<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/NCT01697800</url>
  </required_header>
  <id_info>
    <org_study_id>J1247</org_study_id>
    <secondary_id>2P50DE019032</secondary_id>
    <secondary_id>NA_00073880</secondary_id>
    <nct_id>NCT01697800</nct_id>
  </id_info>
  <brief_title>A Phase II Trial of Tadalafil in Patients With Squamous Cell Carcinoma of the Upper Aero Digestive Tract</brief_title>
  <official_title>A Phase II Trial of Tadalafil in Patients With Squamous Cell Carcinoma of the Upper Aero Digestive Tract</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Dental and Craniofacial Research (NIDCR)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Head and neck squamous cell carcinoma (HNSCC) is a lethal solid malignancy with 5 year&#xD;
      survival estimates of approximately 50%, and is associated with a high rate of systemic&#xD;
      immune impairment as well as evasion of a tumor specific immune response. Preclinical and&#xD;
      clinical data have shown that phosphodiesterase 5 (PDE5) inhibitors (tadalafil) can be used&#xD;
      to augment immune function in HNSCC patients through inhibition of the cancer-induced myeloid&#xD;
      derived suppressor cells (MDSCs).&#xD;
&#xD;
      A multi site phase II, randomized, prospective, biomarker endpoint trial to determine optimum&#xD;
      timing and design of PDE5 antitumor immunotherapy (tadalafil) in conjunction with&#xD;
      conventional therapy for HNSCC.&#xD;
&#xD;
      40 patients with biopsy proven HNSCC will be randomized to receive tadalafil (n=25) or&#xD;
      placebo (n=15) for at least 10-14 days before starting conventional therapy and continuing&#xD;
      until 90 days after completion of conventional therapy. Tumor-specific T cell responses will&#xD;
      be assessed using HNSCC cell lines, in blood collected before initiation of tadalafil/placebo&#xD;
      and at 60 and 90 days after completion of conventional therapy. Number and function of MDSC&#xD;
      and Treg cells will be assessed before and at 60 and 90 days after completion of conventional&#xD;
      therapy. Prevnar 13® vaccine will be administered 10-14 days after commencing&#xD;
      tadalafil/placebo (before conventional therapy begins) and again at 60 days after completion&#xD;
      of conventional therapy. Vaccine-specific responses assessed at 60 and 90 days&#xD;
      post-conventional therapy will be used to measure the ability of tadalafil to augment immune&#xD;
      response to vaccine.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">July 14, 2014</completion_date>
  <primary_completion_date type="Actual">July 14, 2014</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Immune Response After Tadalafil Administration</measure>
    <time_frame>Baseline and 120-150 Days</time_frame>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Head and Neck Squamous Cell Carcinoma</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients received placebo capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Tadalafil</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients received 20 mg tadalafil capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tadalafil</intervention_name>
    <arm_group_label>Tadalafil</arm_group_label>
    <other_name>Cialis</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥21 years&#xD;
&#xD;
          2. Histologically confirmed, previously untreated invasive head and neck squamous cell&#xD;
             carcinoma OR histologically confirmed not yet treated recurrent head and neck squamous&#xD;
             cell carcinoma (must be at least 3 months after diagnosis and completion of treatment&#xD;
             for primary disease or last recurrence). Patients may have local Stage I or II, or&#xD;
             locoregionally advanced HNSCC Stage III or IV of the oral cavity, oropharynx, larynx,&#xD;
             hypopharynx, or unknown primary, but no metastatic disease; Intent to treat with&#xD;
             primary radiotherapy +/-chemotherapy&#xD;
&#xD;
          3. Disease location amenable to biopsy in outpatient clinical setting or operative biopsy&#xD;
             within routine accepted schedule and practice of clinical care&#xD;
&#xD;
          4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1&#xD;
&#xD;
          5. Required laboratory data (to be obtained within 2 weeks of initiation):&#xD;
&#xD;
               -  Platelets &gt; 75,000/mm³&#xD;
&#xD;
               -  Calculated Creatinine Clearance (CRCL)&gt; 60 mL/min&#xD;
&#xD;
               -  Total serum bilirubin &lt; 1.5 mg/dL&#xD;
&#xD;
          6. Willingness and ability to give signed written informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Medical contraindication to biopsy of target lesion&#xD;
&#xD;
          2. Intercurrent illness likely to prevent protocol therapy or conventional planned&#xD;
             therapy&#xD;
&#xD;
          3. Prior daily use of tadalafil or other long-acting PDE5 inhibitors for one month or&#xD;
             greater&#xD;
&#xD;
          4. Known severe hypersensitivity to tadalafil or any of the excipients of this product&#xD;
&#xD;
          5. Current treatment with nitrates&#xD;
&#xD;
          6. Current systemic treatment with a potent cytochrome P450 3A4 (CYP3A4) inhibitor such&#xD;
             as ketoconazole or ritonavir&#xD;
&#xD;
          7. History of hypotension and/or blindness during prior treatment with tadalafil or other&#xD;
             PDE5 inhibitors&#xD;
&#xD;
          8. Prior history of non-arterial ischemic optic retinopathy&#xD;
&#xD;
          9. Prior adverse reaction to diphtheria vaccine&#xD;
&#xD;
         10. Pregnant or breastfeeding; a negative pregnancy test is required within 14 days of&#xD;
             randomization for all women of childbearing potential.&#xD;
&#xD;
         11. Concurrent malignancy or a history of previous malignancy treated with curative&#xD;
             therapy within the last 3 months (other than squamous/basal cell cancer of the skin or&#xD;
             cervical cancer), for which the survival prognosis is &lt; 5 years&#xD;
&#xD;
         12. Treatment with a non-approved or investigational drug within 30 days before visit 1&#xD;
&#xD;
         13. Incomplete healing from previous oncologic or other major surgery&#xD;
&#xD;
         14. As judged by the investigator, any evidence of severe or uncontrolled systemic disease&#xD;
             (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease)&#xD;
&#xD;
         15. Evidence of any other significant clinical disorder or laboratory finding that makes&#xD;
             it undesirable for the subject to participate in the trial&#xD;
&#xD;
         16. History of significant hypotensive episode requiring hospitalization&#xD;
&#xD;
         17. History of acute myocardial infarction within prior 3 months, uncontrolled angina,&#xD;
             uncontrolled arrhythmia, or uncontrolled congestive heart failure&#xD;
&#xD;
         18. History of any of the following cardiac conditions:&#xD;
&#xD;
             I. Angina requiring treatment with long-acting nitrates II. Angina requiring treatment&#xD;
             with short-acting nitrates within 90 days of planned tadalafil administration III.&#xD;
             Unstable angina within 90 days of visit 1 (Braunwald 1989) IV. Positive cardiac stress&#xD;
             test without documented evidence of subsequent, effective cardiac intervention&#xD;
&#xD;
         19. History of any of the following coronary conditions within 90 days of planned&#xD;
             tadalafil administration:&#xD;
&#xD;
             I. Myocardial Infarction II. Coronary artery bypass graft surgery III. Percutaneous&#xD;
             coronary intervention (for example, angioplasty or stent placement) IV. Any evidence&#xD;
             of heart disease (NYHA≥Class III as defined in Protocol Attachment LVHG.3) within 6&#xD;
             months of planned tadalafil administration&#xD;
&#xD;
         20. Prior chronic immune suppressive state (AIDS, immunosuppressive therapy)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Zubair Khan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Johns Hopkins University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Johns Hopkins Hospital</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21231</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2020</verification_date>
  <study_first_submitted>September 28, 2012</study_first_submitted>
  <study_first_submitted_qc>October 1, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 2, 2012</study_first_posted>
  <results_first_submitted>February 13, 2020</results_first_submitted>
  <results_first_submitted_qc>February 27, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">February 28, 2020</results_first_posted>
  <last_update_submitted>February 27, 2020</last_update_submitted>
  <last_update_submitted_qc>February 27, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 28, 2020</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</mesh_term>
    <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>Tadalafil</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Placebo</title>
          <description>Patients received placebo capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment</description>
        </group>
        <group group_id="P2">
          <title>Tadalafil</title>
          <description>Patients received 20 mg tadalafil capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
                <participants group_id="P2" count="25"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
                <participants group_id="P2" count="24"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Placebo</title>
          <description>Patients received placebo capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment</description>
        </group>
        <group group_id="B2">
          <title>Tadalafil</title>
          <description>Patients received 20 mg tadalafil capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment</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="15"/>
            <count group_id="B2" value="25"/>
            <count group_id="B3" value="40"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>18-99 years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="25"/>
                    <measurement group_id="B3" value="40"/>
                  </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="2"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="23"/>
                    <measurement group_id="B3" value="37"/>
                  </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="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </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="4"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="21"/>
                    <measurement group_id="B3" value="34"/>
                  </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="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="25"/>
                    <measurement group_id="B3" value="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Immune Response After Tadalafil Administration</title>
        <time_frame>Baseline and 120-150 Days</time_frame>
        <population>Blood samples were collected. However, the samples were not analyzed and hence no data were generated.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Patients received placebo capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment</description>
          </group>
          <group group_id="O2">
            <title>Tadalafil</title>
            <description>Patients received 20 mg tadalafil capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Immune Response After Tadalafil Administration</title>
          <population>Blood samples were collected. However, the samples were not analyzed and hence no data were generated.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Placebo</title>
          <description>Patients received placebo capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment</description>
        </group>
        <group group_id="E2">
          <title>Tadalafil</title>
          <description>Patients received 20 mg tadalafil capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
              </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>Zubair Khan</name_or_title>
      <organization>Johns Hopkins Medicine</organization>
      <phone>410-955-3157</phone>
      <email>zkhan@jhmi.edu</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/NCT01697800
org study id: J1247
secondary id: 2P50DE019032
secondary id: NA_00073880
nct id: NCT01697800
lead sponsor: 
collaborator: 
has dmc: Yes
Head and neck squamous cell carcinoma (HNSCC) is a lethal solid malignancy with 5 year
      survival estimates of approximately 50%, and is associated with a high rate of systemic
      immune impairment as well as evasion of a tumor specific immune response. Preclinical and
      clinical data have shown that phosphodiesterase 5 (PDE5) inhibitors (tadalafil) can be used
      to augment immune function in HNSCC patients through inhibition of the cancer-induced myeloid
      derived suppressor cells (MDSCs).

      A multi site phase II, randomized, prospective, biomarker endpoint trial to determine optimum
      timing and design of PDE5 antitumor immunotherapy (tadalafil) in conjunction with
      conventional therapy for HNSCC.

      40 patients with biopsy proven HNSCC will be randomized to receive tadalafil (n=25) or
      placebo (n=15) for at least 10-14 days before starting conventional therapy and continuing
      until 90 days after completion of conventional therapy. Tumor-specific T cell responses will
      be assessed using HNSCC cell lines, in blood collected before initiation of tadalafil/placebo
      and at 60 and 90 days after completion of conventional therapy. Number and function of MDSC
      and Treg cells will be assessed before and at 60 and 90 days after completion of conventional
      therapy. Prevnar 13® vaccine will be administered 10-14 days after commencing
      tadalafil/placebo (before conventional therapy begins) and again at 60 days after completion
      of conventional therapy. Vaccine-specific responses assessed at 60 and 90 days
      post-conventional therapy will be used to measure the ability of tadalafil to augment immune
      response to vaccine.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Investigator, Outcomes Assessor)
measure: Change in Immune Response After Tadalafil Administration
time frame: Baseline and 120-150 Days
arm group label: Placebo
arm group type: Placebo Comparator
description: Patients received placebo capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment
arm group label: Tadalafil
arm group type: Active Comparator
description: Patients received 20 mg tadalafil capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment
intervention type: Drug
intervention name: Tadalafil
arm group label: Tadalafil
other name: Cialis
intervention type: Drug
intervention name: Placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 21 Years
maximum age: 99 Years
healthy volunteers: No
last name: Zubair Khan, MD
role: Principal Investigator
affiliation: Johns Hopkins University
facility: 
country: United States
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Squamous Cell
mesh term: Squamous Cell Carcinoma of Head and Neck
mesh term: Tadalafil
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 