<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/NCT03838029</url>
  </required_header>
  <id_info>
    <org_study_id>0308-17-ASF</org_study_id>
    <secondary_id>MOH_2018-03-12_002226</secondary_id>
    <nct_id>NCT03838029</nct_id>
  </id_info>
  <brief_title>Perioperative Intervention to Reduce Metastatic Processes in Pancreatic Cancer Patients Undergoing Curative Surgery</brief_title>
  <acronym>BC-PC</acronym>
  <official_title>Perioperative Use of a Beta-adrenergic Blocker and a COX-2 Inhibitor in Patients Undergoing Surgery With Primary Pancreatic Cancer: Intervention Aiming to Reduce Pro-metastatic Processes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assaf-Harofeh Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Sheba Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Assaf-Harofeh Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      In Israel, of the ~1000 patients diagnosed annually with pancreatic cancer (PC),&#xD;
      approximately 250 (25 percent) will be eligible for curative surgery, of which 80 percent&#xD;
      will succumb to post-surgical metastatic disease. A reduction in post-surgical metastatic&#xD;
      disease will save dozens of patients in Israel annually, and tens-of thousands-around the&#xD;
      world. The short perioperative period (days to weeks around surgery) is characterized by&#xD;
      stress-inflammatory responses, including catecholamines (CAs, e.g., adrenaline) and&#xD;
      prostaglandins (PGs, e.g., prostaglandin-E2) release, and induce deleterious pro-metastatic&#xD;
      effects. Animal studies implicated excess perioperative release of CAs and PGs in&#xD;
      facilitating cancer progression by affecting the malignant tissue, its local environment, and&#xD;
      anti-metastatic immune functions. Congruently, our animal studies indicate that combined use&#xD;
      of the beta-adrenergic blocker, propranolol, and the prostaglandins inhibitor, etodolac - but&#xD;
      neither drug separately - efficiently prevented post-operative metastatic development. We&#xD;
      recently conducted two clinical trials in three medical centers in Israel, recruiting breast&#xD;
      (n=38) and colorectal (n=34) cancer patients, assessing the safety and short-term efficacy of&#xD;
      perioperative propranolol and etodolac treatment. Drugs were well tolerated, without severe&#xD;
      adverse events. Importantly, molecular/biological analyses of the excised primary tumor&#xD;
      indicated that drug treatment caused promising anti-metastatic transformations, as well as&#xD;
      improvements in immune and inflammatory indices. These included (i) decreased tumor cell&#xD;
      capacity to migrate, (ii) reduced pro-metastatic capacity of the malignant tissue, and (iii)&#xD;
      improvement in immune infiltrating into the tumor (Paper published in Clinical Cancer&#xD;
      Research, 2017). Herein, we propose to conduct a double-blind placebo-controlled two-arm&#xD;
      Phase II clinical trial in 210 pancreatic cancer patients undergoing curative surgery in&#xD;
      Israel. A perioperative 35-day drug treatment will be initiated 5 days before surgery.&#xD;
      Primary outcomes will include (i) 1-year disease-free-survival (DFS), and 5-year overall&#xD;
      survival (OS); and (ii) biological markers in blood samples, and in the excised tumor tissue.&#xD;
      Secondary outcomes will include safety indices and psychological measures of depression,&#xD;
      anxiety, distress, and fatigue.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Anticipated">November 20, 2019</start_date>
  <completion_date type="Anticipated">January 2026</completion_date>
  <primary_completion_date type="Anticipated">January 2026</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>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Rate of cancer recurrence</measure>
    <time_frame>From the date of surgery until malignant disease is identified, assessed up to 60 months post-surgery</time_frame>
    <description>Data regrading post-surgical recurrence will be recorded at 1,3,6,12,18,24,36,48, and 60 following surgery</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Biomarkers in extracted tumor tissue samples</measure>
    <time_frame>An average of one year following surgery</time_frame>
    <description>Epithelial-to-mesenchymal-transition ( EMT) status and natural-killer cell, macrophage, T-cell, and B-cell infiltration levels into tumor tissue (as assessed by messenger RNA profiling of tissue samples.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Biomarkers in blood samples</measure>
    <time_frame>An average of one year following surgery</time_frame>
    <description>Cytokine levels in blood samples (interleukin-6, interleukin-10, C-reactive protein, interferon-gamma, and vascular endothelial growth factor and additional exploratory analysis of other cytokines)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of patients with treatment related adverse events</measure>
    <time_frame>30 days following surgery</time_frame>
    <description>According to the Clavien-Dindo classification system (7 grades of events depicting the severity of the event)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Depression, Anxiety, Global distress</measure>
    <time_frame>At baseline and at 30 days post-surgery</time_frame>
    <description>Assessed by changes on the brief symptom inventory 18 questionnaire (this questionnaire assess all three scales for depression, anxiety and global distress)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fatigue</measure>
    <time_frame>At baseline and at 30 days post-surgery</time_frame>
    <description>4 items related to fatigue in the 36 item short-form survey questionnaire.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">210</enrollment>
  <condition>Pancreatic Neoplasms</condition>
  <arm_group>
    <arm_group_label>Propranolol and etodolac</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Both study medications will be given orally for an intervention phase of 35 days as follows. Etodolac:400mg PO bid for the entire intervention period,Propranolol:20 mg PO bid for 5 preoperative days, 80 mg PO bid on the day of surgery and the following morning, 40 mg PO bid for following 6.5 days, and 20 mg PO bid for next 22 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Same schedule as in the active comparator arm</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Propranolol and etodolac</intervention_name>
    <description>A perioperative combined drug regimen</description>
    <arm_group_label>Propranolol and etodolac</arm_group_label>
    <other_name>Deralin and etopan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Newly diagnosed Stage I or II adenocarcinoma of the head, neck, or uncinated- process&#xD;
             of the pancreas.&#xD;
&#xD;
          -  Surgically resectable disease (R0 or R1) by spiral CT chest and abdomen scan, No&#xD;
             distant metastases&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1&#xD;
&#xD;
          -  Signed informed consent form&#xD;
&#xD;
          -  Willing and able to comply with study procedures&#xD;
&#xD;
          -  Men and women from age 20 up to age 80&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with metastatic disease, known prior to surgery&#xD;
&#xD;
          -  Patients with history or concomitant malignant disease of any type (except for the&#xD;
             current pancreatic cancer&#xD;
&#xD;
          -  Patients who were treated with chemotherapy in the last 10 years for any reason&#xD;
&#xD;
          -  Patients in whom surgical resection is planned without curative intent&#xD;
&#xD;
          -  Patients exhibiting levels Carbohydrate antigen (CA) 19-9 above 500&#xD;
&#xD;
          -  Patients with renal failure, measured by creatinine level &gt;1.5&#xD;
&#xD;
          -  Patients with significant heart failure (NYHA functional class 3 or higher),&#xD;
&#xD;
          -  Patients with significant liver failure (known cirrhosis)&#xD;
&#xD;
          -  Patients suffering from active asthma&#xD;
&#xD;
          -  Patients with known allergy to any medication from the non-steroidal anti-&#xD;
             inflammatory or beta-blockers drug group&#xD;
&#xD;
          -  Patients treated chronically with any type of a beta-adrenergic blocker or a&#xD;
             cyclooxygenase (COX) inhibitor&#xD;
&#xD;
          -  Patients with bradycardia or second or third degree atrioventricular block (AV) block&#xD;
&#xD;
          -  Patients with a history of cerebrovascular accident (CVA) or established diagnosed&#xD;
             transient ischemic attack (TIA)&#xD;
&#xD;
          -  Patients with prinzmetal's angina&#xD;
&#xD;
          -  Patients with right sided heart failure owing to pulmonary hypertension&#xD;
&#xD;
          -  Patients with significant diagnosed cardiomegaly&#xD;
&#xD;
          -  Patients with (current) pheochromocytoma&#xD;
&#xD;
          -  Patients with chronic Digoxin treatment&#xD;
&#xD;
          -  Patients with active peptic disease&#xD;
&#xD;
          -  Patients with peripheral vascular disease&#xD;
&#xD;
          -  Pregnant woman&#xD;
&#xD;
          -  Special population with impaired judgment&#xD;
&#xD;
          -  Patients currently actively participating in any other clinical trial&#xD;
&#xD;
          -  contraindication for Whipple procedure&#xD;
&#xD;
          -  Patients suffering from sick sinus syndrome&#xD;
&#xD;
          -  Patients with borderline resectable tumors, as defined by one of the following:&#xD;
&#xD;
               -  an infiltration &gt;180° of the portal vein&#xD;
&#xD;
               -  abutment of the tumor to the superior mesenteric artery&#xD;
&#xD;
               -  infiltration of the superior mesenteric artery or the celiac trunk&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Oded Zmora, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Asaf Harofeh Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Oded Zmora, MD</last_name>
    <phone>+97289779202</phone>
    <email>ozmora@post.tau.ac.il</email>
  </overall_contact>
  <location>
    <facility>
      <name>Sheba Medical Center</name>
      <address>
        <city>Tel Hashomer</city>
        <zip>45858</zip>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Talia Golan, MD</last_name>
      <email>Talia.Golan@sheba.health.gov.il</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Sourasky Medical Center</name>
      <address>
        <city>Tel-Aviv</city>
        <zip>6423906</zip>
        <country>Israel</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Ido Nachmany, MD</last_name>
    </contact>
    <contact_backup>
      <email>idon@tlvmc.gov.il</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Asaf Harofeh Medical Center</name>
      <address>
        <city>Tsrifin</city>
        <zip>70300</zip>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Oded Zmora, MD</last_name>
      <phone>+97289779202</phone>
      <email>ozmora@post.tau.ac.il</email>
    </contact>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <results_reference>
    <citation>Haldar R, Shaashua L, Lavon H, Lyons YA, Zmora O, Sharon E, Birnbaum Y, Allweis T, Sood AK, Barshack I, Cole S, Ben-Eliyahu S. Perioperative inhibition of beta-adrenergic and COX2 signaling in a clinical trial in breast cancer patients improves tumor Ki-67 expression, serum cytokine levels, and PBMCs transcriptome. Brain Behav Immun. 2018 Oct;73:294-309. doi: 10.1016/j.bbi.2018.05.014. Epub 2018 May 22.</citation>
    <PMID>29800703</PMID>
  </results_reference>
  <results_reference>
    <citation>Shaashua L, Shabat-Simon M, Haldar R, Matzner P, Zmora O, Shabtai M, Sharon E, Allweis T, Barshack I, Hayman L, Arevalo J, Ma J, Horowitz M, Cole S, Ben-Eliyahu S. Perioperative COX-2 and beta-Adrenergic Blockade Improves Metastatic Biomarkers in Breast Cancer Patients in a Phase-II Randomized Trial. Clin Cancer Res. 2017 Aug 15;23(16):4651-4661. doi: 10.1158/1078-0432.CCR-17-0152. Epub 2017 May 10.</citation>
    <PMID>28490464</PMID>
  </results_reference>
  <verification_date>November 2019</verification_date>
  <study_first_submitted>January 23, 2019</study_first_submitted>
  <study_first_submitted_qc>February 11, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 12, 2019</study_first_posted>
  <last_update_submitted>November 19, 2019</last_update_submitted>
  <last_update_submitted_qc>November 19, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">November 20, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Beta-blocker</keyword>
  <keyword>Propranolol</keyword>
  <keyword>COX-2 inhibitor</keyword>
  <keyword>Etodolac</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pancreatic Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Etodolac</mesh_term>
    <mesh_term>Propranolol</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/NCT03838029
org study id: 0308-17-ASF
secondary id: MOH_2018-03-12_002226
nct id: NCT03838029
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
In Israel, of the ~1000 patients diagnosed annually with pancreatic cancer (PC),
      approximately 250 (25 percent) will be eligible for curative surgery, of which 80 percent
      will succumb to post-surgical metastatic disease. A reduction in post-surgical metastatic
      disease will save dozens of patients in Israel annually, and tens-of thousands-around the
      world. The short perioperative period (days to weeks around surgery) is characterized by
      stress-inflammatory responses, including catecholamines (CAs, e.g., adrenaline) and
      prostaglandins (PGs, e.g., prostaglandin-E2) release, and induce deleterious pro-metastatic
      effects. Animal studies implicated excess perioperative release of CAs and PGs in
      facilitating cancer progression by affecting the malignant tissue, its local environment, and
      anti-metastatic immune functions. Congruently, our animal studies indicate that combined use
      of the beta-adrenergic blocker, propranolol, and the prostaglandins inhibitor, etodolac - but
      neither drug separately - efficiently prevented post-operative metastatic development. We
      recently conducted two clinical trials in three medical centers in Israel, recruiting breast
      (n=38) and colorectal (n=34) cancer patients, assessing the safety and short-term efficacy of
      perioperative propranolol and etodolac treatment. Drugs were well tolerated, without severe
      adverse events. Importantly, molecular/biological analyses of the excised primary tumor
      indicated that drug treatment caused promising anti-metastatic transformations, as well as
      improvements in immune and inflammatory indices. These included (i) decreased tumor cell
      capacity to migrate, (ii) reduced pro-metastatic capacity of the malignant tissue, and (iii)
      improvement in immune infiltrating into the tumor (Paper published in Clinical Cancer
      Research, 2017). Herein, we propose to conduct a double-blind placebo-controlled two-arm
      Phase II clinical trial in 210 pancreatic cancer patients undergoing curative surgery in
      Israel. A perioperative 35-day drug treatment will be initiated 5 days before surgery.
      Primary outcomes will include (i) 1-year disease-free-survival (DFS), and 5-year overall
      survival (OS); and (ii) biological markers in blood samples, and in the excised tumor tissue.
      Secondary outcomes will include safety indices and psychological measures of depression,
      anxiety, distress, and fatigue.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Rate of cancer recurrence
time frame: From the date of surgery until malignant disease is identified, assessed up to 60 months post-surgery
description: Data regrading post-surgical recurrence will be recorded at 1,3,6,12,18,24,36,48, and 60 following surgery
measure: Biomarkers in extracted tumor tissue samples
time frame: An average of one year following surgery
description: Epithelial-to-mesenchymal-transition ( EMT) status and natural-killer cell, macrophage, T-cell, and B-cell infiltration levels into tumor tissue (as assessed by messenger RNA profiling of tissue samples.
measure: Biomarkers in blood samples
time frame: An average of one year following surgery
description: Cytokine levels in blood samples (interleukin-6, interleukin-10, C-reactive protein, interferon-gamma, and vascular endothelial growth factor and additional exploratory analysis of other cytokines)
measure: Number of patients with treatment related adverse events
time frame: 30 days following surgery
description: According to the Clavien-Dindo classification system (7 grades of events depicting the severity of the event)
measure: Depression, Anxiety, Global distress
time frame: At baseline and at 30 days post-surgery
description: Assessed by changes on the brief symptom inventory 18 questionnaire (this questionnaire assess all three scales for depression, anxiety and global distress)
measure: Fatigue
time frame: At baseline and at 30 days post-surgery
description: 4 items related to fatigue in the 36 item short-form survey questionnaire.
arm group label: Propranolol and etodolac
arm group type: Active Comparator
description: Both study medications will be given orally for an intervention phase of 35 days as follows. Etodolac:400mg PO bid for the entire intervention period,Propranolol:20 mg PO bid for 5 preoperative days, 80 mg PO bid on the day of surgery and the following morning, 40 mg PO bid for following 6.5 days, and 20 mg PO bid for next 22 days.
arm group label: Placebo
arm group type: Placebo Comparator
description: Same schedule as in the active comparator arm
intervention type: Drug
intervention name: Propranolol and etodolac
description: A perioperative combined drug regimen
arm group label: Propranolol and etodolac
other name: Deralin and etopan
intervention type: Other
intervention name: Placebo
description: Placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 20 Years
maximum age: 80 Years
healthy volunteers: No
last name: Oded Zmora, MD
role: Principal Investigator
affiliation: Asaf Harofeh Medical Center
last name: Oded Zmora, MD
phone: +97289779202
email: ozmora@post.tau.ac.il
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
country: Israel
citation: Haldar R, Shaashua L, Lavon H, Lyons YA, Zmora O, Sharon E, Birnbaum Y, Allweis T, Sood AK, Barshack I, Cole S, Ben-Eliyahu S. Perioperative inhibition of beta-adrenergic and COX2 signaling in a clinical trial in breast cancer patients improves tumor Ki-67 expression, serum cytokine levels, and PBMCs transcriptome. Brain Behav Immun. 2018 Oct;73:294-309. doi: 10.1016/j.bbi.2018.05.014. Epub 2018 May 22.
PMID: 29800703
citation: Shaashua L, Shabat-Simon M, Haldar R, Matzner P, Zmora O, Shabtai M, Sharon E, Allweis T, Barshack I, Hayman L, Arevalo J, Ma J, Horowitz M, Cole S, Ben-Eliyahu S. Perioperative COX-2 and beta-Adrenergic Blockade Improves Metastatic Biomarkers in Breast Cancer Patients in a Phase-II Randomized Trial. Clin Cancer Res. 2017 Aug 15;23(16):4651-4661. doi: 10.1158/1078-0432.CCR-17-0152. Epub 2017 May 10.
PMID: 28490464
responsible party type: Sponsor
mesh term: Pancreatic Neoplasms
mesh term: Etodolac
mesh term: Propranolol