<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/NCT04414540</url>
  </required_header>
  <id_info>
    <org_study_id>UCCC-HN-19-01</org_study_id>
    <nct_id>NCT04414540</nct_id>
  </id_info>
  <brief_title>Combining Pembrolizumab and Metformin in Metastatic Head and Neck Cancer Patients</brief_title>
  <official_title>A Phase 2 Feasibility Study Combining Pembrolizumab and Metformin to Harness the Natural Killer Cytotoxic Response in Metastatic Head and Neck Cancer Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Trisha Wise-Draper</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>American Cancer Society, Inc.</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Cincinnati</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine anti-tumor activity by measuring overall response&#xD;
      rate in recurrent and/or metastatic HNSCC patients receiving the combination of metformin and&#xD;
      pembrolizumab.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Recurrent and/or metastatic HNSCC patients will be treated with combination of metformin and&#xD;
      pembrolizumab. Patients will be randomized into arms 1 and 2, to either receive Metformin&#xD;
      prior to pembrolizumab or to begin Metformin after pembrolizumab treatment begins. The&#xD;
      patients are randomized for the exploratory endpoints in order to better understand the&#xD;
      difference of effects of metformin versus pembrolizumab on the immune system although&#xD;
      efficacy is based on combination.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 31, 2020</start_date>
  <completion_date type="Anticipated">July 2024</completion_date>
  <primary_completion_date type="Anticipated">July 2023</primary_completion_date>
  <phase>Phase 2</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>
    <intervention_model_description>Patients will be on one of two arms that will be studied in parallel.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall Response by RECIST 1.1 and iRECIST</measure>
    <time_frame>2 years</time_frame>
    <description>To determine anti-tumor activity by measuring overall response rate by RECIST 1.1 and iRECIST in recurrent and/or metastatic HNSCC patients receiving the combination of metformin and pembrolizumab.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of patients with adverse events measured by CTCAE v5.0</measure>
    <time_frame>2 years</time_frame>
    <description>To observe and record safety of combination in metastatic HNSCC patients receiving the combination of metformin and pembrolizumab. AEs will be graded and recorded according to NCI CTCAE Version 5.0.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS)</measure>
    <time_frame>1 year</time_frame>
    <description>To observe and record progression free survival in recurrent and/or metastatic HNSCC patients receiving the combination of metformin and pembrolizumab.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>1 year</time_frame>
    <description>To observe and record overall survival in recurrent and/or metastatic HNSCC patients receiving the combination of metformin and pembrolizumab.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Percentage of peripheral blood immune cell populations determined by flow cytometry</measure>
    <time_frame>4 weeks</time_frame>
    <description>Peripheral blood will be collected from each treatment group</description>
  </other_outcome>
  <other_outcome>
    <measure>Percent tumor infiltrating NK cells determined by immunofluorescence</measure>
    <time_frame>4 weeks</time_frame>
    <description>FFPE will be stained with NK cell antibodies to determine infiltrating NK cells</description>
  </other_outcome>
  <other_outcome>
    <measure>Cytokine levels including IL-2, IL-4, IL-6, IL-8, IL-10, INFgamma, TNFalpha in Plasma via ELISA based technology.</measure>
    <time_frame>4 weeks</time_frame>
    <description>Plasma will be separated from peripheral blood from both treatment groups</description>
  </other_outcome>
  <other_outcome>
    <measure>Percentage of NK cell cytotoxicity via Natural Killer Cell Cytotoxicity Flow Based Assays.</measure>
    <time_frame>4 weeks</time_frame>
    <description>Peripheral Blood separated for NK cells will be used from both treatment groups.</description>
  </other_outcome>
  <other_outcome>
    <measure>Stat-3 RNA levels in NK cells via RNA in situ</measure>
    <time_frame>4 weeks</time_frame>
    <description>FFPE will be used from both treatment groups.</description>
  </other_outcome>
  <other_outcome>
    <measure>Percent secretion of NKG2D soluble ligands via ELISA.</measure>
    <time_frame>4 weeks</time_frame>
    <description>Peripheral Blood will be used from both treatment groups</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Head and Neck Squamous Cell Carcinoma</condition>
  <arm_group>
    <arm_group_label>Arm 1: Metformin before Pembrolizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Metformin ER 1000mg daily D-14 to D-7. Metformin ER 2000mg daily D-7 to D1. D1 Begin Pembrolizumab 200mg every 3 weeks, while continuing Metformin ER 2000mg daily.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm 2: Metformin after Pembrolizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>D-21 Begin Pembrolizumab 200mg. D-7 begin Metformin ER 1000mg daily. D1 begin Metformin ER 2000mg daily. Continue Pembrolizumab 200mg every 3 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin Extended Release Oral Tablet</intervention_name>
    <description>Metformin ER starting dose 1000mg daily Metformin ER escalation dose 2000mg daily</description>
    <arm_group_label>Arm 1: Metformin before Pembrolizumab</arm_group_label>
    <arm_group_label>Arm 2: Metformin after Pembrolizumab</arm_group_label>
    <other_name>Glucophage XR</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Pembrolizumab q 3 weeks</description>
    <arm_group_label>Arm 1: Metformin before Pembrolizumab</arm_group_label>
    <arm_group_label>Arm 2: Metformin after Pembrolizumab</arm_group_label>
    <other_name>Keytruda</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically or cytologically confirmed recurrent or metastatic non-cutaneous HNSCC&#xD;
             for which there are no surgical or radiation curative options.&#xD;
&#xD;
          -  Patients may have received up to 3 prior lines of therapy for metastatic or recurrent&#xD;
             disease.&#xD;
&#xD;
          -  ECOG performance status ≤2&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with nasopharyngeal HNSCC will be excluded&#xD;
&#xD;
          -  Patients who have had chemotherapy or radiotherapy within 2 weeks prior to entering&#xD;
             the study.&#xD;
&#xD;
          -  Patients who have not recovered from adverse events due to prior anti-cancer therapy&#xD;
&#xD;
          -  Patients who have previously received PD-1 or PD-L1 inhibitors for&#xD;
             metastatic/recurrent disease&#xD;
&#xD;
          -  Patients currently receiving metformin or who have received metformin in the last 6&#xD;
             months&#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>Trisha Wise-Draper, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Cincinnati</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>UCCC Clinical Trials Office</last_name>
    <phone>513-584-7698</phone>
    <email>cancer@uchealth.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>University of Cincinnati Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45219</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>UCCC CTO</last_name>
      <phone>513-584-7698</phone>
      <email>cancer@uchealth.com</email>
    </contact>
    <investigator>
      <last_name>Trisha Wise-Draper, MD,PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>May 11, 2020</study_first_submitted>
  <study_first_submitted_qc>May 29, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 4, 2020</study_first_posted>
  <last_update_submitted>October 3, 2022</last_update_submitted>
  <last_update_submitted_qc>October 3, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 4, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Cincinnati</investigator_affiliation>
    <investigator_full_name>Trisha Wise-Draper</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Head and Neck Neoplasms</mesh_term>
    <mesh_term>Squamous Cell Carcinoma of Head and Neck</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metformin</mesh_term>
    <mesh_term>Pembrolizumab</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/NCT04414540
org study id: UCCC-HN-19-01
nct id: NCT04414540
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study is to determine anti-tumor activity by measuring overall response
      rate in recurrent and/or metastatic HNSCC patients receiving the combination of metformin and
      pembrolizumab.
Recurrent and/or metastatic HNSCC patients will be treated with combination of metformin and
      pembrolizumab. Patients will be randomized into arms 1 and 2, to either receive Metformin
      prior to pembrolizumab or to begin Metformin after pembrolizumab treatment begins. The
      patients are randomized for the exploratory endpoints in order to better understand the
      difference of effects of metformin versus pembrolizumab on the immune system although
      efficacy is based on combination.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Patients will be on one of two arms that will be studied in parallel.
primary purpose: Treatment
masking: None (Open Label)
measure: Overall Response by RECIST 1.1 and iRECIST
time frame: 2 years
description: To determine anti-tumor activity by measuring overall response rate by RECIST 1.1 and iRECIST in recurrent and/or metastatic HNSCC patients receiving the combination of metformin and pembrolizumab.
measure: Number of patients with adverse events measured by CTCAE v5.0
time frame: 2 years
description: To observe and record safety of combination in metastatic HNSCC patients receiving the combination of metformin and pembrolizumab. AEs will be graded and recorded according to NCI CTCAE Version 5.0.
measure: Progression Free Survival (PFS)
time frame: 1 year
description: To observe and record progression free survival in recurrent and/or metastatic HNSCC patients receiving the combination of metformin and pembrolizumab.
measure: Overall Survival (OS)
time frame: 1 year
description: To observe and record overall survival in recurrent and/or metastatic HNSCC patients receiving the combination of metformin and pembrolizumab.
measure: Percentage of peripheral blood immune cell populations determined by flow cytometry
time frame: 4 weeks
description: Peripheral blood will be collected from each treatment group
measure: Percent tumor infiltrating NK cells determined by immunofluorescence
time frame: 4 weeks
description: FFPE will be stained with NK cell antibodies to determine infiltrating NK cells
measure: Cytokine levels including IL-2, IL-4, IL-6, IL-8, IL-10, INFgamma, TNFalpha in Plasma via ELISA based technology.
time frame: 4 weeks
description: Plasma will be separated from peripheral blood from both treatment groups
measure: Percentage of NK cell cytotoxicity via Natural Killer Cell Cytotoxicity Flow Based Assays.
time frame: 4 weeks
description: Peripheral Blood separated for NK cells will be used from both treatment groups.
measure: Stat-3 RNA levels in NK cells via RNA in situ
time frame: 4 weeks
description: FFPE will be used from both treatment groups.
measure: Percent secretion of NKG2D soluble ligands via ELISA.
time frame: 4 weeks
description: Peripheral Blood will be used from both treatment groups
arm group label: Arm 1: Metformin before Pembrolizumab
arm group type: Experimental
description: Metformin ER 1000mg daily D-14 to D-7. Metformin ER 2000mg daily D-7 to D1. D1 Begin Pembrolizumab 200mg every 3 weeks, while continuing Metformin ER 2000mg daily.
arm group label: Arm 2: Metformin after Pembrolizumab
arm group type: Experimental
description: D-21 Begin Pembrolizumab 200mg. D-7 begin Metformin ER 1000mg daily. D1 begin Metformin ER 2000mg daily. Continue Pembrolizumab 200mg every 3 weeks.
intervention type: Drug
intervention name: Metformin Extended Release Oral Tablet
description: Metformin ER starting dose 1000mg daily Metformin ER escalation dose 2000mg daily
arm group label: Arm 1: Metformin before Pembrolizumab
arm group label: Arm 2: Metformin after Pembrolizumab
other name: Glucophage XR
intervention type: Drug
intervention name: Pembrolizumab
description: Pembrolizumab q 3 weeks
arm group label: Arm 1: Metformin before Pembrolizumab
arm group label: Arm 2: Metformin after Pembrolizumab
other name: Keytruda
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Trisha Wise-Draper, MD, PhD
role: Principal Investigator
affiliation: University of Cincinnati
last name: UCCC Clinical Trials Office
phone: 513-584-7698
email: cancer@uchealth.com
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Cincinnati
investigator full name: Trisha Wise-Draper
investigator title: Principal Investigator
mesh term: Head and Neck Neoplasms
mesh term: Squamous Cell Carcinoma of Head and Neck
mesh term: Metformin
mesh term: Pembrolizumab
sharing ipd: No