<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/NCT03021993</url>
  </required_header>
  <id_info>
    <org_study_id>102510</org_study_id>
    <nct_id>NCT03021993</nct_id>
  </id_info>
  <brief_title>Trial of Nivolumab as a Novel Neoadjuvant Pre-Surgical Therapy for Locally Advanced Oral Cavity Cancer</brief_title>
  <official_title>Phase II Trial of Nivolumab, an Anti-PD-1 Monoclonal Antibody, as a Novel Neoadjuvant Pre-Surgical Therapy for Locally Advanced Oral Cavity Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medical University of South Carolina</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Medical University of South Carolina</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to look at the effectiveness of nivolumab in patients with oral&#xD;
      cavity cancer (OCC) who are about to undergo surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      OCC patients who are scheduled for surgery will be given Nivolumab prior to surgery to see if&#xD;
      there are any changes in surgical outcomes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 30, 2017</start_date>
  <completion_date type="Actual">November 15, 2021</completion_date>
  <primary_completion_date type="Actual">November 15, 2021</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>Objective response rate using pathological response</measure>
    <time_frame>Time of surgery (day 36 or day 50)</time_frame>
    <description>Objective response rate: the sum of patients with either a pCR defined as no invasive and no in situ residuals present in the surgical specimen or partial pathologic response defined at least a 30% reduction in the size of the lesion in the surgical specimen. The reduction in size will be determined by comparing the pretreatment clinical measurements (the sum of the greatest axial measurement obtained with calipers at the time of initial evaluation) with the final pathologic measurements.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Level of Treg cells in peripheral blood using immunostaining</measure>
    <time_frame>Day 1 and time of surgery (day 36 or day 50)</time_frame>
    <description>1. Levels of Treg cells in pre and post treatment peripheral blood will be evaluated using immunostaining for CD4 and flow cytometric analysis of Foxp3. Differences will be calculated (absolute change and percentage change) between pre and post treatment measures.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Level of activated T-cells in peripheral blood</measure>
    <time_frame>Day 1 and time of surgery (day 36 or day 50)</time_frame>
    <description>2. Levels of activated T-cells in peripheral blood will be assessed using flow cytometry for expression of CD69, IFN γ, T-bet and ICOS in CD4+ cells. Differences will be calculated (absolute change and percentage change) between pre and post treatment measures.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Level of immune stimulatory cytokines in peripheral blood</measure>
    <time_frame>Day 1 and time of surgery (day 36 or day 50)</time_frame>
    <description>3. Intratumoral immune activity assessed by levels of immune stimulatory cytokines including IL-2, IFN γ, and IL-12 or inhibitory cytokine, IL10 and TGF-beta, in OCSCC tumor lysates will be measured flow cytometrically by cytokine bead array. Differences will be calculated (absolute change and percentage change) between pre and post treatment measures.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Expression of Th1 responses in CD4+ cells from peripheral blood</measure>
    <time_frame>Day 1 and time of surgery (day 36 or day 50)</time_frame>
    <description>Expression of IL-2 (Th1 responses) in CD4+ cells from peripheral blood of patients following PD-1 inhibition therapy will be compared between pre-treatment peripheral blood samples and post-treatment samples from the same patient.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Expression of Th2 responses in CD4+ cells from peripheral blood</measure>
    <time_frame>Day 1 and time of surgery (day 36 or day 50)</time_frame>
    <description>Expression of IIL 10 (Th2 responses) in CD4+ cells from peripheral blood of patients following PD-1 inhibition therapy will be compared between pre-treatment peripheral blood samples and post-treatment samples from the same patient.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Expression of CD8+ cells expressing granzyme B (ctolytic response) from peripheral blood</measure>
    <time_frame>Day 1 and time of surgery (day 36 or day 50)</time_frame>
    <description>2. Expression of CD8+ cells expressing granzyme B (cytolytic response) from peripheral blood of patients following PD-1 inhibition therapy will be compared between pre-treatment peripheral blood samples and post-treatment samples from the same patient.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">17</enrollment>
  <condition>Oral Cavity SCC</condition>
  <arm_group>
    <arm_group_label>Nivolumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab (OPDIVO) will be administered every two weeks for up to four doses prior to surgery at 3mg/kg</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Nivolumab will be administered on days 1, 15 and 29. If disease has progressed at day 29, the subject will proceed to surgery. If a response or stable disease is present after the third dose, a fourth dose will be given on day 43, then the subject will proceed to surgery.</description>
    <arm_group_label>Nivolumab</arm_group_label>
    <other_name>OPDIVO</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Newly diagnosed histologically proven locoregional OCSCC without evidence of distant&#xD;
             metastases and a clinically determined T-stage of 2-4,&#xD;
&#xD;
             OR&#xD;
&#xD;
             Recurrent or persistent histologically proven locoregional OCSCC that was initially&#xD;
             treated with surgery alone, and a clinically determined recurrent T-stage of 2-4.&#xD;
&#xD;
             Note - OCSCC includes the subsites of oral tongue, floor of mouth, gingiva, retromolar&#xD;
             trigone, and buccal mucosa.&#xD;
&#xD;
             Note - To allow sufficient tumor tissue for the immunological analyses, patients with&#xD;
             T-stage 1 OCSCC will be excluded&#xD;
&#xD;
          2. Greater than or equal to 18 years of age&#xD;
&#xD;
          3. ECOG performance status of 0 or 1&#xD;
&#xD;
          4. Screening labs must meet the following criteria and must be obtained within 14 days&#xD;
             prior to registration:&#xD;
&#xD;
               -  WBC &gt; 2,000/µL&#xD;
&#xD;
               -  Absolute Neutrophil Count &gt;1,500/µL&#xD;
&#xD;
               -  Platelets &gt; 100 X 103/µL&#xD;
&#xD;
               -  Hemoglobin &gt; 9.0 g/dL&#xD;
&#xD;
               -  Serum creatinine &lt; 1.5 X ULN or CrCl &gt; 40mL/min (if using the Cockcroft-Gault&#xD;
                  formula below):&#xD;
&#xD;
             Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in&#xD;
             mg/dL Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in&#xD;
             mg/dL&#xD;
&#xD;
               -  AST/ALT ≤ 3 x ULN&#xD;
&#xD;
               -  Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have&#xD;
                  total bilirubin &lt; 3.0 mg/dL)&#xD;
&#xD;
          5. Reproductive Status:&#xD;
&#xD;
        WOCBP must use appropriate method(s) of contraception. WOCBP should use an adequate method&#xD;
        to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo&#xD;
        five half-lives) after the last dose of investigational drug.&#xD;
&#xD;
        Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere&#xD;
        to contraception with a failure rate of less than 1% per year for a period of 31 weeks&#xD;
        after the last dose of investigational product.&#xD;
&#xD;
        WOCBP is defined as any female who has experienced menarche and who has not undergone&#xD;
        surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not&#xD;
        postmenopausal. Menopause is defined clinically as 12 consecutive months of amenorrhea in a&#xD;
        woman over 45.&#xD;
&#xD;
        Women of childbearing potential must have a negative serum pregnancy test (minimum&#xD;
        sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to registration Women&#xD;
        who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile)&#xD;
        and azoospermic men, are not required to use contraception.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Prior immunotherapy or treatment with another anti PD 1 agent&#xD;
&#xD;
          2. Prior chemotherapy including Cetuximab or radiation therapy&#xD;
&#xD;
          3. Previous severe hypersensitivity reaction to another monoclonal antibody&#xD;
&#xD;
          4. Women who are pregnant, lactating or expecting to conceive&#xD;
&#xD;
          5. Men who are expecting to father children within the research period&#xD;
&#xD;
          6. Known history of HIV or AIDS&#xD;
&#xD;
          7. Positive test for HBV sAg or HCV antibody indicating acute or chronic infection&#xD;
&#xD;
          8. Concomitant malignancies except cutaneous squamous cell carcinoma or basal cell&#xD;
             carcinoma&#xD;
&#xD;
          9. Unresectable primary tumor or regional disease; presence of distant metastases.&#xD;
&#xD;
         10. History of pneumonitis or interstitial lung disease&#xD;
&#xD;
         11. Active, known or suspected autoimmune disease. Note: Subjects are permitted to enroll&#xD;
             if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to&#xD;
             autoimmune condition only requiring hormone replacement, psoriasis not requiring&#xD;
             systemic treatment, or conditions not expected to recur in the absence of an external&#xD;
             trigger&#xD;
&#xD;
         12. Presence of condition requiring systemic treatment with either corticosteroids (&gt; 10&#xD;
             mg daily prednisone or equivalents) or other immunosuppressive medications within 14&#xD;
             days of study drug administration. Inhaled or topical steroids and adrenal replacement&#xD;
             doses &gt; 10 mg daily prednisone equivalents are permitted in the absence of active&#xD;
             autoimmune disease&#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>David Neskey, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Medical University of South Carolina</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Medical University of South Carolina</name>
      <address>
        <city>Charleston</city>
        <state>South Carolina</state>
        <zip>29425</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2021</verification_date>
  <study_first_submitted>December 20, 2016</study_first_submitted>
  <study_first_submitted_qc>January 13, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 16, 2017</study_first_posted>
  <last_update_submitted>December 10, 2021</last_update_submitted>
  <last_update_submitted_qc>December 10, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">December 13, 2021</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>Mouth Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>December 14, 2022</submitted>
    <returned>January 6, 2023</returned>
    <submitted>January 11, 2023</submitted>
    <submission_canceled>January 17, 2023</submission_canceled>
    <submitted>February 6, 2023</submitted>
    <returned>March 2, 2023</returned>
  </pending_results>
  <!-- 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/NCT03021993
org study id: 102510
nct id: NCT03021993
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study is to look at the effectiveness of nivolumab in patients with oral
      cavity cancer (OCC) who are about to undergo surgery.
OCC patients who are scheduled for surgery will be given Nivolumab prior to surgery to see if
      there are any changes in surgical outcomes.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Objective response rate using pathological response
time frame: Time of surgery (day 36 or day 50)
description: Objective response rate: the sum of patients with either a pCR defined as no invasive and no in situ residuals present in the surgical specimen or partial pathologic response defined at least a 30% reduction in the size of the lesion in the surgical specimen. The reduction in size will be determined by comparing the pretreatment clinical measurements (the sum of the greatest axial measurement obtained with calipers at the time of initial evaluation) with the final pathologic measurements.
measure: Level of Treg cells in peripheral blood using immunostaining
time frame: Day 1 and time of surgery (day 36 or day 50)
description: 1. Levels of Treg cells in pre and post treatment peripheral blood will be evaluated using immunostaining for CD4 and flow cytometric analysis of Foxp3. Differences will be calculated (absolute change and percentage change) between pre and post treatment measures.
measure: Level of activated T-cells in peripheral blood
time frame: Day 1 and time of surgery (day 36 or day 50)
description: 2. Levels of activated T-cells in peripheral blood will be assessed using flow cytometry for expression of CD69, IFN γ, T-bet and ICOS in CD4+ cells. Differences will be calculated (absolute change and percentage change) between pre and post treatment measures.
measure: Level of immune stimulatory cytokines in peripheral blood
time frame: Day 1 and time of surgery (day 36 or day 50)
description: 3. Intratumoral immune activity assessed by levels of immune stimulatory cytokines including IL-2, IFN γ, and IL-12 or inhibitory cytokine, IL10 and TGF-beta, in OCSCC tumor lysates will be measured flow cytometrically by cytokine bead array. Differences will be calculated (absolute change and percentage change) between pre and post treatment measures.
measure: Expression of Th1 responses in CD4+ cells from peripheral blood
time frame: Day 1 and time of surgery (day 36 or day 50)
description: Expression of IL-2 (Th1 responses) in CD4+ cells from peripheral blood of patients following PD-1 inhibition therapy will be compared between pre-treatment peripheral blood samples and post-treatment samples from the same patient.
measure: Expression of Th2 responses in CD4+ cells from peripheral blood
time frame: Day 1 and time of surgery (day 36 or day 50)
description: Expression of IIL 10 (Th2 responses) in CD4+ cells from peripheral blood of patients following PD-1 inhibition therapy will be compared between pre-treatment peripheral blood samples and post-treatment samples from the same patient.
measure: Expression of CD8+ cells expressing granzyme B (ctolytic response) from peripheral blood
time frame: Day 1 and time of surgery (day 36 or day 50)
description: 2. Expression of CD8+ cells expressing granzyme B (cytolytic response) from peripheral blood of patients following PD-1 inhibition therapy will be compared between pre-treatment peripheral blood samples and post-treatment samples from the same patient.
arm group label: Nivolumab
arm group type: Experimental
description: Nivolumab (OPDIVO) will be administered every two weeks for up to four doses prior to surgery at 3mg/kg
intervention type: Drug
intervention name: Nivolumab
description: Nivolumab will be administered on days 1, 15 and 29. If disease has progressed at day 29, the subject will proceed to surgery. If a response or stable disease is present after the third dose, a fourth dose will be given on day 43, then the subject will proceed to surgery.
arm group label: Nivolumab
other name: OPDIVO
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: David Neskey, MD
role: Principal Investigator
affiliation: Medical University of South Carolina
facility: 
country: United States
responsible party type: Sponsor
mesh term: Mouth Neoplasms
mesh term: Nivolumab
sharing ipd: No
submitted: December 14, 2022
returned: January 6, 2023
submitted: January 11, 2023
submission canceled: January 17, 2023
submitted: February 6, 2023
returned: March 2, 2023