
          8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, uncontrolled hypertension, symptomatic congestive heart failure, unstable&#xD;
             angina pectoris, cardiac arrhythmia, chronic hepatitis, acute hepatitis, or&#xD;
             psychiatric illness/social situation that would limit compliance with study&#xD;
             requirements&#xD;
&#xD;
          9. Pregnant women are excluded&#xD;
&#xD;
         10. Patients with human immunodeficiency virus (HIV), hepatitis B surface antigen or&#xD;
             hepatitis C positive; or with a history of chronic active hepatitis or cirrhosis&#xD;
&#xD;
         11. 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;
         12. Patients who are not available for follow-up assessments or unable to comply with&#xD;
             study requirements&#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>Gary Gallia, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Johns Hopkins University School of Medicine, Department of Neurosurgery</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>The Johs Hopkins Hospital</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2021</verification_date>
  <study_first_submitted>November 13, 2012</study_first_submitted>
  <study_first_submitted_qc>November 13, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 20, 2012</study_first_posted>
  <last_update_submitted>May 6, 2021</last_update_submitted>
  <last_update_submitted_qc>May 6, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">May 7, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Glioblastoma</keyword>
  <keyword>mebendazole</keyword>
  <keyword>temozolomide</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mebendazole</mesh_term>
    <mesh_term>Piperazine</mesh_term>
    <mesh_term>Piperazine citrate</mesh_term>
    <mesh_term>DMP 777</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/NCT01729260
org study id: J1194
secondary id: NA_00049848
nct id: NCT01729260
lead sponsor: 
collaborator: 
has dmc: Yes
The purpose of this study is to find the highest dose of mebendazole (MBZ) that can be safely
      given to people with malignant brain tumors in combination with the current standard of care
      (temozolomide) without causing severe side effects. We also want to find out if MBZ can slow
      the growth of the brain tumor. The study doctors have found that MBZ is effective against
      malignant brain tumors in the laboratory and animal models of brain tumors.
Glioblastoma (GBM) is the most common and aggressive brain cancer, and despite significant
      advances in treatment the majority of patients die within two years of diagnosis. During
      routine animal studies we serendipitously observed that fenbendazole, a benzimidazole
      antihelminthic used for pinworms, prevented tumor engraftment. Subsequent in vitro and in
      vivo experiments with benzimidazoles identified mebendazole as the drug having the best
      results in preclinical testing 1. In GBM cell lines, mebendazole displayed cytotoxicity with
      IC50s ranging from 0.1-0.3 μM. Mebendazole disrupted microtubule formation in GBM cells and
      it's in vitro activity was correlated with reduced tubulin polymerization. In two orthotopic
      mouse glioma models, one syngeneic and one xenograft, mebendazole significantly extended
      average survival up to 63% compared to untreated controls 1.

      Mebendazole is an FDA approved antiparasitic agent with a well-established side effect and
      safety record and was effective in our animal models in dosing schedules that are documented
      as safe in humans. Therefore, mebendazole is a possible anti-cancer therapeutic with
      pre-clinical safety and efficacy and provides a promising opportunity for a clinical trial in
      patients with malignant gliomas.

      In addition, a recently published case report case report from the University of Michigan
      documented successful long term control in metastatic adrenocortical adenocarcinoma using
      mebendazole 2. Mebendazole was well tolerated at 200 mg/day and used as the sole treatment
      after the patient failed other chemotherapies.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: maximum tolerated dose (MTD) of mebendazole
time frame: 8 months
description: To determine the maximum tolerated dose (MTD) of mebendazole in combination with temozolomide (TMZ) given after surgery and the standard radiation and TMZ treatment in patients with newly diagnosed malignant gliomas.
measure: Overall Survival
time frame: 10 years
description: Overall survival in years.
arm group label: Mebendazole
arm group type: Experimental
description: All study participants will receive study drug; Mebendazole.
intervention type: Drug
intervention name: Mebendazole
description: The mebendazole will be given by mouth three times every day on a 28 day cycle. it's in the form of 500 mg chewable tablets, to be taken with meals.
arm group label: Mebendazole
other name: Brand name: Vermox
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Gary Gallia, MD
role: Principal Investigator
affiliation: Johns Hopkins University School of Medicine, Department of Neurosurgery
facility: 
country: United States
responsible party type: Sponsor
mesh term: Glioma
mesh term: Mebendazole
mesh term: Piperazine
mesh term: Piperazine citrate
mesh term: DMP 777