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Colorectal Metastasis Prevention International Trial 2 (COMPIT-2)

Primary Purpose

Colorectal Neoplasms

Status

Recruiting

Phase

Phase 2

Locations

Israel

Study Type

Interventional

Intervention

Propranolol and etodolac

Placebo

About this trial

This is an interventional prevention trial for Colorectal Neoplasms focused on measuring Beta-blocker, Propranolol, COX-2 inhibitor, Etodolac

Eligibility Criteria

20 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept 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:

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

Sites / Locations

HaEmek Medical Center
Rambam Health Care Campus
Rabin Medical Center
Sourasky Medical Center
Sheba Medical Center
Asaf Harofeh Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Propranolol and etodolac

Placebo

Arm 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.

Same schedule as in the active comparator arm

Outcomes

Primary Outcome Measures

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.

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

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)

Secondary Outcome Measures

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)

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)

Fatigue

4 items related to fatigue in the 36 item short-form survey questionnaire.

Full Information

NCT ID

NCT03919461

First Posted

February 28, 2019

Last Updated

April 15, 2019

Sponsor

Assaf-Harofeh Medical Center

Collaborators

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

1. Study Identification

Unique Protocol Identification Number

NCT03919461

Brief Title

Colorectal Metastasis Prevention International Trial 2

Acronym

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2019

Overall Recruitment Status

Recruiting

Study Start Date

February 28, 2019 (Actual)

Primary Completion Date

February 28, 2027 (Anticipated)

Study Completion Date

February 28, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Assaf-Harofeh Medical Center

Collaborators

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

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Colorectal Neoplasms

Keywords

Beta-blocker, Propranolol, COX-2 inhibitor, Etodolac

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

200 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Propranolol and etodolac

Arm Type

Active Comparator

Arm Description

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Same schedule as in the active comparator arm

Intervention Type

Drug

Intervention Name(s)

Propranolol and etodolac

Other Intervention Name(s)

Deralin and etopan

Intervention Description

A perioperative combined drug regimen

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

Placebo

Primary Outcome Measure Information:

Title

5-year disease-free-survival

Description

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.

Time Frame

From the date of surgery until malignant disease is identified, assessed up to 60 months post-surgery]

Title

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

Description

Time Frame

An average of one year following surgery

Title

Biomarkers in blood samples assessing pro- and anti-metastatic processes

Description

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)

Time Frame

An average of one year following surgery

Secondary Outcome Measure Information:

Title

Number of patients with treatment related adverse events

Description

According to the Clavien-Dindo classification system (7 grades of events depicting the severity of the event)

Time Frame

30 days following surgery

Title

Depression, Anxiety, Global distress

Description

Assessed by changes on the brief symptom inventory 18 questionnaire (this questionnaire assess all three scales for depression, anxiety and global distress)

Time Frame

At baseline and at 30 days post-surgery

Title

Fatigue

Description

4 items related to fatigue in the 36 item short-form survey questionnaire.

Time Frame

At baseline and at 30 days post-surgery

10. Eligibility

Sex

All

Minimum Age & Unit of Time

20 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility 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 - 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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Oded Zmora, MD

Phone

+97289779202

ozmora@post.tau.ac.il

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Oded Zmora, MD

Organizational Affiliation

Asaf Harofeh Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

HaEmek Medical Center

City

Afula

ZIP/Postal Code

1834111

Country

Israel

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Doron Kopelman, MD

kopelman_d@clalit.org.il

Facility Name

Rambam Health Care Campus

City

Haifa

ZIP/Postal Code

3109601

Country

Israel

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Simon D Duek, MD

d_duek@rambam.health.gov.il

Facility Name

Rabin Medical Center

City

Petah-Tikva

ZIP/Postal Code

4941492

Country

Israel

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Nir Wasserberg, MD

nirw@clalit.org.il

Facility Name

Sourasky Medical Center

City

Tel Aviv

ZIP/Postal Code

6423906

Country

Israel

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Hagit Tulchinsky, MD

hagitt@tlvmc.gov.il

Facility Name

Sheba Medical Center

City

Tel HaShomer

ZIP/Postal Code

45858

Country

Israel

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Mordechai Gutman, MD

motti.gutman@sheba.health.gov.il

Facility Name

Asaf Harofeh Medical Center

City

Tsrifin

ZIP/Postal Code

70300

Country

Israel

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Oded Zmora, MD

Phone

+97289779202

ozmora@post.tau.ac.il

12. IPD Sharing Statement

Citations:

PubMed Identifier

29800703

Citation

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 beta-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.

Results Reference

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PubMed Identifier

28490464

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 beta-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.

Results Reference

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Learn more about this trial

Colorectal Metastasis Prevention International Trial 2

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