<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/NCT03800602</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00106678</org_study_id>
    <secondary_id>NCI-2018-02201</secondary_id>
    <secondary_id>Winship4494-18</secondary_id>
    <secondary_id>P30CA138292</secondary_id>
    <nct_id>NCT03800602</nct_id>
  </id_info>
  <brief_title>Nivolumab and Metformin in Patients With Treatment Refractory MSS Colorectal Cancer</brief_title>
  <official_title>Phase II Trial of Nivolumab and Metformin in Patients With Treatment Refractory MSS Metastatic Colorectal Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Emory University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institutes of Health (NIH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Emory University</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>
      This phase II trial studies how well nivolumab and metformin work in treating patients with&#xD;
      microsatellite stable (MSS) stage IV colorectal cancer that has not responded to previous&#xD;
      treatment. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's&#xD;
      immune system attack the cancer, and may interfere with the ability of tumor cells to grow&#xD;
      and spread. Metformin is an antidiabetic drug that and may reduce the risk of colorectal&#xD;
      cancer development in patients. Giving nivolumab and metformin may work better in treating&#xD;
      patients with refractory microsatellite metastatic colorectal cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVE:&#xD;
&#xD;
      I. To evaluate the effect of nivolumab and metformin combination on the overall response rate&#xD;
      (ORR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the effect of nivolumab and metformin combination on clinical outcomes,&#xD;
      progression free survival and overall survival, and biochemical response (CEA).&#xD;
&#xD;
      II. To compare the effect of nivolumab and metformin combination on immune and metabolic&#xD;
      biomarkers in the tumor microenvironment and systemic circulation (pre and post treatment&#xD;
      paired biopsies required).&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive metformin PO BID starting on day 1. After 14 days of metformin only period&#xD;
      patients also receive nivolumab IV every 4 weeks starting on day 15. Courses repeat every 28&#xD;
      days for up to 2 years in the absence of disease progression, unacceptable toxicity or&#xD;
      consent withdrawal&#xD;
&#xD;
      After completion of study treatment, patients are followed up at day 30 and then periodically&#xD;
      thereafter.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 15, 2019</start_date>
  <completion_date type="Anticipated">January 31, 2025</completion_date>
  <primary_completion_date type="Anticipated">January 31, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <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>Overall response rate (ORR)</measure>
    <time_frame>Up to 1 year after study start</time_frame>
    <description>Response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1., and rate will be calculated as a proportion (responders/total patients).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression free survival (PFS)</measure>
    <time_frame>Assessed up to 2 years after study start</time_frame>
    <description>For progression free survival, progression or death from any cause will be defined as the event. Patients will be censored at time of last follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Assessed up to 2 years after study start</time_frame>
    <description>For overall survival, death from any cause will be defined as the event. Patients will be censored at time of last follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biological response: carcinoembryonic antigen (CEA)</measure>
    <time_frame>Up to 1 year after study start</time_frame>
    <description>Tumor marker carcinoembryonic antigen (CEA) will be assessed.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">24</enrollment>
  <condition>Colorectal Adenocarcinoma</condition>
  <condition>Metastatic Microsatellite Stable Colorectal Carcinoma</condition>
  <condition>Refractory Colorectal Carcinoma</condition>
  <condition>Stage IV Colorectal Cancer</condition>
  <condition>Stage IVA Colorectal Cancer</condition>
  <condition>Stage IVB Colorectal Cancer</condition>
  <condition>Stage IVC Colorectal Cancer</condition>
  <condition>Colorectal Cancer Metastatic</condition>
  <arm_group>
    <arm_group_label>Treatment (nivolumab, metformin)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive metformin PO BID starting on day 1. After 14 days of metformin only period patients also receive nivolumab IV every 4 weeks starting on day 15. Courses repeat every 28 days for up to 2 years in the absence of disease progression, unacceptable toxicity or consent withdrawal.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (nivolumab, metformin)</arm_group_label>
    <other_name>Glucophage</other_name>
    <other_name>Glumetza</other_name>
    <other_name>Fortamet</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (nivolumab, metformin)</arm_group_label>
    <other_name>BMS-936558</other_name>
    <other_name>MDX-1106</other_name>
    <other_name>NIVO</other_name>
    <other_name>ONO-4538</other_name>
    <other_name>Opdivo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have histologically or cytologically confirmed stage IV colorectal&#xD;
             adenocarcinoma with measurable disease&#xD;
&#xD;
          -  Prior treatment with 5 Fluorouracil (or capecitabine), oxaliplatin and irinotecan&#xD;
             containing chemotherapy (needs to be treated with anti-epidermal growth factor&#xD;
             receptor (EGFR) agent if extended RAS wild type)&#xD;
&#xD;
          -  Patients must have measurable disease, defined as at least one lesion that can be&#xD;
             accurately measured in at least one dimension (longest diameter to be recorded for&#xD;
             non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm with conventional&#xD;
             techniques or as ≥ 10 mm with spiral computed tomography (CT) scan, magnetic resonance&#xD;
             imaging (MRI), or calipers by clinical exam&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky ≥ 70%)&#xD;
&#xD;
          -  Life expectancy of greater than 3 months&#xD;
&#xD;
          -  Absolute neutrophil count ≥ 1,500/µL&#xD;
&#xD;
          -  Platelets ≥ 100,000/µL&#xD;
&#xD;
          -  Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or erythropoietin (EPO)&#xD;
             dependency (within 7 days of assessment)&#xD;
&#xD;
          -  Serum creatinine ≤ 1.5 x upper limit of normal (ULN) OR creatinine clearance ≥ 60&#xD;
             mL/min/1.73 m² for patients with creatinine levels &gt; 1.5 x ULN. Creatinine clearance&#xD;
             should be calculated per institutional standard&#xD;
&#xD;
          -  Serum total bilirubin ≤ 1.5 x the upper limit of normal (ULN) OR direct bilirubin ≤&#xD;
             ULN for subjects with total bilirubin &gt; 1.5 ULN&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic&#xD;
             transaminase[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate&#xD;
             transaminase [SGPT] ≤ 2.5 x institutional upper limit of normal&#xD;
&#xD;
          -  Serum albumin ≥ 2.5 mg/dl&#xD;
&#xD;
          -  International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless&#xD;
             subject is receiving anticoagulant therapy as long as PT or partial thromboplastin&#xD;
             time (PTT) is within therapeutic range of intended use of anticoagulants. Activated&#xD;
             partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless subject is receiving&#xD;
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use&#xD;
             of anticoagulants&#xD;
&#xD;
          -  Patients with diabetes mellitus should be on a stable diabetic treatment regimen for&#xD;
             at least 1 month prior to trial enrollment and keep a blood glucose level log at home&#xD;
             for the first 4 weeks of the trial&#xD;
&#xD;
          -  Female subject of childbearing potential should have a negative urine or serum&#xD;
             pregnancy within 72 hours prior to receiving the first dose of study medication; if&#xD;
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test&#xD;
             will be required&#xD;
&#xD;
          -  Male subjects of childbearing potential must agree to use an adequate method of&#xD;
             contraception, starting with the first dose of study therapy through 120 days after&#xD;
             the last dose of study therapy.&#xD;
&#xD;
               -  Note: Abstinence is acceptable if this is the usual lifestyle and preferred&#xD;
                  contraception for the subject&#xD;
&#xD;
          -  Female subjects of childbearing potential must be willing to use an adequate method of&#xD;
             contraception for the course of the study through 120 days after the last dose of&#xD;
             study medication&#xD;
&#xD;
               -  Note: Abstinence is acceptable if this is the usual lifestyle and preferred&#xD;
                  contraception for the subject&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering&#xD;
             the study or those who have not recovered from adverse events due to agents&#xD;
             administered more than 4 weeks earlier&#xD;
&#xD;
               -  Note: Subjects with ≤ grade 2 neuropathy are an exception to this criterion and&#xD;
                  may qualify for the study&#xD;
&#xD;
               -  Note: If subject received major surgery, they must have recovered adequately from&#xD;
                  the toxicity and/or complications from the intervention prior to starting therapy&#xD;
&#xD;
          -  Metformin use in the last 3 months&#xD;
&#xD;
          -  Patients who are receiving any other investigational agents&#xD;
&#xD;
          -  Has known active central nervous system (CNS) metastases and/or carcinomatous&#xD;
             meningitis; subjects with previously treated brain metastases may participate provided&#xD;
             they are stable (without evidence of progression by imaging for at least four weeks&#xD;
             prior to the first dose of trial treatment and any neurologic symptoms have returned&#xD;
             to baseline), have no evidence of new or enlarging brain metastases, and are not using&#xD;
             steroids for at least 7 days prior to trial treatment; this exception does not include&#xD;
             carcinomatous meningitis which is excluded regardless of clinical stability&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to nivolumab and metformin&#xD;
&#xD;
          -  Has a known history of active tuberculosis (TB) (Bacillus tuberculosis)&#xD;
&#xD;
          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any&#xD;
             other form of immunosuppressive therapy within 7 days prior to the first dose of trial&#xD;
             treatment&#xD;
&#xD;
          -  Has active autoimmune disease that has required systemic treatment in the past 2 years&#xD;
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive&#xD;
             drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid&#xD;
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a&#xD;
             form of systemic treatment&#xD;
&#xD;
          -  Has known history of, or any evidence of active, non-infectious pneumonitis&#xD;
&#xD;
          -  Has an active infection requiring systemic therapy&#xD;
&#xD;
          -  Has known substance abuse disorders that would interfere with cooperation with the&#xD;
             requirements of the trial&#xD;
&#xD;
          -  Has received prior therapy with an anti-programmed death (PD)-1, anti-PD-L1, or&#xD;
             anti-PD-L2 agent&#xD;
&#xD;
          -  Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)&#xD;
&#xD;
          -  Has known active hepatitis B (e.g., hepatitis surface antigen [HBsAg] reactive) or&#xD;
             hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is&#xD;
             detected)&#xD;
&#xD;
          -  Has received a live vaccine within 30 days of planned start of study therapy.&#xD;
&#xD;
               -  Note: Seasonal influenza vaccines for injection are generally inactivated flu&#xD;
                  vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist)&#xD;
                  are live attenuated vaccines, and are not allowed&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris or&#xD;
             myocardial infraction within 6 months of study entry, serious cardiac arrhythmia&#xD;
             requiring medications, baseline corrected QT (QTc) &gt; 450 msec or previous history of&#xD;
             QT prolongation while taking other medications&#xD;
&#xD;
          -  Other medications, or severe acute/chronic medical or psychiatric condition, or&#xD;
             laboratory abnormality that may increase the risk associated with study participation&#xD;
             or study drug administration, or may interfere with the interpretation of study&#xD;
             results, and in the judgment of the investigator would make the subject inappropriate&#xD;
             for entry into this study&#xD;
&#xD;
          -  Has a known additional malignancy that is progressing or requires active treatment;&#xD;
             exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the&#xD;
             skin that has undergone potentially curative therapy or in situ cervical cancer;&#xD;
             subjects with prior malignancies are eligible if the subject has been disease free for&#xD;
             &gt; 5 years&#xD;
&#xD;
          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the&#xD;
             projected duration of the trial, starting with the screening visit through 120 days&#xD;
             after the last dose of trial treatment&#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>Olumide B. Gbolahan, MBBS, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Emory University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Emory University Hospital Midtown</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30308</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Emory University Hospital/Winship Cancer Institute</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Emory Saint Joseph's Hospital</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30342</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>January 9, 2019</study_first_submitted>
  <study_first_submitted_qc>January 9, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 11, 2019</study_first_posted>
  <last_update_submitted>June 30, 2023</last_update_submitted>
  <last_update_submitted_qc>June 30, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 5, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Emory University</investigator_affiliation>
    <investigator_full_name>Olumide Gbolahan</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>Carcinoma</mesh_term>
    <mesh_term>Colorectal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metformin</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>January 15, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/02/NCT03800602/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03800602
org study id: IRB00106678
secondary id: NCI-2018-02201
secondary id: Winship4494-18
secondary id: P30CA138292
nct id: NCT03800602
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase II trial studies how well nivolumab and metformin work in treating patients with
      microsatellite stable (MSS) stage IV colorectal cancer that has not responded to previous
      treatment. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's
      immune system attack the cancer, and may interfere with the ability of tumor cells to grow
      and spread. Metformin is an antidiabetic drug that and may reduce the risk of colorectal
      cancer development in patients. Giving nivolumab and metformin may work better in treating
      patients with refractory microsatellite metastatic colorectal cancer.
PRIMARY OBJECTIVE:

      I. To evaluate the effect of nivolumab and metformin combination on the overall response rate
      (ORR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

      SECONDARY OBJECTIVES:

      I. To determine the effect of nivolumab and metformin combination on clinical outcomes,
      progression free survival and overall survival, and biochemical response (CEA).

      II. To compare the effect of nivolumab and metformin combination on immune and metabolic
      biomarkers in the tumor microenvironment and systemic circulation (pre and post treatment
      paired biopsies required).

      OUTLINE:

      Patients receive metformin PO BID starting on day 1. After 14 days of metformin only period
      patients also receive nivolumab IV every 4 weeks starting on day 15. Courses repeat every 28
      days for up to 2 years in the absence of disease progression, unacceptable toxicity or
      consent withdrawal

      After completion of study treatment, patients are followed up at day 30 and then periodically
      thereafter.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall response rate (ORR)
time frame: Up to 1 year after study start
description: Response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1., and rate will be calculated as a proportion (responders/total patients).
measure: Progression free survival (PFS)
time frame: Assessed up to 2 years after study start
description: For progression free survival, progression or death from any cause will be defined as the event. Patients will be censored at time of last follow-up.
measure: Overall survival (OS)
time frame: Assessed up to 2 years after study start
description: For overall survival, death from any cause will be defined as the event. Patients will be censored at time of last follow-up.
measure: Biological response: carcinoembryonic antigen (CEA)
time frame: Up to 1 year after study start
description: Tumor marker carcinoembryonic antigen (CEA) will be assessed.
arm group label: Treatment (nivolumab, metformin)
arm group type: Experimental
description: Patients receive metformin PO BID starting on day 1. After 14 days of metformin only period patients also receive nivolumab IV every 4 weeks starting on day 15. Courses repeat every 28 days for up to 2 years in the absence of disease progression, unacceptable toxicity or consent withdrawal.
intervention type: Drug
intervention name: Metformin
description: Given PO
arm group label: Treatment (nivolumab, metformin)
other name: Glucophage
other name: Glumetza
other name: Fortamet
intervention type: Biological
intervention name: Nivolumab
description: Given IV
arm group label: Treatment (nivolumab, metformin)
other name: BMS-936558
other name: MDX-1106
other name: NIVO
other name: ONO-4538
other name: Opdivo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Olumide B. Gbolahan, MBBS, MSc
role: Principal Investigator
affiliation: Emory University
facility: 
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Emory University
investigator full name: Olumide Gbolahan
investigator title: Principal Investigator
mesh term: Carcinoma
mesh term: Colorectal Neoplasms
mesh term: Metformin
mesh term: Nivolumab
provided document: 