Perioperative Intervention to Reduce Metastatic Processes in Pancreatic Cancer Patients Undergoing Curative Surgery

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Pancreatic Neoplasms

Intervention / Treatment
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* Drug: Propranolol and etodolac
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Propranolol and etodolac<br>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<br>* A perioperative combined drug regimen<br>* Other names: Deralin and etopan;|
| Placebo Comparator: Placebo<br>Same schedule as in the active comparator arm | Other: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of cancer recurrence | Data regrading post-surgical recurrence will be recorded at 1,3,6,12,18,24,36,48, and 60 following surgery | From the date of surgery until malignant disease is identified, assessed up to 60 months post-surgery | 
| Biomarkers in extracted tumor tissue samples | 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. | An average of one year following surgery | 
| Biomarkers in blood samples | 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) | An average of one year following surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with treatment related adverse events | According to the Clavien-Dindo classification system (7 grades of events depicting the severity of the event) | 30 days following surgery | 
| Depression, Anxiety, Global distress | Assessed by changes on the brief symptom inventory 18 questionnaire (this questionnaire assess all three scales for depression, anxiety and global distress) | At baseline and at 30 days post-surgery | 
| Fatigue | 4 items related to fatigue in the 36 item short-form survey questionnaire. | At baseline and at 30 days post-surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Beta-blocker, Propranolol, COX-2 inhibitor, Etodolac