<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/NCT02998736</url>
  </required_header>
  <id_info>
    <org_study_id>20160855-01H</org_study_id>
    <nct_id>NCT02998736</nct_id>
  </id_info>
  <brief_title>Trial of Perioperative Tadalafil and Influenza Vaccination in Cancer Patients Undergoing Major Surgical Resection of a Primary Abdominal Malignancy</brief_title>
  <acronym>PERIOP-04</acronym>
  <official_title>PERIOP-04 Phase Ib Trial of Perioperative Tadalafil and Influenza Vaccination in Cancer Patients Undergoing Major Surgical Resection of a Primary Abdominal Malignancy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ottawa Hospital Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Ottawa Hospital Research Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</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 determine if giving Cialis for 5 days prior to surgery, on&#xD;
      the day of surgery along with the influenza vaccine and Cialis 10 days after surgery will&#xD;
      have an affect at the cell level for decreasing the chances of the spread of disease post&#xD;
      surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Surgical resection of a primary malignancy, while critical for cure, results in postoperative&#xD;
      immune suppression, characterized by MDSC mediated inhibition of NK cell killing. In&#xD;
      preclinical models the causal link between this immune suppression and the formation of&#xD;
      postoperative metastases is undeniable. Fortunately, this postoperative immune suppression is&#xD;
      preventable using modulators of MDSC and NK cell function. In this Phase Ib study the&#xD;
      hypothesis is that simultaneous administration of perioperative tadalafil, to prevent MDSCs&#xD;
      from suppressing NK cells, and influenza vaccine, to directly activate NK cells will safely&#xD;
      and effectively reverse the effects of surgical stress on NK cell cytotoxicity. This is a&#xD;
      necessary first step towards demonstrating that this re-purposed perioperative regimen can&#xD;
      reduce the formation of postoperative metastatic disease in cancer surgery patients.&#xD;
&#xD;
      In this proposed Phase I trial a carefully selected promising perioperative immunomodulatory&#xD;
      regimen, which includes tadalafil and influenza vaccination, for rapid clinical translation.&#xD;
      The proposal is to re-purpose these drugs, they already have ample safety data associated&#xD;
      with their use but neither agent has been systematically administered immediately prior to&#xD;
      surgery. This trial will allow us to not only establish the safety of this regimen but will&#xD;
      permit a rigorous assessment of its ability to reverse surgery-induced suppression of NK&#xD;
      cells. If this regimen can effectively prevent postoperative NK cell dysfunction without any&#xD;
      regimen limiting toxicity then this will provide the necessary data required to undertake a&#xD;
      randomized efficacy study in a specific cancer subtype, with cancer recurrence as the primary&#xD;
      endpoint.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 21, 2017</start_date>
  <completion_date type="Actual">October 1, 2022</completion_date>
  <primary_completion_date type="Actual">September 1, 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Determine the change in the number of regimen limiting toxicities (RLT) in the experimental cohort</measure>
    <time_frame>measured at day 1, 3, 7, 10 and 35 post surgery</time_frame>
    <description>Adverse events, vitals and medications will be collected.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Document the change in the number and severity of CTCAE adverse events that are probably or definitely related to study treatment (tadalafil or influenza) in the experimental cohort.</measure>
    <time_frame>measured at day 1, 3, 7, 10 and 35 post surgery</time_frame>
    <description>Adverse events reported</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Compare the reduction in Natural Killer cell killing as measured on PBMC collected on SD1 as compared to baseline between the control and experimental cohorts, using a standard Natural Killer cell killing assay (51Chromium release assay).</measure>
    <time_frame>measured on day 1, 3, 7, 10 and 35 post surgery blood specimens</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">28</enrollment>
  <condition>Abdominal Cancer</condition>
  <arm_group>
    <arm_group_label>Intervention</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cialis 20 mg daily by mouth for 16 day. 5 days prior to surgery, day of surgery and 10 days post surgery.&#xD;
Influenza vaccine 0.5mL day of surgery</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>No intervention in the perioperative period</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cialis</intervention_name>
    <description>Cialis 20 mg daily by mouth for 16 day. 5 days prior to surgery, day of surgery and 10 days post surgery.&#xD;
Influenza vaccine 0.5mL day of surgery</description>
    <arm_group_label>Intervention</arm_group_label>
    <other_name>Tadalafil</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Influenza vaccine</intervention_name>
    <description>One 0.5mL intramuscular injection the day of surgery</description>
    <arm_group_label>Intervention</arm_group_label>
    <other_name>Agriflu</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with a diagnosis of a primary abdominal malignancy consented to undergo major&#xD;
             surgery with a planned length of stay of 3 or more days.&#xD;
&#xD;
          -  Eligible patients must have signed a consent for surgical resection of the malignancy.&#xD;
&#xD;
          -  Adequate hematological function defined as: platelet count ≥ 100 x 109/L, absolute&#xD;
             neutrophil count ≥ 1 x 109/L, white blood count ≥ 2.5 x 109/L, hemoglobin count ≥ 90&#xD;
             g/L.&#xD;
&#xD;
          -  Adequate organ functioning, including: total bilirubin ≤ 1.5 x upper limit of normal&#xD;
             (ULN); AST, ALT &lt; 2.5 x ULN; INR &lt;1.5 ; CrCl&gt;30mL/min.&#xD;
&#xD;
          -  If sexually active, and of childbearing potential, subjects must agree to use&#xD;
             acceptable birth control from screening until the final study visit (study day, SD35)&#xD;
             or early termination. Acceptable methods of birth control include: spermicide with&#xD;
             condom, diaphragm, or cervical cap, IUD (intrauterine device), hormonal contraception,&#xD;
             vasectomy, and abstinence. (Plan B or the rhythm method are not considered reliable&#xD;
             methods.&#xD;
&#xD;
          -  Male subjects should agree to avoid having sex for 5 days before surgery and 10 days&#xD;
             post surgery taking tadalafil due to the risk of sustained erection&#xD;
&#xD;
          -  Ability to understand and provide a signed informed consent form (ICF) approved by the&#xD;
             Institutional Review Board (IRB/IEC/REB).&#xD;
&#xD;
          -  Ability to comply with protocol requirements.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior adjuvant chemotherapy or radiation within 8 weeks of planned surgery.&#xD;
&#xD;
          -  Pregnant or nursing mothers or women of childbearing potential not using acceptable&#xD;
             methods of birth control.&#xD;
&#xD;
          -  Documented significant immunodeficiency due to underlying illness (e.g. HIV/AIDS)&#xD;
             and/or medication (e.g. systemic corticosteroids, azathioprine, cyclosporin A).&#xD;
             Subjects may be on physiologic doses of replacement prednisone or equivalent doses of&#xD;
             corticosteroid (&lt;7.5 mg daily).&#xD;
&#xD;
          -  History of autoimmune disease (even if controlled with medication) such as but not&#xD;
             restricted to, inflammatory bowel disease, systemic lupus erythematosus, ankylosing&#xD;
             spondylitis, scleroderma, or multiple sclerosis.&#xD;
&#xD;
          -  Allergies or any contraindication to the use of tadalafil or any components of Cialis®&#xD;
             or the influenza vaccine (including eggs), Agriflu®.&#xD;
&#xD;
          -  Serious intercurrent chronic or acute illness, or other illness considered by the&#xD;
             investigator as an unwarranted high risk for an investigational product.&#xD;
&#xD;
          -  Patients who have suffered a myocardial infarction, stroke, or life-threatening&#xD;
             arrhythmia within the last 6 months.&#xD;
&#xD;
          -  Patients with resting hypotension (BP &lt;90/50 at rest) or hypertension (BP &gt;170/110 at&#xD;
             rest).&#xD;
&#xD;
          -  Patients with cardiac failure or coronary artery disease causing unstable angina.&#xD;
&#xD;
          -  Use any type of nitrate drug therapy, including short-acting nitrate-containing&#xD;
             medications, due to the risk of developing potentially life-threatening hypotension.&#xD;
             The use of organic nitrates, either regularly and/or intermittently, in any form (e.g.&#xD;
             oral, sublingual, transdermal, by inhalation) is absolutely contraindicated (see list&#xD;
             Appendix II).&#xD;
&#xD;
          -  Use of guanylate cyclase stimulators (cinaciguat or riociguat).&#xD;
&#xD;
          -  Use of alpha-blocker therapy (see list in Appendix I).&#xD;
&#xD;
          -  Previous episode of non-arteritic anterior ischaemic optic neuropathy (NAION) or&#xD;
             history of retinitis pigmentosa.&#xD;
&#xD;
          -  Use of anti-platelet (excluding ASA) or anti-coagulation medication (Patients who&#xD;
             discontinue such medications at least 7 days prior to first treatment may be eligible&#xD;
             for this study).&#xD;
&#xD;
          -  Use of the following anti-viral agents: ribavirin, adefovir, cidofovir (at least 7&#xD;
             days prior to the first treatment), and PEG-IFN (at least14 days prior to the first&#xD;
             treatment).&#xD;
&#xD;
          -  Active infection of any site requiring ongoing treatment.&#xD;
&#xD;
          -  Known anatomical deformities of the penis (such as angulation, cavernosal fibrosis or&#xD;
             Peyronie's disease) or any condition that might predispose the patient to priapism.&#xD;
&#xD;
          -  History of Guillaine-Barré Syndrome.&#xD;
&#xD;
          -  Subjects with a medical or psychological impediment to probable compliance with the&#xD;
             protocol should be excluded.&#xD;
&#xD;
          -  Active drug or alcohol use or dependence or other conditions that, in the opinion of&#xD;
             the investigator, would interfere with adherence to study requirements. Social alcohol&#xD;
             use is acceptable.&#xD;
&#xD;
          -  Concurrent inhibitors of moderate or strong CYP3A4 inhibitors&#xD;
&#xD;
          -  Taking any other PDE-5 inhibitor (such as sildenafil) during the active phase of the&#xD;
             study between enrollment to SD35.&#xD;
&#xD;
          -  History of lactose or milk sugar intolerance&#xD;
&#xD;
          -  Liver or Kidney disease&#xD;
&#xD;
          -  Sickle cell anemia&#xD;
&#xD;
          -  Peptic ulcer or other bleeding disorders&#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>Rebecca Auer, Doctor</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Ottawa Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>The Ottawa Hospital</name>
      <address>
        <city>Ottawa</city>
        <state>Ontario</state>
        <zip>K1H 8L6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>December 6, 2016</study_first_submitted>
  <study_first_submitted_qc>December 16, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 20, 2016</study_first_posted>
  <last_update_submitted>December 23, 2022</last_update_submitted>
  <last_update_submitted_qc>December 23, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 28, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Colon</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Influenza, Human</mesh_term>
    <mesh_term>Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tadalafil</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT02998736
org study id: 20160855-01H
nct id: NCT02998736
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to determine if giving Cialis for 5 days prior to surgery, on
      the day of surgery along with the influenza vaccine and Cialis 10 days after surgery will
      have an affect at the cell level for decreasing the chances of the spread of disease post
      surgery.
Surgical resection of a primary malignancy, while critical for cure, results in postoperative
      immune suppression, characterized by MDSC mediated inhibition of NK cell killing. In
      preclinical models the causal link between this immune suppression and the formation of
      postoperative metastases is undeniable. Fortunately, this postoperative immune suppression is
      preventable using modulators of MDSC and NK cell function. In this Phase Ib study the
      hypothesis is that simultaneous administration of perioperative tadalafil, to prevent MDSCs
      from suppressing NK cells, and influenza vaccine, to directly activate NK cells will safely
      and effectively reverse the effects of surgical stress on NK cell cytotoxicity. This is a
      necessary first step towards demonstrating that this re-purposed perioperative regimen can
      reduce the formation of postoperative metastatic disease in cancer surgery patients.

      In this proposed Phase I trial a carefully selected promising perioperative immunomodulatory
      regimen, which includes tadalafil and influenza vaccination, for rapid clinical translation.
      The proposal is to re-purpose these drugs, they already have ample safety data associated
      with their use but neither agent has been systematically administered immediately prior to
      surgery. This trial will allow us to not only establish the safety of this regimen but will
      permit a rigorous assessment of its ability to reverse surgery-induced suppression of NK
      cells. If this regimen can effectively prevent postoperative NK cell dysfunction without any
      regimen limiting toxicity then this will provide the necessary data required to undertake a
      randomized efficacy study in a specific cancer subtype, with cancer recurrence as the primary
      endpoint.
allocation: Randomized
intervention model: Single Group Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Determine the change in the number of regimen limiting toxicities (RLT) in the experimental cohort
time frame: measured at day 1, 3, 7, 10 and 35 post surgery
description: Adverse events, vitals and medications will be collected.
measure: Document the change in the number and severity of CTCAE adverse events that are probably or definitely related to study treatment (tadalafil or influenza) in the experimental cohort.
time frame: measured at day 1, 3, 7, 10 and 35 post surgery
description: Adverse events reported
measure: Compare the reduction in Natural Killer cell killing as measured on PBMC collected on SD1 as compared to baseline between the control and experimental cohorts, using a standard Natural Killer cell killing assay (51Chromium release assay).
time frame: measured on day 1, 3, 7, 10 and 35 post surgery blood specimens
arm group label: Intervention
arm group type: Experimental
description: Cialis 20 mg daily by mouth for 16 day. 5 days prior to surgery, day of surgery and 10 days post surgery.
Influenza vaccine 0.5mL day of surgery
arm group label: Control
arm group type: No Intervention
description: No intervention in the perioperative period
intervention type: Drug
intervention name: Cialis
description: Cialis 20 mg daily by mouth for 16 day. 5 days prior to surgery, day of surgery and 10 days post surgery.
Influenza vaccine 0.5mL day of surgery
arm group label: Intervention
other name: Tadalafil
intervention type: Biological
intervention name: Influenza vaccine
description: One 0.5mL intramuscular injection the day of surgery
arm group label: Intervention
other name: Agriflu
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Rebecca Auer, Doctor
role: Principal Investigator
affiliation: The Ottawa Hospital
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Influenza, Human
mesh term: Neoplasms
mesh term: Tadalafil
sharing ipd: No