Colorectal Metastasis Prevention International Trial 2 (COMPIT-2)

Shamir Medical Center (Assaf-Harofeh)

Status and phase: Enrolling; Phase 2

Conditions: Colorectal Neoplasms

Treatments: Other: Placebo; Drug: Propranolol and etodolac

Study type: Interventional

Funder types: Other

Identifiers

NCT03919461

0196-17-ASF

Details and patient eligibility

About

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

Enrollment: 200 estimated patients

Sex: All

Ages: 20 to 80 years old

Volunteers: No Healthy Volunteers

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

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

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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200 participants in 2 patient groups, including a placebo group

Propranolol and etodolac

Active Comparator group

Description:

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.

Treatment:

Drug: Propranolol and etodolac

Placebo

Placebo Comparator group

Description:

Same schedule as in the active comparator arm

Treatment:

Other: Placebo