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NCT Number: NCT03919461

Colorectal Metastasis Prevention International Trial 2

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

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Key information

Conditions

Colorectal Neoplasms Colonic Diseases Digestive System Diseases Digestive System Neoplasms Gastrointestinal Diseases Gastrointestinal Neoplasms Intestinal Diseases Intestinal Neoplasms Neoplasms Neoplasms by Site Rectal Diseases

Age range

20 year–80 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

HaEmek Medical Center, Afula, Israel

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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

  • 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

Treatment and study plan

Propranolol and etodolac

Drug

A perioperative combined drug regimen

Other names: Deralin and etopan

Placebo

Other

Placebo

Primary outcomes

  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 outcomes

  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.

Study contacts

Contact information is provided by the study sponsor or research team.

Oded Zmora, MD

CONTACT

[email protected]

+97289779202

Sponsors and collaborators

Lead sponsor

Assaf-Harofeh Medical Center

Other Gov

Collaborators

  • HaEmek Medical Center, Israel
  • Rabin Medical Center
  • Rambam Health Care Campus
  • Sheba Medical Center
  • Tel-Aviv Sourasky Medical Center

Registry information

Official study 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

Acronym: COMPIT-2

Important dates

Study start
2019
Primary completion
2027
Study completion
2027
First posted
Apr 18, 2019
Registry last updated
Apr 18, 2019

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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