<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/NCT03785210</url>
  </required_header>
  <id_info>
    <org_study_id>190033</org_study_id>
    <secondary_id>19-C-0033</secondary_id>
    <nct_id>NCT03785210</nct_id>
  </id_info>
  <brief_title>Nivolumab (Anti-PD1), Tadalafil and Oral Vancomycin in People With Refractory Primary Hepatocellular Carcinoma or Liver Dominant Metastatic Cancer From Colorectal or Pancreatic Cancers</brief_title>
  <official_title>Phase II Study of Nivolumab (Anti-PD1), Tadalafil and Oral Vancomycin in Patients With Refractory Primary Hepatocellular Carcinoma or Liver Dominant Metastatic Cancer From Colorectal or Pancreatic Cancers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      A most common liver cancer in adults is hepatocellular carcinoma. Other kinds of liver cancer&#xD;
      happen when colorectal or pancreatic cancer spreads to the liver. Researchers want to study&#xD;
      if a combination of drugs helps people with these cancers. The drugs are nivolumab,&#xD;
      tadalafil, and vancomycin.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      To investigate if nivolumab given with tadalafil and vancomycin causes liver cancer to&#xD;
      shrink.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      Adults ages 18 years and older with hepatocellular carcinoma or metastases to the liver from&#xD;
      colorectal or pancreatic cancer for which standard treatment has not worked&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Participants will be screened with:&#xD;
&#xD;
      Medical and cancer history&#xD;
&#xD;
      Review of symptoms and ability to perform normal activities&#xD;
&#xD;
      Physical exam&#xD;
&#xD;
      Heart test. Some participants may meet with a cardiologist and/or have another heart test.&#xD;
&#xD;
      Scan of the chest, abdomen, and pelvis&#xD;
&#xD;
      Blood and urine tests&#xD;
&#xD;
      Tumor sample review. This can be from a previous procedure.&#xD;
&#xD;
      Participants will receive the study drugs in 4-week cycles. In each cycle participants will:&#xD;
&#xD;
      Get nivolumab through a small plastic tube in the arm on Day 1.&#xD;
&#xD;
      Take tadalafil by mouth 1 time every day.&#xD;
&#xD;
      Take vancomycin by mouth 4 times a day. They will take it every day for weeks 1 3, then not&#xD;
      take it for week 4.&#xD;
&#xD;
      Complete a medicine diary of dates, times, missed doses and symptoms.&#xD;
&#xD;
      Throughout the study, participants will repeat screening tests and will give stool samples or&#xD;
      rectal swabs.&#xD;
&#xD;
      After their last cycle, participants will have 3 follow-up visits over 3 months. Then they&#xD;
      will be contacted every 6 months by phone or email and asked about their general well-being.&#xD;
&#xD;
      ...&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
        -  Current treatment options for patients with liver cancers, including hepatocellular&#xD;
           carcinoma (HCC) and advanced liver cancers are limited and take no account of the known&#xD;
           biological and genetic heterogeneity in these diseases. Median survival for advanced&#xD;
           disease remains poor at approximately 1 year.&#xD;
&#xD;
        -  Nivolumab is a fully human monoclonal immunoglobulin G4 (IgG4) antibody that is specific&#xD;
           for human programmed death-1 (PD-1, cluster of differentiation 279 [CD279]) cell surface&#xD;
           membrane receptor. Nivolumab has been approved by the Food and Drug Administration (FDA)&#xD;
           for the treatment of HCC and other solid tumors.&#xD;
&#xD;
        -  Tadalafil is a phosphodiesterase type 5 (PDE5) inhibitor which have been approved by the&#xD;
           FDA for the treatment of pulmonary arterial hypertension, benign prostatic hyperplasia&#xD;
           and erectile dysfunction, with a relative safe clinical profile. PDE5 inhibitors have&#xD;
           been examined in multiple malignancies and cancer cell lines for their direct anticancer&#xD;
           activities, for their&#xD;
&#xD;
      efficacy as chemo-sensitizers and for cancer chemoprevention.&#xD;
&#xD;
        -  Oral vancomycin is antibiotic that has effect on altering gut commensal bacteria&#xD;
           subsequently inducing a liver-selective anti-tumor effect.&#xD;
&#xD;
        -  The aim of the study is to evaluate whether the immunomodulatory effect induced by PDE5&#xD;
           inhibitor and oral vancomycin can be enhanced by immune checkpoint inhibition in&#xD;
           advanced liver cancer.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      -To determine the Best Overall Response (BOR) according to Response Evaluation Criteria&#xD;
      (RECIST 1.1) to combined treatment of nivolumab, oral vancomycin and tadalafil in patients&#xD;
      with refractory primary HCC or liver dominant metastatic cancer from colorectal cancer (CRC)&#xD;
      or pancreatic adenocarcinoma (PDAC).&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
        -  Histologically confirmed, hepatocellular carcinoma (HCC) Or&#xD;
&#xD;
        -  Histologically confirmed carcinoma highly suggestive of a diagnosis of HCC Or&#xD;
&#xD;
        -  Histologically confirmed advanced colorectal or pancreatic malignancy with liver&#xD;
           involvement as dominant site of metastasis&#xD;
&#xD;
        -  Measurable lesion, accessible for biopsy.&#xD;
&#xD;
        -  Age greater than or equal to 18 years&#xD;
&#xD;
        -  ECOG less than or equal to 1&#xD;
&#xD;
        -  Acceptable renal, bone marrow and liver function.&#xD;
&#xD;
        -  Willingness to undergo two mandatory tumor biopsies.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  The proposed study is a phase II study of combined nivolumab, oral vancomycin and&#xD;
           tadalafil treatment in patients with HCC or liver dominant metastatic cancer from&#xD;
           colorectal or pancreatic cancers.&#xD;
&#xD;
        -  Treatment will be delivered in cycles consisting of 4 weeks (+/- 3 days) until&#xD;
           progression or unacceptable toxicity.&#xD;
&#xD;
        -  Patients will be seen in Clinical Center on monthly basis with disease status evaluation&#xD;
           every&#xD;
&#xD;
           8 (+/-1) weeks after start of study therapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 5, 2019</start_date>
  <completion_date type="Actual">December 31, 2022</completion_date>
  <primary_completion_date type="Actual">October 31, 2022</primary_completion_date>
  <phase>Phase 2</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>Best Overall Response (BOR)</measure>
    <time_frame>Every 2 months and then every 6 months after discontinuation of treatment, for survival purposes, up to 3 years</time_frame>
    <description>Best overall response is defined as the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions). Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Serious Adverse Events Possibly, Probably, and/or Definitely Related to Treatment</measure>
    <time_frame>From first study treatment, approximately 90 days</time_frame>
    <description>Adverse events were assessed by the by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS) of Nivolumab Combined With Oral Vancomycin and Tadalafil in Participants With Refractory Hepatocellular Carcinoma (HCC) or Liver Dominant Metastatic Cancer From Colorectal Cancer or Pancreatic Ductal Adenocarcinoma (PDAC)</measure>
    <time_frame>Participants were followed from the on-study date to post discontinuation of treatment until the day of death, an average of 8 months.</time_frame>
    <description>Overall survival is calculated from the on-study date to the day of death using the Kaplan-Meier method.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)</measure>
    <time_frame>Date treatment consent signed to date off study, approximately 41 months/11 days and 36 months/22 days for the first and second group respectively.</time_frame>
    <description>Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">22</enrollment>
  <condition>Hepatocellular Carcinoma</condition>
  <condition>Hepatocellular Cancer</condition>
  <condition>Metastatic Pancreatic Cancer</condition>
  <condition>Metastatic Colorectal Cancer</condition>
  <condition>Liver Metastasis</condition>
  <arm_group>
    <arm_group_label>1/Arm 1 - Nivolumab, Tadalafil and Oral Vancomycin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab, tadalafil and oral vancomycin</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>nivolumab</intervention_name>
    <description>480 mg intravenous (IV) every 4 weeks</description>
    <arm_group_label>1/Arm 1 - Nivolumab, Tadalafil and Oral Vancomycin</arm_group_label>
    <other_name>Opdivo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>tadalafil</intervention_name>
    <description>10 mg by mouth (PO) daily</description>
    <arm_group_label>1/Arm 1 - Nivolumab, Tadalafil and Oral Vancomycin</arm_group_label>
    <other_name>Cialis</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>oral vancomycin</intervention_name>
    <description>125 mg every 6-hour (500 mg total daily dose) by mouth (PO) from week 1 to week 3, week 4 off.</description>
    <arm_group_label>1/Arm 1 - Nivolumab, Tadalafil and Oral Vancomycin</arm_group_label>
    <other_name>Vancocin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
          -  Patients must have&#xD;
&#xD;
               -  histopathological confirmation of Hepatocellular Carcinoma (HCC) (Cohort 1) OR&#xD;
&#xD;
               -  histopathological confirmation of carcinoma by in the setting of clinical and&#xD;
                  radiological characteristics which, together with the pathology, are highly&#xD;
                  suggestive of a diagnosis of HCC (Cohort 1) OR&#xD;
&#xD;
               -  histopathological confirmation of advanced colorectal or pancreatic malignancy&#xD;
                  with liver involvement as dominant site of metastasis (Per multidiscipline tumor&#xD;
                  board review and approval) (Cohort 2).&#xD;
&#xD;
          -  Patients must have disease that is not amenable to potentially curative resection,&#xD;
             transplantation or ablation.&#xD;
&#xD;
          -  Patients must have progressed on, been intolerant to, or refused prior&#xD;
             sorafenib/lenvatinib and/or atezolizumab/bevacizumab therapy (Cohort 1 only).&#xD;
&#xD;
          -  Subjects must have progressed on or after standard systemic chemotherapy (at least one&#xD;
             line of chemotherapy for patients with liver metastasis from pancreatic ductal&#xD;
             adenocarcinoma (PDAC), at least two lines of chemotherapy for patients with liver&#xD;
             metastasis from colorectal cancer (CRC) (Cohort 2 only).&#xD;
&#xD;
          -  Patients must have evaluable or measurable disease per Response Evaluation Criteria in&#xD;
             Solid Tumors (RECIST) 1.1&#xD;
&#xD;
          -  Patients must have lesion accessible for biopsy and be willing to undergo pre- and&#xD;
             posttreatment biopsies.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1&#xD;
&#xD;
          -  If liver cirrhosis is present, patient must have a Child-Pugh score less than or equal&#xD;
             to 7&#xD;
&#xD;
          -  Active chronic hepatitis B virus (HBV) infected subjects must be on antivirals and&#xD;
             have HBV deoxyribonucleic acid (DNA) &lt;100IU/mL. hepatitis C virus (HCV) infected&#xD;
             subjects can be enrolled with close HCV RNA level monitoring.&#xD;
&#xD;
          -  Age greater than or equal to 18 years. Because no dosing or adverse event data are&#xD;
             currently available on the use of nivolumab in combination with tadalafil and&#xD;
             vancomycin in patients less than 18 years of age, children are excluded from this&#xD;
             study, but will be eligible for future pediatric trials&#xD;
&#xD;
          -  Adequate hematological function defined by:&#xD;
&#xD;
               -  white blood cell (WBC) count greater than or equal to 3x10^9/L&#xD;
&#xD;
               -  absolute neutrophil count (ANC) greater than or equal to 1.5x10^9/L,&#xD;
&#xD;
               -  lymphocyte count greater than or equal to 0.5x10^9/L,&#xD;
&#xD;
               -  platelet count greater than or equal to 60x10^9/L, and&#xD;
&#xD;
               -  Hemoglobin (Hgb) greater than or equal to 9 g/ dL (more than 48 hours&#xD;
                  post-completion of blood transfusion)&#xD;
&#xD;
          -  Adequate hepatic function defined by:&#xD;
&#xD;
               -  a total bilirubin level less than or equal to 1.5 X Upper limit of normal (ULN),&#xD;
&#xD;
               -  an aspartate transaminase (AST) level &lt;5xULN,&#xD;
&#xD;
               -  an alanine aminotransferase (ALT) level &lt;5xULN.&#xD;
&#xD;
          -  Adequate renal function defined by:&#xD;
&#xD;
               -  Creatinine clearance (CrCl) greater than or equal to 50 mL/min/1.73 m^2 by 24&#xD;
                  hours urine collection or as predicted by the Cockcroft-Gault formula:&#xD;
&#xD;
               -  CrCl = (140 age (y)) x (weight in kg) x (0.85, if female) x1.73 m^2/72 x Serum&#xD;
                  Creatinine (mg/dL) x patient's body surface area (BSA) (m^2) Or&#xD;
&#xD;
          -  The effects of nivolumab on the developing human fetus are unknown. For this reason,&#xD;
             women of child-bearing potential and men must agree to use adequate contraception&#xD;
             (hormonal or barrier method of birth control; abstinence) prior to study entry and for&#xD;
             the duration of study participation and up to 5 months (women) and 7 months (men)&#xD;
             after the last dose of the drug. Should a woman become pregnant or suspect she is&#xD;
             pregnant while she or her partner is participating in this study, she should inform&#xD;
             her treating physician immediately.&#xD;
&#xD;
          -  Patients with a history of cardiovascular disease may be enrolled per cardiology&#xD;
             consultation and approval with echocardiogram and troponin level in normal range at&#xD;
             the time of enrollment.&#xD;
&#xD;
          -  Patient must be able to understand and willing to sign a written informed consent&#xD;
             document.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  Patients who have had standard-of-care anti-cancer therapy or therapy with&#xD;
             investigational agents (e.g., chemotherapy, immunotherapy, endocrine therapy, targeted&#xD;
             therapy, biologic therapy, tumor embolization, monoclonal antibodies or other&#xD;
             investigation agents), large field radiotherapy, or major surgery within 4 weeks prior&#xD;
             to enrollment.&#xD;
&#xD;
          -  Therapy with antibiotics within 30 days prior to enrollment.&#xD;
&#xD;
          -  Therapy with nitrates, alpha-blockers, or cytochrome P450 (CYP3A4) inhibitors within&#xD;
             7- days prior to enrollment and for whom stopping is unsafe and/or a safe substitute&#xD;
             is not medically recommended. Use of PDE5 inhibitors such as vardenafil (Levitra),&#xD;
             tadalafil (Cialis), and sildenafil citrate (Viagra) less than or equal to 15-days&#xD;
             prior to enrollment.&#xD;
&#xD;
          -  The patient must not be currently on a corticosteroid dose greater than physiologic&#xD;
             replacement dosing defined as 10 mg of cortisone per day or its equivalent.&#xD;
&#xD;
          -  For PDAC patients with liver metastases, primary PDAC has not been resected (unless&#xD;
             the primary is in the tail of the pancreas).&#xD;
&#xD;
          -  Patients with known brain metastases will be excluded from this clinical trial because&#xD;
             of their poor prognosis and because they often develop progressive neurologic&#xD;
             dysfunction that would confound the evaluation of neurologic and other adverse events.&#xD;
&#xD;
          -  Have signs of liver failure, e.g., clinical significant ascites, encephalopathy, or&#xD;
             variceal bleeding within 6 months prior to enrollment.&#xD;
&#xD;
          -  Prior major liver resection: remnant liver &lt;50% of the initial liver volume. Patients&#xD;
             with a biliary stent can be included.&#xD;
&#xD;
          -  Patients with active autoimmune disease or history of autoimmune disease that might&#xD;
             recur, which may affect vital organ function or require immune suppressive treatment&#xD;
             including systemic corticosteroids. These include but are not limited to patients with&#xD;
             a history of immune related neurologic disease, multiple sclerosis, autoimmune&#xD;
             (demyelinating) neuropathy, Guillain-Barre syndrome or Chronic Inflammatory&#xD;
             Demyelinating Polyneuropathy (CIDP), myasthenia gravis; systemic autoimmune disease&#xD;
             such as Systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma,&#xD;
             inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients&#xD;
             with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or&#xD;
             phospholipid syndrome. Such diseases should be excluded because of the risk of&#xD;
             recurrence or exacerbation of disease.&#xD;
&#xD;
        Of note, patients with vitiligo, endocrine deficiencies including thyroiditis managed with&#xD;
        replacement hormones including physiologic corticosteroids are eligible. Patients with&#xD;
        rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled&#xD;
        with topical medication and patients with positive serology, such as antinuclear antibodies&#xD;
        (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ&#xD;
        involvement and potential need for systemic treatment but should otherwise be eligible.&#xD;
&#xD;
          -  Have history of idiopathic pulmonary fibrosis (including bronchiolitis obliterans with&#xD;
             organizing pneumonia) or evidence of active pneumonitis on screening chest computed&#xD;
             tomography (CT) scan.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements.&#xD;
&#xD;
          -  Patients with myocardial infarction or myocarditis within 12 months prior to&#xD;
             enrollment.&#xD;
&#xD;
          -  History of severe or unstable cerebrovascular disease.&#xD;
&#xD;
          -  Sustained hypotension (&lt;90/50 mmHg) or uncontrolled hypertension (&gt;160/100 mmHg)&#xD;
&#xD;
          -  Stroke within 6 months prior to enrollment.&#xD;
&#xD;
          -  Human immunodeficiency virus (HIV)-positive patients are excluded because HIV causes&#xD;
             complicated immune deficiency and study treatment can possess more risks for these&#xD;
             patients.&#xD;
&#xD;
          -  Have had prior transplant of any kind.&#xD;
&#xD;
          -  Have ascites.&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to nivolumab, tadalafil or vancomycin.&#xD;
&#xD;
          -  History of severe hypersensitivity reaction to any monoclonal antibody.&#xD;
&#xD;
          -  Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free&#xD;
             for a minimum of 3 years prior to enrollment.&#xD;
&#xD;
          -  Pregnant women are excluded from this study because nivolumabs potential for&#xD;
             teratogenic or abortifacient effects is unknown. Because there is an unknown but&#xD;
             potential risk for adverse events in nursing infants secondary to treatment of the&#xD;
             mother with nivolumab, breastfeeding should be discontinued if the mother is treated&#xD;
             with nivolumab&#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>Tim F Greten, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2019-C-0033.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>December 20, 2018</study_first_submitted>
  <study_first_submitted_qc>December 21, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 24, 2018</study_first_posted>
  <results_first_submitted>May 24, 2023</results_first_submitted>
  <results_first_submitted_qc>June 22, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">July 11, 2023</results_first_posted>
  <last_update_submitted>June 22, 2023</last_update_submitted>
  <last_update_submitted_qc>June 22, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 11, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>National Cancer Institute (NCI)</investigator_affiliation>
    <investigator_full_name>Tim Greten, M.D.</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Anticancer Activities</keyword>
  <keyword>Altering Gut Commensal Bacteria</keyword>
  <keyword>Immunomdulatory Effect</keyword>
  <keyword>Checkpoint Inhibition</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Pancreatic Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Hepatocellular</mesh_term>
    <mesh_term>Liver Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vancomycin</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Tadalafil</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the Database of Genotypes and Phenotypes (dbGaP).</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.</ipd_time_frame>
    <ipd_access_criteria>Clinical data will be made available via subscription to the Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via the Database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.</ipd_access_criteria>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>January 19, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/10/NCT03785210/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <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>February 2, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/10/NCT03785210/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Cohort 1, Arm 1, Treatment Assignment Code 1, Participants With Hepatocellular Carcinoma</title>
          <description>Participants with hepatocellular carcinoma highly suggestive of a diagnosis of hepatocellular carcinoma. Nivolumab 480 mg intravenously every 4 weeks; Tadalafil 10mg by mouth (PO) daily, and oral vancomycin 125mg every 6 hours by mouth (PO) from week 1 to week 3, week 4 off, 500 mg total daily.</description>
        </group>
        <group group_id="P2">
          <title>Cohort 2, Arm 1, Treatment Assignment Code 1, Participants With Liver Metastases</title>
          <description>Participants with liver metastases from colorectal cancer or pancreatic ductal adenocarcinoma (PDAC). Nivolumab 480 mg intravenously every 4 weeks; Tadalafil 10mg by mouth (PO) daily, and oral vancomycin 125mg every 6 hours by mouth (PO) from week 1 to week 3, week 4 off, 500 mg total daily.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="16"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Principal investigator decision - clinical progression</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Cohort 1, Arm 1, Treatment Assignment Code 1, Participants With Hepatocellular Carcinoma</title>
          <description>Participants with hepatocellular carcinoma highly suggestive of a diagnosis of hepatocellular carcinoma. Nivolumab 480 mg intravenously every 4 weeks; Tadalafil 10mg by mouth (PO) daily, and oral vancomycin 125mg every 6 hours by mouth (PO) from week 1 to week 3, week 4 off, 500 mg total daily.</description>
        </group>
        <group group_id="B2">
          <title>Cohort 2, Arm 1, Treatment Assignment Code 1, Participants With Liver Metastases</title>
          <description>Participants with liver metastases from colorectal cancer or pancreatic ductal adenocarcinoma (PDAC). Nivolumab 480 mg intravenously every 4 weeks; Tadalafil 10mg by mouth (PO) daily, and oral vancomycin 125mg every 6 hours by mouth (PO) from week 1 to week 3, week 4 off, 500 mg total daily.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="6"/>
            <count group_id="B2" value="16"/>
            <count group_id="B3" value="22"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="69.08" spread="8.15"/>
                    <measurement group_id="B2" value="63.61" spread="11.52"/>
                    <measurement group_id="B3" value="65.1" spread="10.81"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="20"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Best Overall Response (BOR)</title>
        <description>Best overall response is defined as the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions). Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.</description>
        <time_frame>Every 2 months and then every 6 months after discontinuation of treatment, for survival purposes, up to 3 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1, Arm 1, Treatment Assignment Code 1, Participants With Hepatocellular Carcinoma</title>
            <description>Participants with hepatocellular carcinoma highly suggestive of a diagnosis of hepatocellular carcinoma. Nivolumab 480 mg intravenously every 4 weeks; Tadalafil 10mg by mouth (PO) daily, and oral vancomycin 125mg every 6 hours by mouth (PO) from week 1 to week 3, week 4 off, 500 mg total daily.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2, Arm 1, Treatment Assignment Code 1, Participants With Liver Metastases</title>
            <description>Participants with liver metastases from colorectal cancer or pancreatic ductal adenocarcinoma (PDAC). Nivolumab 480 mg intravenously every 4 weeks; Tadalafil 10mg by mouth (PO) daily, and oral vancomycin 125mg every 6 hours by mouth (PO) from week 1 to week 3, week 4 off, 500 mg total daily.</description>
          </group>
        </group_list>
        <measure>
          <title>Best Overall Response (BOR)</title>
          <description>Best overall response is defined as the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions). Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Complete Response</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Partial Response</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Stable Disease</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Progressive Disease</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Not Evaluable</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Serious Adverse Events Possibly, Probably, and/or Definitely Related to Treatment</title>
        <description>Adverse events were assessed by the by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
        <time_frame>From first study treatment, approximately 90 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1, Arm 1, Treatment Assignment Code 1, Participants With Hepatocellular Carcinoma</title>
            <description>Participants with hepatocellular carcinoma highly suggestive of a diagnosis of hepatocellular carcinoma. Nivolumab 480 mg intravenously every 4 weeks; Tadalafil 10mg by mouth (PO) daily, and oral vancomycin 125mg every 6 hours by mouth (PO) from week 1 to week 3, week 4 off, 500 mg total daily.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2, Arm 1, Treatment Assignment Code 1, Participants With Liver Metastases</title>
            <description>Participants with liver metastases from colorectal cancer or pancreatic ductal adenocarcinoma (PDAC). Nivolumab 480 mg intravenously every 4 weeks; Tadalafil 10mg by mouth (PO) daily, and oral vancomycin 125mg every 6 hours by mouth (PO) from week 1 to week 3, week 4 off, 500 mg total daily.</description>
          </group>
        </group_list>
        <measure>
          <title>Serious Adverse Events Possibly, Probably, and/or Definitely Related to Treatment</title>
          <description>Adverse events were assessed by the by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
          <units>adverse events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS) of Nivolumab Combined With Oral Vancomycin and Tadalafil in Participants With Refractory Hepatocellular Carcinoma (HCC) or Liver Dominant Metastatic Cancer From Colorectal Cancer or Pancreatic Ductal Adenocarcinoma (PDAC)</title>
        <description>Overall survival is calculated from the on-study date to the day of death using the Kaplan-Meier method.</description>
        <time_frame>Participants were followed from the on-study date to post discontinuation of treatment until the day of death, an average of 8 months.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1, Arm 1, Treatment Assignment Code 1, Participants With Hepatocellular Carcinoma</title>
            <description>Participants with hepatocellular carcinoma highly suggestive of a diagnosis of hepatocellular carcinoma. Nivolumab 480 mg intravenously every 4 weeks; Tadalafil 10mg by mouth (PO) daily, and oral vancomycin 125mg every 6 hours by mouth (PO) from week 1 to week 3, week 4 off, 500 mg total daily.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2, Arm 1, Treatment Assignment Code 1, Participants With Liver Metastases</title>
            <description>Participants with liver metastases from colorectal cancer or pancreatic ductal adenocarcinoma (PDAC). Nivolumab 480 mg intravenously every 4 weeks; Tadalafil 10mg by mouth (PO) daily, and oral vancomycin 125mg every 6 hours by mouth (PO) from week 1 to week 3, week 4 off, 500 mg total daily.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (OS) of Nivolumab Combined With Oral Vancomycin and Tadalafil in Participants With Refractory Hepatocellular Carcinoma (HCC) or Liver Dominant Metastatic Cancer From Colorectal Cancer or Pancreatic Ductal Adenocarcinoma (PDAC)</title>
          <description>Overall survival is calculated from the on-study date to the day of death using the Kaplan-Meier method.</description>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.4" lower_limit="2.4" upper_limit="18.3"/>
                    <measurement group_id="O2" value="3.4" lower_limit="2.6" upper_limit="8.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)</title>
        <description>Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
        <time_frame>Date treatment consent signed to date off study, approximately 41 months/11 days and 36 months/22 days for the first and second group respectively.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1, Arm 1, Treatment Assignment Code 1, Participants With Hepatocellular Carcinoma</title>
            <description>Participants with hepatocellular carcinoma highly suggestive of a diagnosis of hepatocellular carcinoma. Nivolumab 480 mg intravenously every 4 weeks; Tadalafil 10mg by mouth (PO) daily, and oral vancomycin 125mg every 6 hours by mouth (PO) from week 1 to week 3, week 4 off, 500 mg total daily.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2, Arm 1, Treatment Assignment Code 1, Participants With Liver Metastases</title>
            <description>Participants with liver metastases from colorectal cancer or pancreatic ductal adenocarcinoma (PDAC). Nivolumab 480 mg intravenously every 4 weeks; Tadalafil 10mg by mouth (PO) daily, and oral vancomycin 125mg every 6 hours by mouth (PO) from week 1 to week 3, week 4 off, 500 mg total daily.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)</title>
          <description>Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Date treatment consent signed to date off study, approximately 41 months/11 days and 36 months/22 days for the first and second group respectively.</time_frame>
      <desc>No deaths were related to research.</desc>
      <group_list>
        <group group_id="E1">
          <title>Cohort 1, Arm 1, Treatment Assignment Code 1, Participants With Hepatocellular Carcinoma</title>
          <description>Participants with hepatocellular carcinoma highly suggestive of a diagnosis of hepatocellular carcinoma. Nivolumab 480 mg intravenously every 4 weeks; Tadalafil 10mg by mouth (PO) daily, and oral vancomycin 125mg every 6 hours by mouth (PO) from week 1 to week 3, week 4 off, 500 mg total daily.</description>
        </group>
        <group group_id="E2">
          <title>Cohort 2, Arm 1, Treatment Assignment Code 1, Participants With Liver Metastases</title>
          <description>Participants with liver metastases from colorectal cancer or pancreatic ductal adenocarcinoma (PDAC). Nivolumab 480 mg intravenously every 4 weeks; Tadalafil 10mg by mouth (PO) daily, and oral vancomycin 125mg every 6 hours by mouth (PO) from week 1 to week 3, week 4 off, 500 mg total daily.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (5.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Ascites</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Colonic perforation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Duodenal obstruction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Disease progression</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary retention</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hematoma</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (5.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="7" subjects_affected="5" subjects_at_risk="6"/>
                <counts group_id="E2" events="20" subjects_affected="12" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Ventricular arrhythmia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal distension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="6" subjects_affected="5" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Ascites</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Esophagitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hemorrhoidal hemorrhage</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="6" subjects_affected="5" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="9" subjects_affected="9" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="5" subjects_affected="4" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Shingles</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Activated partial thromboplastin time prolonged</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="5" subjects_affected="3" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="5" subjects_affected="3" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="9" subjects_affected="4" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="12" subjects_affected="7" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="6" subjects_affected="4" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="7" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" events="19" subjects_affected="9" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="6"/>
                <counts group_id="E2" events="7" subjects_affected="3" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Serum amylase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="4" subjects_affected="2" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="5" subjects_affected="4" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hyperuricemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="12" subjects_affected="9" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="10" subjects_affected="7" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" events="10" subjects_affected="7" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Depressed level of consciousness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Lethargy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other, Altered mental status</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Presyncope</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Stroke</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Irritability</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hiccups</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Pleuritic pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Erythema multiforme</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Palmar-plantar erythrodysesthesia syndrome</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, blister right bottom foot</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, burning sensation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hematoma</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Tim F. Greten</name_or_title>
      <organization>National Cancer Institute</organization>
      <phone>240-760-6114</phone>
      <email>gretentf@mail.nih.gov</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03785210
org study id: 190033
secondary id: 19-C-0033
nct id: NCT03785210
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
Background:

      A most common liver cancer in adults is hepatocellular carcinoma. Other kinds of liver cancer
      happen when colorectal or pancreatic cancer spreads to the liver. Researchers want to study
      if a combination of drugs helps people with these cancers. The drugs are nivolumab,
      tadalafil, and vancomycin.

      Objective:

      To investigate if nivolumab given with tadalafil and vancomycin causes liver cancer to
      shrink.

      Eligibility:

      Adults ages 18 years and older with hepatocellular carcinoma or metastases to the liver from
      colorectal or pancreatic cancer for which standard treatment has not worked

      Design:

      Participants will be screened with:

      Medical and cancer history

      Review of symptoms and ability to perform normal activities

      Physical exam

      Heart test. Some participants may meet with a cardiologist and/or have another heart test.

      Scan of the chest, abdomen, and pelvis

      Blood and urine tests

      Tumor sample review. This can be from a previous procedure.

      Participants will receive the study drugs in 4-week cycles. In each cycle participants will:

      Get nivolumab through a small plastic tube in the arm on Day 1.

      Take tadalafil by mouth 1 time every day.

      Take vancomycin by mouth 4 times a day. They will take it every day for weeks 1 3, then not
      take it for week 4.

      Complete a medicine diary of dates, times, missed doses and symptoms.

      Throughout the study, participants will repeat screening tests and will give stool samples or
      rectal swabs.

      After their last cycle, participants will have 3 follow-up visits over 3 months. Then they
      will be contacted every 6 months by phone or email and asked about their general well-being.

      ...
Background:

        -  Current treatment options for patients with liver cancers, including hepatocellular
           carcinoma (HCC) and advanced liver cancers are limited and take no account of the known
           biological and genetic heterogeneity in these diseases. Median survival for advanced
           disease remains poor at approximately 1 year.

        -  Nivolumab is a fully human monoclonal immunoglobulin G4 (IgG4) antibody that is specific
           for human programmed death-1 (PD-1, cluster of differentiation 279 [CD279]) cell surface
           membrane receptor. Nivolumab has been approved by the Food and Drug Administration (FDA)
           for the treatment of HCC and other solid tumors.

        -  Tadalafil is a phosphodiesterase type 5 (PDE5) inhibitor which have been approved by the
           FDA for the treatment of pulmonary arterial hypertension, benign prostatic hyperplasia
           and erectile dysfunction, with a relative safe clinical profile. PDE5 inhibitors have
           been examined in multiple malignancies and cancer cell lines for their direct anticancer
           activities, for their

      efficacy as chemo-sensitizers and for cancer chemoprevention.

        -  Oral vancomycin is antibiotic that has effect on altering gut commensal bacteria
           subsequently inducing a liver-selective anti-tumor effect.

        -  The aim of the study is to evaluate whether the immunomodulatory effect induced by PDE5
           inhibitor and oral vancomycin can be enhanced by immune checkpoint inhibition in
           advanced liver cancer.

      Objective:

      -To determine the Best Overall Response (BOR) according to Response Evaluation Criteria
      (RECIST 1.1) to combined treatment of nivolumab, oral vancomycin and tadalafil in patients
      with refractory primary HCC or liver dominant metastatic cancer from colorectal cancer (CRC)
      or pancreatic adenocarcinoma (PDAC).

      Eligibility:

        -  Histologically confirmed, hepatocellular carcinoma (HCC) Or

        -  Histologically confirmed carcinoma highly suggestive of a diagnosis of HCC Or

        -  Histologically confirmed advanced colorectal or pancreatic malignancy with liver
           involvement as dominant site of metastasis

        -  Measurable lesion, accessible for biopsy.

        -  Age greater than or equal to 18 years

        -  ECOG less than or equal to 1

        -  Acceptable renal, bone marrow and liver function.

        -  Willingness to undergo two mandatory tumor biopsies.

      Design:

        -  The proposed study is a phase II study of combined nivolumab, oral vancomycin and
           tadalafil treatment in patients with HCC or liver dominant metastatic cancer from
           colorectal or pancreatic cancers.

        -  Treatment will be delivered in cycles consisting of 4 weeks (+/- 3 days) until
           progression or unacceptable toxicity.

        -  Patients will be seen in Clinical Center on monthly basis with disease status evaluation
           every

           8 (+/-1) weeks after start of study therapy.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Best Overall Response (BOR)
time frame: Every 2 months and then every 6 months after discontinuation of treatment, for survival purposes, up to 3 years
description: Best overall response is defined as the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions). Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.
measure: Serious Adverse Events Possibly, Probably, and/or Definitely Related to Treatment
time frame: From first study treatment, approximately 90 days
description: Adverse events were assessed by the by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
measure: Overall Survival (OS) of Nivolumab Combined With Oral Vancomycin and Tadalafil in Participants With Refractory Hepatocellular Carcinoma (HCC) or Liver Dominant Metastatic Cancer From Colorectal Cancer or Pancreatic Ductal Adenocarcinoma (PDAC)
time frame: Participants were followed from the on-study date to post discontinuation of treatment until the day of death, an average of 8 months.
description: Overall survival is calculated from the on-study date to the day of death using the Kaplan-Meier method.
measure: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)
time frame: Date treatment consent signed to date off study, approximately 41 months/11 days and 36 months/22 days for the first and second group respectively.
description: Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
arm group label: 1/Arm 1 - Nivolumab, Tadalafil and Oral Vancomycin
arm group type: Experimental
description: Nivolumab, tadalafil and oral vancomycin
intervention type: Drug
intervention name: nivolumab
description: 480 mg intravenous (IV) every 4 weeks
arm group label: 1/Arm 1 - Nivolumab, Tadalafil and Oral Vancomycin
other name: Opdivo
intervention type: Drug
intervention name: tadalafil
description: 10 mg by mouth (PO) daily
arm group label: 1/Arm 1 - Nivolumab, Tadalafil and Oral Vancomycin
other name: Cialis
intervention type: Drug
intervention name: oral vancomycin
description: 125 mg every 6-hour (500 mg total daily dose) by mouth (PO) from week 1 to week 3, week 4 off.
arm group label: 1/Arm 1 - Nivolumab, Tadalafil and Oral Vancomycin
other name: Vancocin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Tim F Greten, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
facility: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2019-C-0033.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Principal Investigator
investigator affiliation: National Cancer Institute (NCI)
investigator full name: Tim Greten, M.D.
investigator title: Principal Investigator
mesh term: Carcinoma
mesh term: Neoplasm Metastasis
mesh term: Pancreatic Neoplasms
mesh term: Carcinoma, Hepatocellular
mesh term: Liver Neoplasms
mesh term: Vancomycin
mesh term: Nivolumab
mesh term: Tadalafil
sharing ipd: Yes
ipd description: All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the Database of Genotypes and Phenotypes (dbGaP).
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
ipd access criteria: Clinical data will be made available via subscription to the Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via the Database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 