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Perioperative Intervention to Reduce Metastatic Processes in Pancreatic Cancer Patients Undergoing Curative Surgery (BC-PC)

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ClinicalTrials.gov Identifier: NCT03838029
Recruitment Status : Recruiting
First Posted : February 12, 2019
Last Update Posted : November 20, 2019
Sponsor:
Collaborator:
Sheba Medical Center
Information provided by (Responsible Party):
Assaf-Harofeh Medical Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Pancreatic Neoplasms Drug: Propranolol and etodolac Other: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 210 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
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
Estimated Study Start Date : November 20, 2019
Estimated Primary Completion Date : January 2026
Estimated Study Completion Date : January 2026


Arm Intervention/treatment
Active Comparator: Propranolol and etodolac
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.
Drug: Propranolol and etodolac
A perioperative combined drug regimen
Other Name: Deralin and etopan

Placebo Comparator: Placebo
Same schedule as in the active comparator arm
Other: Placebo
Placebo




Primary Outcome Measures :
  1. Rate of cancer recurrence [ Time Frame: From the date of surgery until malignant disease is identified, assessed up to 60 months post-surgery ]
    Data regrading post-surgical recurrence will be recorded at 1,3,6,12,18,24,36,48, and 60 following surgery

  2. Biomarkers in extracted tumor tissue samples [ Time Frame: An average of one year following surgery ]
    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.

  3. Biomarkers in blood samples [ Time Frame: An average of one year following surgery ]
    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)


Secondary Outcome Measures :
  1. Number of patients with treatment related adverse events [ Time Frame: 30 days following surgery ]
    According to the Clavien-Dindo classification system (7 grades of events depicting the severity of the event)

  2. Depression, Anxiety, Global distress [ Time Frame: At baseline and at 30 days post-surgery ]
    Assessed by changes on the brief symptom inventory 18 questionnaire (this questionnaire assess all three scales for depression, anxiety and global distress)

  3. Fatigue [ Time Frame: At baseline and at 30 days post-surgery ]
    4 items related to fatigue in the 36 item short-form survey questionnaire.



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Ages Eligible for Study:   20 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Newly diagnosed Stage I or II adenocarcinoma of the head, neck, or uncinated- process of the pancreas.
  • Surgically resectable disease (R0 or R1) by spiral CT chest and abdomen scan, No distant metastases
  • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1
  • Signed informed consent form
  • Willing and able to comply with study procedures
  • Men and women from age 20 up to age 80

Exclusion Criteria:

  • Patients with metastatic disease, known prior to surgery
  • Patients with history or concomitant malignant disease of any type (except for the current pancreatic cancer
  • Patients who were treated with chemotherapy in the last 10 years for any reason
  • Patients in whom surgical resection is planned without curative intent
  • Patients exhibiting levels Carbohydrate antigen (CA) 19-9 above 500
  • Patients with renal failure, measured by creatinine level >1.5
  • Patients with significant heart failure (NYHA functional class 3 or higher),
  • Patients with significant liver failure (known cirrhosis)
  • Patients suffering from active asthma
  • Patients with known allergy to any medication from the non-steroidal anti- inflammatory or beta-blockers drug group
  • Patients treated chronically with any type of a beta-adrenergic blocker or a cyclooxygenase (COX) inhibitor
  • Patients with bradycardia or second or third degree atrioventricular block (AV) block
  • Patients with a history of cerebrovascular accident (CVA) or established diagnosed transient ischemic attack (TIA)
  • Patients with prinzmetal's angina
  • Patients with right sided heart failure owing to pulmonary hypertension
  • Patients with significant diagnosed cardiomegaly
  • Patients with (current) pheochromocytoma
  • Patients with chronic Digoxin treatment
  • Patients with active peptic disease
  • Patients with peripheral vascular disease
  • Pregnant woman
  • Special population with impaired judgment
  • Patients currently actively participating in any other clinical trial
  • contraindication for Whipple procedure
  • Patients suffering from sick sinus syndrome
  • Patients with borderline resectable tumors, as defined by one of the following:

    • an infiltration >180° of the portal vein
    • abutment of the tumor to the superior mesenteric artery
    • infiltration of the superior mesenteric artery or the celiac trunk

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03838029


Contacts
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Contact: Oded Zmora, MD +97289779202 ozmora@post.tau.ac.il

Locations
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Israel
Sheba Medical Center Recruiting
Tel Hashomer, Israel, 45858
Contact: Talia Golan, MD       Talia.Golan@sheba.health.gov.il   
Sourasky Medical Center Not yet recruiting
Tel-Aviv, Israel, 6423906
Contact: Ido Nachmany, MD         
Contact       idon@tlvmc.gov.il   
Asaf Harofeh Medical Center Recruiting
Tsrifin, Israel, 70300
Contact: Oded Zmora, MD    +97289779202    ozmora@post.tau.ac.il   
Sponsors and Collaborators
Assaf-Harofeh Medical Center
Sheba Medical Center
Investigators
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Principal Investigator: Oded Zmora, MD Asaf Harofeh Medical Center
Publications of Results:
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Responsible Party: Assaf-Harofeh Medical Center
ClinicalTrials.gov Identifier: NCT03838029    
Other Study ID Numbers: 0308-17-ASF
MOH_2018-03-12_002226 ( Registry Identifier: The Israeli Ministry of Health )
First Posted: February 12, 2019    Key Record Dates
Last Update Posted: November 20, 2019
Last Verified: November 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Assaf-Harofeh Medical Center:
Beta-blocker
Propranolol
COX-2 inhibitor
Etodolac
Additional relevant MeSH terms:
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Pancreatic Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Etodolac
Propranolol
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Antihypertensive Agents
Vasodilator Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors