Colorectal Metastasis Prevention International Trial 2

Colorectal Neoplasms Clinical Trial

— COMPIT-2  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03919461
• Other study ID #: 0196-17-ASF
• Status: Recruiting
• Phase: Phase 2
• Start date: February 28, 2019
• Est. completion date: February 28, 2027

Study information

• Verified date: April 2019
• Source: Assaf-Harofeh Medical Center
• Contact: Oded Zmora, MD
• Phone: +97289779202
• Email: ozmora[@]post.tau.ac.il
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: February 28, 2027
• Est. primary completion date: February 28, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Colorectal Neoplasms

Intervention

Drug:
• Propranolol and etodolac
A perioperative combined drug regimen

Other:
• Placebo
Placebo

Locations

Country	Name	City	State
Israel	HaEmek Medical Center	Afula
Israel	Rambam Health Care Campus	Haifa
Israel	Rabin Medical Center	Petah-Tikva
Israel	Sourasky Medical Center	Tel Aviv
Israel	Sheba Medical Center	Tel HaShomer
Israel	Asaf Harofeh Medical Center	Tsrifin

Sponsors (6)

Lead Sponsor	Collaborator
Assaf-Harofeh Medical Center	HaEmek Medical Center, Israel, Rabin Medical Center, Rambam Health Care Campus, Sheba Medical Center, Tel-Aviv Sourasky Medical Center

Country where clinical trial is conducted

Israel, 

References & Publications (2)

Haldar R, Shaashua L, Lavon H, Lyons YA, Zmora O, Sharon E, Birnbaum Y, Allweis T, Sood AK, Barshack I, Cole S, Ben-Eliyahu S. Perioperative inhibition of ß-adrenergic and COX2 signaling in a clinical trial in breast cancer patients improves tumor Ki-67 expression, serum cytokine levels, and PBMCs transcriptome. Brain Behav Immun. 2018 Oct;73:294-309. doi: 10.1016/j.bbi.2018.05.014. Epub 2018 May 22. — View Citation

Shaashua L, Shabat-Simon M, Haldar R, Matzner P, Zmora O, Shabtai M, Sharon E, Allweis T, Barshack I, Hayman L, Arevalo J, Ma J, Horowitz M, Cole S, Ben-Eliyahu S. Perioperative COX-2 and ß-Adrenergic Blockade Improves Metastatic Biomarkers in Breast Cancer Patients in a Phase-II Randomized Trial. Clin Cancer Res. 2017 Aug 15;23(16):4651-4661. doi: 10.1158/1078-0432.CCR-17-0152. Epub 2017 May 10. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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]
Primary	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
Primary	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	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
Secondary	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
Secondary	Fatigue	4 items related to fatigue in the 36 item short-form survey questionnaire.	At baseline and at 30 days post-surgery