<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/NCT03238365</url>
  </required_header>
  <id_info>
    <org_study_id>17P.210</org_study_id>
    <nct_id>NCT03238365</nct_id>
  </id_info>
  <brief_title>Window of Opportunity Trial of Nivolumab and Tadalafil in Patients With Squamous Cell Carcinoma of the Head and Neck</brief_title>
  <official_title>Window of Opportunity Trial of Nivolumab and Tadalafil in Patients With Squamous Cell Carcinoma of the Head and Neck</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sidney Kimmel Cancer Center at Thomas Jefferson University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Thomas Jefferson University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This randomized pilot early phase I trial studies how well nivolumab with or without&#xD;
      tadalafil work in treating patients with head and neck squamous cell carcinoma that has come&#xD;
      back and can be removed by surgery. Monoclonal antibodies, such as nivolumab, may interfere&#xD;
      with the ability of tumor cells to grow and spread. Tadalafil may stop the growth of tumor&#xD;
      cells by blocking some of the enzymes needed for cell growth. Giving nivolumab and tadalafil&#xD;
      may work better in treating patients head and neck squamous cell carcinoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To investigate whether adding the PDE5 inhibitor, tadalafil, to nivolumab therapy affects&#xD;
      intratumoral and systemic anti-tumor immunity.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. Characterize the combined effects of nivolumab and tadalafil on safety, exosome&#xD;
      composition and function, the composition of intratumoral immune cell populations, wound&#xD;
      healing, and tumor radiographic response.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 10, 2017</start_date>
  <completion_date type="Actual">September 8, 2022</completion_date>
  <primary_completion_date type="Actual">July 30, 2019</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in immune cell polarization (Th1/Th2; M1/M2) in peripheral blood and tumor specimens using multiplex cytokine analysis</measure>
    <time_frame>Baseline up to day 31 of treatment</time_frame>
    <description>Analyze the immune cell polarization (Th1/Th2; M1/M2) in peripheral blood and tumor specimen supernatants will look at an entire panel of inflammatory markers, utilizing Luminex technology with the milliplex MAP human cytokine/chemokine magnetic kit I</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Prevalence of intratumoral immune cell populations</measure>
    <time_frame>Baseline up to 29 months</time_frame>
    <description>We will use immunohistochemistry (IHC) to determine the prevalence of intratumoral immune cell populations in patients treated with nivolumab and tadalafil as compared to patients treated with nivolumab alone.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>Lip, Oral Cavity and Pharynx</condition>
  <condition>Larynx</condition>
  <arm_group>
    <arm_group_label>Arm I (nivolumab)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients receive nivolumab IV over 60 minutes on days 3 and 17 and undergo surgery on day 31.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm II (nivolumab, tadalafil)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive nivolumab IV over 60 minutes on days 3 and 17 and tadalafil PO QD on days 3-31. Patients then undergo surgery on day 31.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Arm I (nivolumab)</arm_group_label>
    <arm_group_label>Arm II (nivolumab, tadalafil)</arm_group_label>
    <other_name>Opdivo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tadalafil</intervention_name>
    <description>Given orally</description>
    <arm_group_label>Arm II (nivolumab, tadalafil)</arm_group_label>
    <other_name>Cialis</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Therapeutic Conventional Surgery</intervention_name>
    <description>Undergo surgery</description>
    <arm_group_label>Arm I (nivolumab)</arm_group_label>
    <arm_group_label>Arm II (nivolumab, tadalafil)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Pathologically confirmed head and neck squamous cell carcinoma (HNSCC)&#xD;
&#xD;
          -  Any stage HNSCC of the 1) oral cavity, 2) oropharynx, 3) larynx, 4) hypopharynx, 5)&#xD;
             nasal cavity/paranasal sinuses, 6) unknown primary considered to have resectable&#xD;
             disease; patients with recurrent disease that is amenable to surgery are eligible&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2&#xD;
&#xD;
          -  While blood cells 2000/ul or more&#xD;
&#xD;
          -  Absolute neutrophil count 1500/ul or more&#xD;
&#xD;
          -  Platelets 100,000/ul or more&#xD;
&#xD;
          -  Hemoglobin 9 g/dl or more&#xD;
&#xD;
          -  Bilirubin less than or equal to 1.5 x the upper limit of normal (except subjects with&#xD;
             Gilbert syndrome, who can have total bilirubin &lt; 3 mg/dl)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal&#xD;
             to 3 x the upper limit of normal&#xD;
&#xD;
          -  Glomerular filtration rate (GFR) greater than or equal to 40 ml/min using the&#xD;
             Cockcroft-Gault formula or serum creatinine less than or equal to 1.5 x upper limit of&#xD;
             normal (ULN)&#xD;
&#xD;
          -  Women of reproductive potential should have a negative serum or urine pregnancy test&#xD;
             (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin&#xD;
             [HCG]) within 21 days of study enrollment&#xD;
&#xD;
          -  Women of reproductive potential must use highly effective contraception methods to&#xD;
             avoid pregnancy for 23 weeks after the last dose of study drugs; &quot;women of&#xD;
             reproductive potential&quot; is defined as any female who has experienced menarche and who&#xD;
             has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or&#xD;
             who is not postmenopausal; menopause is defined clinically as 12 months of amenorrhea&#xD;
             in a woman over 45 in the absence of other biological or physiological causes; in&#xD;
             addition, women under the age of 55 must have a documented serum follicle stimulating&#xD;
             hormone (FSH) level more than 40 mIU/mL&#xD;
&#xD;
          -  Men of reproductive potential who are sexually active with women of reproductive&#xD;
             potential must use any contraceptive method with a failure rate of less than 1% per&#xD;
             year; men who are receiving the study medications will be instructed to adhere to&#xD;
             contraception for 31 weeks after the last dose of study drugs; men who are azoospermic&#xD;
             do not require contraception&#xD;
&#xD;
          -  All subjects must be able to comprehend and sign a written informed consent document&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with nasopharyngeal carcinoma, salivary gland or skin primaries&#xD;
&#xD;
          -  Patients with any anginal chest pain; defined by a known diagnosis of angina; or&#xD;
             defined by chest pressure, squeezing, radiating pain to arms, shoulders, or neck from&#xD;
             the chest; with or without exertion&#xD;
&#xD;
          -  Patients taking nitrates&#xD;
&#xD;
          -  Patients taking PDE5 inhibitors more then 1/week during the previous 28 days&#xD;
&#xD;
          -  Patients with a secondary condition (sickle cell anemia) that cause priapism&#xD;
&#xD;
          -  Any history of a severe hypersensitivity reaction to any monoclonal antibody&#xD;
&#xD;
          -  Any history of allergy to the study drug components&#xD;
&#xD;
          -  Any concurrent malignancies; exceptions include- basal cell carcinoma of the skin,&#xD;
             squamous cell carcinoma of the skin, superficial bladder cancer or in situ cervical&#xD;
             cancer that has undergone potentially curative therapy; patients with a history of&#xD;
             other prior malignancy must have been treated with curative intent and must have&#xD;
             remained disease-free for 2 years post-diagnosis&#xD;
&#xD;
          -  Any diagnosis of immunodeficiency or current immunosuppressive therapy including&#xD;
             &gt;10mg/day of prednisone within 14 days of enrollment is not permitted.&#xD;
&#xD;
          -  Patients that have an active autoimmune disease requiring systemic treatment within&#xD;
             the past 3 months or a documented history of clinically severe autoimmune disease, or&#xD;
             a syndrome that requires systemic steroids (&gt; 10 mg daily prednisone equivalents) or&#xD;
             immunosuppressive agents; subjects with vitiligo, type I diabetes mellitus, or&#xD;
             resolved childhood asthma/atopy would be an exception to this rule. Inhaled or topical&#xD;
             steroids, and adrena replacement steroid doses =&lt;10mg daily prednisone equivalent, are&#xD;
             permitted in the absence of active autoimmune disease. Subjects that require&#xD;
             intermittent use of bronchodilators or local steroid injections would not be excluded&#xD;
             from the study; subjects with hypothyroidism stable on hormone replacement or&#xD;
             Sjorgen's syndrome will not be excluded from the study&#xD;
&#xD;
          -  Patients must not be receiving any other investigational agents&#xD;
&#xD;
          -  Patients with uncontrolled intercurrent illnesses including, but not limited to an&#xD;
             active infection requiring systemic therapy or a known psychiatric or substance abuse&#xD;
             disorder(s) that would interfere with cooperation with the requirements of the trial&#xD;
&#xD;
          -  Patients must not be pregnant or breastfeeding&#xD;
&#xD;
          -  Patients with a known human immunodeficiency virus infection (HIV 1/2 antibodies) or&#xD;
             acquired immunodeficiency syndrome (HIV/AIDS), active hepatitis B (e.g., hepatitis B&#xD;
             surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV]&#xD;
             ribonucleic acid [RNA] [qualitative] is detected)&#xD;
&#xD;
          -  Patients with any evidence of current interstitial lung disease (ILD) or pneumonitis&#xD;
&#xD;
          -  Patients with prior history of ILD or non-infectious pneumonitis that required&#xD;
             steroids&#xD;
&#xD;
          -  Patients who have received a live vaccine within 30 days of the planned start of study&#xD;
             therapy&#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>Adam Luginbuhl, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sidney Kimmel Cancer Center at Thomas Jefferson University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Sidney Kimmel Cancer Center at Thomas Jefferson University</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vanderbilt University</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://hospitals.jefferson.edu/</url>
    <description>Thomas Jefferson University Hospital</description>
  </link>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>July 31, 2017</study_first_submitted>
  <study_first_submitted_qc>July 31, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 3, 2017</study_first_posted>
  <last_update_submitted>October 4, 2022</last_update_submitted>
  <last_update_submitted_qc>October 4, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 5, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma, Squamous Cell</mesh_term>
    <mesh_term>Squamous Cell Carcinoma of Head and Neck</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Tadalafil</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03238365
org study id: 17P.210
nct id: NCT03238365
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This randomized pilot early phase I trial studies how well nivolumab with or without
      tadalafil work in treating patients with head and neck squamous cell carcinoma that has come
      back and can be removed by surgery. Monoclonal antibodies, such as nivolumab, may interfere
      with the ability of tumor cells to grow and spread. Tadalafil may stop the growth of tumor
      cells by blocking some of the enzymes needed for cell growth. Giving nivolumab and tadalafil
      may work better in treating patients head and neck squamous cell carcinoma.
PRIMARY OBJECTIVES:

      I. To investigate whether adding the PDE5 inhibitor, tadalafil, to nivolumab therapy affects
      intratumoral and systemic anti-tumor immunity.

      SECONDARY OBJECTIVES:

      I. Characterize the combined effects of nivolumab and tadalafil on safety, exosome
      composition and function, the composition of intratumoral immune cell populations, wound
      healing, and tumor radiographic response.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in immune cell polarization (Th1/Th2; M1/M2) in peripheral blood and tumor specimens using multiplex cytokine analysis
time frame: Baseline up to day 31 of treatment
description: Analyze the immune cell polarization (Th1/Th2; M1/M2) in peripheral blood and tumor specimen supernatants will look at an entire panel of inflammatory markers, utilizing Luminex technology with the milliplex MAP human cytokine/chemokine magnetic kit I
measure: Prevalence of intratumoral immune cell populations
time frame: Baseline up to 29 months
description: We will use immunohistochemistry (IHC) to determine the prevalence of intratumoral immune cell populations in patients treated with nivolumab and tadalafil as compared to patients treated with nivolumab alone.
arm group label: Arm I (nivolumab)
arm group type: Active Comparator
description: Patients receive nivolumab IV over 60 minutes on days 3 and 17 and undergo surgery on day 31.
arm group label: Arm II (nivolumab, tadalafil)
arm group type: Experimental
description: Patients receive nivolumab IV over 60 minutes on days 3 and 17 and tadalafil PO QD on days 3-31. Patients then undergo surgery on day 31.
intervention type: Biological
intervention name: Nivolumab
description: Given IV
arm group label: Arm I (nivolumab)
arm group label: Arm II (nivolumab, tadalafil)
other name: Opdivo
intervention type: Drug
intervention name: Tadalafil
description: Given orally
arm group label: Arm II (nivolumab, tadalafil)
other name: Cialis
intervention type: Procedure
intervention name: Therapeutic Conventional Surgery
description: Undergo surgery
arm group label: Arm I (nivolumab)
arm group label: Arm II (nivolumab, tadalafil)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Adam Luginbuhl, MD
role: Principal Investigator
affiliation: Sidney Kimmel Cancer Center at Thomas Jefferson University
facility: 
facility: 
country: United States
url: http://hospitals.jefferson.edu/
description: Thomas Jefferson University Hospital
responsible party type: Sponsor
mesh term: Carcinoma, Squamous Cell
mesh term: Squamous Cell Carcinoma of Head and Neck
mesh term: Nivolumab
mesh term: Tadalafil