Colorectal Metastasis Prevention International Trial 2

Study Overview
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Brief Summary
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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, animal studies conducted by the investigators 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. Two recently conducted clinical trials, conducted by the investigators, 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, the investigators propose to conduct a double-blind placebo-controlled two-arm Phase II clinical trial in 200 colorectal cancer patients undergoing curative surgery in Israel. A perioperative 20-day drug treatment will be initiated 5 days before surgery. Primary outcomes will include (i) 3-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 β-adrenergic Blocker, Propranolol, and a COX2 Inhibitor, Etodolac, in Patients Undergoing Resection With Curative Intent for Primary Colon and Rectal Cancer: Effect on Tumor Recurrence and Survival

Conditions
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Colorectal 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: 1. Patients planned for surgery for primary resection of colon or rectal cancer with curative intent. 2. Single colonic or rectal carcinoma, proven by full colonoscopy and tumor biopsy. 3. No evidence of metastatic disease prior to surgery. Minimal workup would include abdominal CT with IV contrast (or CT+liver US) and chest XR. 4. ASA score of 1-3 or ECOG Performance Status of 0 to 1 5. Signed informed consent form 6. Willing and able to comply with study procedures (physically and mentally) 7. Men and women from age 20 to age 80 - Exclusion Criteria: Patients with metastatic disease, known prior to surgery Patients in whom surgical resection is planned without curative intent 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, Bilirubin level>2) Patients currently suffering from asthma or Chronic Obstructive Pulmonary Disease (COPD) Patients treated pharmacologically for diabetes mellitus (type 1/2), Patients with peripheral vascular disease Patients with known allergy to one or more of the study medications. Patients with known allergy to any medication from the non-steroidal anti- inflammatory drug group or beta-blockers family Patients treated chronically with any type of a beta-adrenergic blocker or a COX inhibitor Patients with bradycardia or second or third degree AV block Patients with a history of CVA/TIA Patients with Printzmetal'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 Pregnant women Patients who participate in another interventional study Patients with history or concomitant malignant disease of any type (except for the current colon/rectal cancer) Patients who were treated with chemotherapy in the last 10 years for any reason besides neo-adjuvant therapy for rectal cancer within the last six months. Patients who are treated with immunosuppressive medications Patients with Immunodeficiency Disorders, or autoimmune disease treated by immunosuppressive medications. Patients suffering from sick sinus syndrome

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 20 days as follows. Etodolac:400mg PO bid for the entire intervention period, Propranolol (slow release): 20 mg PO b.i.d. for 5 preoperative days; 80 mg PO b.i.d. on the day of surgery; 40 mg PO b.i.d. for the first post-operative week and 20 mg PO b.i.d. for the second post-operative week. | 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 |
| --- | --- | --- |
| 5-year disease-free-survival | Data regrading post-surgical recurrence will be recorded at 1,3,6,12,18,24,36,48, and 60 following surgery. Primary outcome 1 will be rate of recurrence/disease at 60 months. | From the date of surgery until malignant disease is identified, assessed up to 60 months post-surgery] | 
| Biomarkers in extracted tumor tissue samples assessing pro- and anti-metastatic processes | 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 assessing pro- and anti-metastatic processes | 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