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Colorectal Metastasis Prevention International Trial 2 (COMPIT-2)

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ClinicalTrials.gov Identifier: NCT03919461
Recruitment Status : Recruiting
First Posted : April 18, 2019
Last Update Posted : April 18, 2019
Sponsor:
Collaborators:
Sheba Medical Center
Rabin Medical Center
Tel-Aviv Sourasky Medical Center
Rambam Health Care Campus
HaEmek Medical Center, Israel
Information provided by (Responsible Party):
Assaf-Harofeh Medical Center

Brief Summary:
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

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: 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
Actual Study Start Date : February 28, 2019
Estimated Primary Completion Date : February 28, 2027
Estimated Study Completion Date : February 28, 2027

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Propranolol and etodolac
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
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. 5-year disease-free-survival [ 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. Primary outcome 1 will be rate of recurrence/disease at 60 months.

  2. Biomarkers in extracted tumor tissue samples assessing pro- and anti-metastatic processes [ 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 assessing pro- and anti-metastatic processes [ 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.



Information from the National Library of Medicine

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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:

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

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Exclusion Criteria:

  1. Patients with metastatic disease, known prior to surgery
  2. Patients in whom surgical resection is planned without curative intent
  3. Patients with renal failure, measured by creatinine level >1.5
  4. Patients with significant heart failure (NYHA functional class 3 or higher)
  5. Patients with significant liver failure (known cirrhosis, Bilirubin level>2)
  6. Patients currently suffering from asthma or Chronic Obstructive Pulmonary Disease (COPD)
  7. Patients treated pharmacologically for diabetes mellitus (type 1/2),
  8. Patients with peripheral vascular disease
  9. Patients with known allergy to one or more of the study medications.
  10. Patients with known allergy to any medication from the non-steroidal anti- inflammatory drug group or beta-blockers family
  11. Patients treated chronically with any type of a beta-adrenergic blocker or a COX inhibitor
  12. Patients with bradycardia or second or third degree AV block
  13. Patients with a history of CVA/TIA
  14. Patients with Printzmetal's angina
  15. Patients with right sided heart failure owing to pulmonary hypertension
  16. Patients with significant diagnosed cardiomegaly
  17. Patients with (current) pheochromocytoma
  18. Patients with chronic Digoxin treatment
  19. Patients with active peptic disease
  20. Pregnant women
  21. Patients who participate in another interventional study
  22. Patients with history or concomitant malignant disease of any type (except for the current colon/rectal cancer)
  23. 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.
  24. Patients who are treated with immunosuppressive medications
  25. Patients with Immunodeficiency Disorders, or autoimmune disease treated by immunosuppressive medications.
  26. Patients suffering from sick sinus syndrome

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): NCT03919461


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

Locations
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Israel
HaEmek Medical Center Not yet recruiting
Afula, Israel, 1834111
Contact: Doron Kopelman, MD       kopelman_d@clalit.org.il   
Rambam Health Care Campus Not yet recruiting
Haifa, Israel, 3109601
Contact: Simon D Duek, MD       d_duek@rambam.health.gov.il   
Rabin Medical Center Not yet recruiting
Petah-Tikva, Israel, 4941492
Contact: Nir Wasserberg, MD       nirw@clalit.org.il   
Sourasky Medical Center Not yet recruiting
Tel Aviv, Israel, 6423906
Contact: Hagit Tulchinsky, MD       hagitt@tlvmc.gov.il   
Sheba Medical Center Not yet recruiting
Tel HaShomer, Israel, 45858
Contact: Mordechai Gutman, MD       motti.gutman@sheba.health.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
Rabin Medical Center
Tel-Aviv Sourasky Medical Center
Rambam Health Care Campus
HaEmek Medical Center, Israel
Investigators
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Principal Investigator: Oded Zmora, MD Asaf Harofeh Medical Center

Publications:
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Responsible Party: Assaf-Harofeh Medical Center
ClinicalTrials.gov Identifier: NCT03919461     History of Changes
Other Study ID Numbers: 0196-17-ASF
First Posted: April 18, 2019    Key Record Dates
Last Update Posted: April 18, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Assaf-Harofeh Medical Center:
Beta-blocker
Propranolol
COX-2 inhibitor
Etodolac

Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Propranolol
Cyclooxygenase 2 Inhibitors
Etodolac
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
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents