<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/NCT03268993</url>
  </required_header>
  <id_info>
    <org_study_id>18-028</org_study_id>
    <nct_id>NCT03268993</nct_id>
  </id_info>
  <brief_title>Effects of Avmacol® in the Oral Mucosa of Patients Following Curative Treatment for Tobacco-related Head and Neck Cancer</brief_title>
  <official_title>A Phase 0 Study Evaluating the Systemic Bioavailability and Pharmacodynamic Effects of Avmacol® in the Oral Mucosa of Patients Following Curative Treatment for Tobacco-related Head and Neck Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Pittsburgh</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Arizona</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pittsburgh</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Avmacol is an over-the-counter dietary supplement containing broccoli seed and sprout&#xD;
      extracts in tablet form, hypothesized to activate protective cellular pathways including&#xD;
      detoxication. In this study, participants who have been curatively treatment for head and&#xD;
      neck cancer, will take Avmacol twice a day for 3 months.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The broccoli seed preparation, Avmacol®, results in acute and/or sustained induction of NRF2&#xD;
      target gene transcripts in the oral mucosa of patients who have been curatively treated for a&#xD;
      tobacco-related head and neck squamous cell carcinoma (HNSCC), including high grade&#xD;
      dysplasia, carcinoma in situ, or invasive carcinoma. This study is not designed to examine&#xD;
      the therapeutic or reparative effects of Avmacol® on premalignant lesions of the oral cavity.&#xD;
&#xD;
      We will systematically assess the clinical chemopreventive potential of Avmacol®&#xD;
      administration to patients with tobacco-related HNSCC at high risk for second primary tumor&#xD;
      by:&#xD;
&#xD;
        1. Conducting this phase 0 clinical study to evaluate the pharmacodynamic range of NRF2&#xD;
           pathway activation in the oral mucosa of HNSCC patients, in response to two tolerable&#xD;
           and bioactive doses of Avmacol®;&#xD;
&#xD;
        2. Determining whether the level of NRF2 pathway activation achieved in human oral&#xD;
           epithelium is chemopreventive in the NQO1 murine model of environmental carcinogenesis;&#xD;
           and&#xD;
&#xD;
        3. Analyzing specimens from the Phase 0 trial to determine whether Avmacol® induces changes&#xD;
           in alternative biomarkers of SF chemopreventive efficacy identified in the laboratory.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 27, 2018</start_date>
  <completion_date type="Actual">July 22, 2019</completion_date>
  <primary_completion_date type="Actual">July 22, 2019</primary_completion_date>
  <phase>N/A</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>
    <intervention_model_description>Thirty-six individuals who have previously been treated for tobacco-related, HPV-negative HNSCC will be recruited for this study.&#xD;
After being deemed eligible, subjects will be assigned a patient number and be registered into the CTMA database.&#xD;
At registration, they will be randomized to receive either 4 tablets/day in Cycle 1 or 8 tablets/day in Cycle 1 (and the other dose in Cycle 2). This randomization is not blinded. Randomization will be stratified by history of head and neck radiation therapy (yes or no).</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in NRF2 target gene expression</measure>
    <time_frame>From baseline throughout treatment period, up to 4 months</time_frame>
    <description>Quantitative changes in NRF2 target gene transcripts expression (i.e. NQO1 and GCLC) in oral mucosa (buccal cytobrush) by quantitative polymerase chain reaction (qPCR) according to a linear mixed model framework.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in NRF2 target proteins</measure>
    <time_frame>From baseline throughout treatment period, up to 4 months</time_frame>
    <description>Changes in NRF2 target proteins in buccal punch biopsies by immunoblotting.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in NRF2 target gene transcripts</measure>
    <time_frame>From baseline throughout treatment period, up to 4 months</time_frame>
    <description>Change in NRF2 target gene transcripts, between the two doses of Avmacol® by immunoblotting.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in NRF2-independent proteins</measure>
    <time_frame>From baseline throughout treatment period, up to 4 months</time_frame>
    <description>Change in NRF2 target gene transcripts, between the two doses of Avmacol® by immunoblotting.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Alterations of Avmacol® activity in PBMCs - NK cells</measure>
    <time_frame>From baseline throughout treatment period, up to 4 months</time_frame>
    <description>Changes in Peripheral Blood Mononuclear Cells (PBMC) gene expression and flow cytometry patterns in NK cells.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Alterations of Avmacol® activity in PBMCs - T cells</measure>
    <time_frame>From baseline throughout treatment period, up to 4 months</time_frame>
    <description>Changes in Peripheral Blood Mononuclear Cells (PBMC) gene expression and flow cytometry patterns in T cells.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum cytokine levels</measure>
    <time_frame>From baseline throughout treatment period, up to 4 months</time_frame>
    <description>Change in serum cytokine levels, as determined by multiplexed bead-based cytokine assays.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measurement of serum albumin-bound SF</measure>
    <time_frame>From baseline throughout treatment period, up to 4 months</time_frame>
    <description>Measurement of urinary metabolites of SF using isotope dilution mass spectrometry.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety profile in accordance with NCI CTCAE v.4</measure>
    <time_frame>Throughout treatment period, up to 4 months</time_frame>
    <description>Patients will receive a diary for daily logging of adverse events. This will tabulated by Avmacol dose and type and grade of adverse events. The mean frequency and grade of events will be calculated by dose, and between-dose differences compared by means</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients primary tumors harboring genomic alteration of NRF2 related genes</measure>
    <time_frame>At baseline</time_frame>
    <description>Genomic alterations in primary tumors will be characterized and the proportion determined by number of patients with NRF2 related genes per the total number of patients studied.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">6</enrollment>
  <condition>Head and Neck Cancer</condition>
  <condition>Head and Neck Squamous Cell Carcinoma (HNSCC)</condition>
  <condition>Head and Neck Carcinoma</condition>
  <condition>Head and Neck</condition>
  <condition>Tobacco-Related Carcinoma</condition>
  <condition>Carcinoma in Situ</condition>
  <condition>Dysplasia</condition>
  <condition>Hyperplasia</condition>
  <condition>Premalignant Lesion</condition>
  <arm_group>
    <arm_group_label>Avmacol</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>You will be given a higher dose of Avmacol® each month, taking 2 Avmacol® tablets per day the first month (Cycle 1), 4 Avmacol® tablets per day the second month (Cycle 2), and 8 Avmacol® tablets per day the third month (Cycle 3). Investigators will study how Avmacol® affects your body by collecting three different tissues: 1) your cheek cells (buccal cells); 2) your urine; and 3) your blood. After you have finished three months of Avmacol®, you will return one month later for an end-of-study visit.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Avmacol</intervention_name>
    <description>Avmacol is a dietary supplement available over the counter</description>
    <arm_group_label>Avmacol</arm_group_label>
    <other_name>broccoli see extract</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Participants must have completed curative-intent therapy (including surgery,&#xD;
             radiation, and/or chemotherapy) for a first tobacco-related oral premalignant lesion&#xD;
             (OPL) or HNSCC of any stage (eligible lesions include high grade dysplasia; carcinoma&#xD;
             in situ; or stage I-IVa HNSCC).&#xD;
&#xD;
          2. Primary site may include oral cavity, pharynx, or larynx. Oropharynx primaries must be&#xD;
             HPV (-) as defined by routine p16 IHC at the local site.&#xD;
&#xD;
          3. Participants may be enrolled between 3 months and 5 years AFTER completion of&#xD;
             curative-intent therapy (including surgery, radiotherapy, and/or chemotherapy).&#xD;
&#xD;
          4. Participants may have untreated OPLs (i.e., hyperplasia, dysplasia, carcinoma in situ)&#xD;
             at the time of study entry, provided the index OPL or HNSCC was definitively treated.&#xD;
&#xD;
          5. Participants must be at least 18 years old.&#xD;
&#xD;
          6. Participants must have a Karnofsky Performance Status of 80% or higher or an ECOG of&#xD;
             0-1 (Appendix A).&#xD;
&#xD;
          7. Current and former tobacco users are eligible. The tobacco use assessment form must be&#xD;
             completed following consent, to assure eligibility (Appendix B). Patients must have&#xD;
             ≥10 pack-year cumulative tobacco exposure or its equivalent to be eligible. This is&#xD;
             defined as follows:&#xD;
&#xD;
               1. Cigarette exposure: ≥10 pack-years OR&#xD;
&#xD;
               2. Cigar exposure: ≥ 10 cigar-years, where 1 cigar year is defined as having smoked&#xD;
                  on average ≥ 1 cigar/day for a year OR&#xD;
&#xD;
               3. Chewing tobacco: ≥10 snuff-years, where 1 snuff year is defined as using on&#xD;
                  average ≥ 1 pinch (dip) of chewing tobacco/day for a year.&#xD;
&#xD;
          8. Able to perform written, informed consent.&#xD;
&#xD;
          9. Women of childbearing potential (WCBP) must have a negative urine pregnancy test&#xD;
             within 7 Days prior to the first study intervention.&#xD;
&#xD;
         10. WCBP and men must agree to use adequate contraception (hormonal or barrier method of&#xD;
             birth control; abstinence) prior to study entry and for the duration of study&#xD;
             participation. Should a woman become pregnant or suspect she is pregnant while she or&#xD;
             her partner is participating in this study, she should inform her treating physician&#xD;
             immediately. Men treated or enrolled on this protocol must also agree to use adequate&#xD;
             contraception prior to the study and for the duration of study participation.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Participants have a history of another malignancy within 2 years prior to starting&#xD;
             study treatment, except for excised and cured carcinoma-in-situ of breast or cervix;&#xD;
             non-melanomatous skin cancer; T1-2, N0, M0 differentiated thyroid carcinoma either&#xD;
             resected or under active surveillance; superficial bladder cancer; T1a or T1b prostate&#xD;
             cancer comprising &lt; 5% of resected tissue with normal prostate specific antigen (PSA)&#xD;
             since resection, or status post external beam radiation or brachytherapy with normal&#xD;
             PSA since radiation.&#xD;
&#xD;
          2. Primary oropharyngeal HNSCC which is HPV (+) as defined by p16 IHC.&#xD;
&#xD;
          3. Participants with acute intercurrent illness or those who had major surgery within the&#xD;
             preceding 4 weeks unless they have fully recovered.&#xD;
&#xD;
          4. Participants who have a positive pregnancy test, are pregnant, or breast feeding.&#xD;
&#xD;
          5. Patients who are not practicing adequate contraception are ineligible if they are of&#xD;
             child bearing potential.&#xD;
&#xD;
          6. Patients currently using anti-neoplastic or anti-tumor agents, including chemotherapy,&#xD;
             radiation therapy, immunotherapy, and hormonal anticancer therapy.&#xD;
&#xD;
          7. Chronic anticoagulation with warfarin. Patients on low molecular weight heparin or&#xD;
             fondaparinux may be enrolled.&#xD;
&#xD;
          8. Use of chronic prescribed medications which are potent inducers or inhibitors of&#xD;
             CYP3A4 (Appendix C).&#xD;
&#xD;
          9. Chronic use of steroids at immunosuppressive doses. (Note, physiologic replacement&#xD;
             doses of glucocorticoid or mineralocorticoid are acceptable, eg. prednisone 5-10&#xD;
             mg/day; fludrocortisone 0.1-0.2 mg/day.)&#xD;
&#xD;
         10. History of severe food intolerance to broccoli.&#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>Dan P Zandberg, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pittsburgh</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UPMC Eye Center - Eye and Ear Institute</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UPMC Hillman Cancer Center</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>July 10, 2017</study_first_submitted>
  <study_first_submitted_qc>August 28, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 31, 2017</study_first_posted>
  <last_update_submitted>April 5, 2023</last_update_submitted>
  <last_update_submitted_qc>April 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 7, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Pittsburgh</investigator_affiliation>
    <investigator_full_name>Dan Zandberg</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>prevention</keyword>
  <keyword>dietary supplement</keyword>
  <keyword>broccoli</keyword>
  <keyword>avmacol</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Head and Neck Neoplasms</mesh_term>
    <mesh_term>Squamous Cell Carcinoma of Head and Neck</mesh_term>
    <mesh_term>Carcinoma in Situ</mesh_term>
    <mesh_term>Precancerous Conditions</mesh_term>
    <mesh_term>Hyperplasia</mesh_term>
  </condition_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/NCT03268993
org study id: 18-028
nct id: NCT03268993
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Avmacol is an over-the-counter dietary supplement containing broccoli seed and sprout
      extracts in tablet form, hypothesized to activate protective cellular pathways including
      detoxication. In this study, participants who have been curatively treatment for head and
      neck cancer, will take Avmacol twice a day for 3 months.
The broccoli seed preparation, Avmacol®, results in acute and/or sustained induction of NRF2
      target gene transcripts in the oral mucosa of patients who have been curatively treated for a
      tobacco-related head and neck squamous cell carcinoma (HNSCC), including high grade
      dysplasia, carcinoma in situ, or invasive carcinoma. This study is not designed to examine
      the therapeutic or reparative effects of Avmacol® on premalignant lesions of the oral cavity.

      We will systematically assess the clinical chemopreventive potential of Avmacol®
      administration to patients with tobacco-related HNSCC at high risk for second primary tumor
      by:

        1. Conducting this phase 0 clinical study to evaluate the pharmacodynamic range of NRF2
           pathway activation in the oral mucosa of HNSCC patients, in response to two tolerable
           and bioactive doses of Avmacol®;

        2. Determining whether the level of NRF2 pathway activation achieved in human oral
           epithelium is chemopreventive in the NQO1 murine model of environmental carcinogenesis;
           and

        3. Analyzing specimens from the Phase 0 trial to determine whether Avmacol® induces changes
           in alternative biomarkers of SF chemopreventive efficacy identified in the laboratory.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Thirty-six individuals who have previously been treated for tobacco-related, HPV-negative HNSCC will be recruited for this study.
After being deemed eligible, subjects will be assigned a patient number and be registered into the CTMA database.
At registration, they will be randomized to receive either 4 tablets/day in Cycle 1 or 8 tablets/day in Cycle 1 (and the other dose in Cycle 2). This randomization is not blinded. Randomization will be stratified by history of head and neck radiation therapy (yes or no).
primary purpose: Basic Science
masking: None (Open Label)
measure: Change in NRF2 target gene expression
time frame: From baseline throughout treatment period, up to 4 months
description: Quantitative changes in NRF2 target gene transcripts expression (i.e. NQO1 and GCLC) in oral mucosa (buccal cytobrush) by quantitative polymerase chain reaction (qPCR) according to a linear mixed model framework.
measure: Change in NRF2 target proteins
time frame: From baseline throughout treatment period, up to 4 months
description: Changes in NRF2 target proteins in buccal punch biopsies by immunoblotting.
measure: Change in NRF2 target gene transcripts
time frame: From baseline throughout treatment period, up to 4 months
description: Change in NRF2 target gene transcripts, between the two doses of Avmacol® by immunoblotting.
measure: Change in NRF2-independent proteins
time frame: From baseline throughout treatment period, up to 4 months
description: Change in NRF2 target gene transcripts, between the two doses of Avmacol® by immunoblotting.
measure: Alterations of Avmacol® activity in PBMCs - NK cells
time frame: From baseline throughout treatment period, up to 4 months
description: Changes in Peripheral Blood Mononuclear Cells (PBMC) gene expression and flow cytometry patterns in NK cells.
measure: Alterations of Avmacol® activity in PBMCs - T cells
time frame: From baseline throughout treatment period, up to 4 months
description: Changes in Peripheral Blood Mononuclear Cells (PBMC) gene expression and flow cytometry patterns in T cells.
measure: Change in serum cytokine levels
time frame: From baseline throughout treatment period, up to 4 months
description: Change in serum cytokine levels, as determined by multiplexed bead-based cytokine assays.
measure: Measurement of serum albumin-bound SF
time frame: From baseline throughout treatment period, up to 4 months
description: Measurement of urinary metabolites of SF using isotope dilution mass spectrometry.
measure: Safety profile in accordance with NCI CTCAE v.4
time frame: Throughout treatment period, up to 4 months
description: Patients will receive a diary for daily logging of adverse events. This will tabulated by Avmacol dose and type and grade of adverse events. The mean frequency and grade of events will be calculated by dose, and between-dose differences compared by means
measure: Proportion of patients primary tumors harboring genomic alteration of NRF2 related genes
time frame: At baseline
description: Genomic alterations in primary tumors will be characterized and the proportion determined by number of patients with NRF2 related genes per the total number of patients studied.
arm group label: Avmacol
arm group type: Other
description: You will be given a higher dose of Avmacol® each month, taking 2 Avmacol® tablets per day the first month (Cycle 1), 4 Avmacol® tablets per day the second month (Cycle 2), and 8 Avmacol® tablets per day the third month (Cycle 3). Investigators will study how Avmacol® affects your body by collecting three different tissues: 1) your cheek cells (buccal cells); 2) your urine; and 3) your blood. After you have finished three months of Avmacol®, you will return one month later for an end-of-study visit.
intervention type: Dietary Supplement
intervention name: Avmacol
description: Avmacol is a dietary supplement available over the counter
arm group label: Avmacol
other name: broccoli see extract
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Dan P Zandberg, MD
role: Principal Investigator
affiliation: University of Pittsburgh
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Pittsburgh
investigator full name: Dan Zandberg
investigator title: Principal Investigator
mesh term: Carcinoma
mesh term: Head and Neck Neoplasms
mesh term: Squamous Cell Carcinoma of Head and Neck
mesh term: Carcinoma in Situ
mesh term: Precancerous Conditions
mesh term: Hyperplasia