Colorectal NeoplasmsPhase 2COMPIT-2NCT03919461
Colorectal Metastasis Prevention International Trial 2
A Phase 2 study testing Propranolol and etodolac in people with Colorectal Neoplasms, run by Assaf-Harofeh Medical Center at 6 sites in Israel.
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. Read more about this study
- Who is it for?
- Ages 20 to 80 years
- Conditions the study is for
- Colorectal Neoplasms
- What is being tested?
- Propranolol and etodolac
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 200 participants
- Where
- 6 sitesIsrael
- Study dates
- 28 Feb 2019to 28 Feb 2027
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
- -
Who cannot join
- 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)
Show all 26Show fewer
- 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
Trial locations and contacts
6 sites in 1 country. Contact the study team or a site near you to ask about taking part.
6 sites in 1 country
Israel6 sites, 6 recruiting
- Not yet recruiting
HaEmek Medical Center
Afula, 1834111
Doron Kopelman, MD, kopelman_d@clalit.org.il
- Not yet recruiting
Rambam Health Care Campus
Haifa, 3109601
Simon D Duek, MD, d_duek@rambam.health.gov.il
- Not yet recruiting
Rabin Medical Center
Petah Tikva, 4941492
Nir Wasserberg, MD, nirw@clalit.org.il
- Not yet recruiting
Sourasky Medical Center
Tel Aviv, 6423906
Hagit Tulchinsky, MD, hagitt@tlvmc.gov.il
- Not yet recruiting
Sheba Medical Center
Tel HaShomer, 45858
Mordechai Gutman, MD, motti.gutman@sheba.health.gov.il
- Recruiting
Asaf Harofeh Medical Center
Tsrifin, 70300
Oded Zmora, MD, +97289779202, ozmora@post.tau.ac.il
About this study
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
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
- Conditions
- Colorectal Neoplasms
- Being tested
- Propranolol and etodolac, Placebo
- Keywords
- Beta-blocker, Propranolol, COX-2 inhibitor, Etodolac
- Medical subject headings
- Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Propranolol and etodolacDrug
Also called Deralin and etopan
A perioperative combined drug regimen
PlaceboOther
Placebo
| Study group | Role | What they receive |
|---|---|---|
| Propranolol and etodolac | Active comparator | 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. Receives: Drug: Propranolol and etodolac |
| Placebo | Placebo comparator | Same schedule as in the active comparator arm Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: From the date of surgery until malignant disease is identified, assessed up to 60 months post-surgery]
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
Measured: An average of one year following surgery
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)
Measured: An average of one year following surgery
Secondary outcomes (3)
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)
Measured: 30 days following surgery
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)
Measured: At baseline and at 30 days post-surgery
Fatigue
4 items related to fatigue in the 36 item short-form survey questionnaire.
Measured: At baseline and at 30 days post-surgery
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Apr 2019
- Study start28 Feb 2019
- Primary completion28 Feb 2027 (estimated)
- Study completion28 Feb 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Colorectal NeoplasmsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 200 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assaf-Harofeh Medical Center
- Sponsor type
- Other government
- Collaborators
- Sheba Medical Center, Rabin Medical Center, Tel-Aviv Sourasky Medical Center, Rambam Health Care Campus, HaEmek Medical Center, Israel
- Responsible party
- Sponsor
- Investigators
- Oded Zmora, MD, Principal investigator, Asaf Harofeh Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03919461
- Sponsor's protocol ID
- 0196-17-ASF
- Acronym
- COMPIT-2
- Status last verified
- Apr 2019
- First submitted
- 28 Feb 2019
- Last updated
- 18 Apr 2019
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
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.
PubMed 29800703Shaashua 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.
PubMed 28490464Sakis N, Sorski L, Asraf E, Ricon-Becker I, Shaashua L, Haldar R, Shvalbo BB, Shabat-Simon M, Gutman M, Nissan A, Nachmany I, Kent I, Pery R, Pencovich N, Shussman N, Wasserberg N, Reshef A, Quint E, Lishtzinsky YY, Kashtan H, Shabtai M, Brenner B, Sharon E, Allweis T, Shahar N, Eckerling A, Sandbank E, Zmora O, Ben-Eliyahu S. Favorable safety outcomes of a perioperative propranolol and etodolac regimen in cancer patients in four randomized controlled trials. Front Pharmacol. 2026 Apr 20;17:1823113. doi: 10.3389/fphar.2026.1823113. eCollection 2026.
PubMed 42088573
Study at a glance
From the registry record, last updated by the sponsor on 18 Apr 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03919461
- Acronym / sponsor ID
- COMPIT-2 / 0196-17-ASF
- Conditions
- Colorectal Neoplasms
- Keywords
- Beta-blocker, Propranolol, COX-2 inhibitor, Etodolac
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 200 participants (estimated)
- Lead sponsor
- Assaf-Harofeh Medical CenterOther government
- Collaborators
- Sheba Medical Center, Rabin Medical Center, Tel-Aviv Sourasky Medical Center, Rambam Health Care Campus, HaEmek Medical Center, Israel
- Study start
- 28 Feb 2019 (actual)
- Primary completion
- 28 Feb 2027 (estimated)
- Study completion
- 28 Feb 2027 (estimated)
- First posted
- 18 Apr 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Propranolol and etodolac | Active comparator | Drug: Propranolol and etodolacBoth 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. |
| Placebo | Placebo comparator | Other: PlaceboSame schedule as in the active comparator arm |
Who may qualify
- Ages
- 20 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- 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
- -
Key exclusion criteria (26 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Propranolol and etodolacAlso: Deralin and etopanA perioperative combined drug regimen | Drug | Propranolol and etodolac |
| PlaceboPlacebo | Other | Placebo |
Primary outcome
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.
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
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)
3 secondary outcomes
Number of patients with treatment related adverse events
Time frame: 30 days following surgery
Depression, Anxiety, Global distress
Time frame: At baseline and at 30 days post-surgery
Fatigue
Time frame: At baseline and at 30 days post-surgery
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Apr 2019.
- Background: PubMed 29800703Haldar 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.
- Background: PubMed 28490464Shaashua 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.
- Derived from this study: PubMed 42088573Sakis N, Sorski L, Asraf E, Ricon-Becker I, Shaashua L, Haldar R, Shvalbo BB, Shabat-Simon M, Gutman M, Nissan A, Nachmany I, Kent I, Pery R, Pencovich N, Shussman N, Wasserberg N, Reshef A, Quint E, Lishtzinsky YY, Kashtan H, Shabtai M, Brenner B, Sharon E, Allweis T, Shahar N, Eckerling A, Sandbank E, Zmora O, Ben-Eliyahu S. Favorable safety outcomes of a perioperative propranolol and etodolac regimen in cancer patients in four randomized controlled trials. Front Pharmacol. 2026 Apr 20;17:1823113. doi: 10.3389/fphar.2026.1823113. eCollection 2026.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Oded Zmora, MD principal investigator
Asaf Harofeh Medical Center
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Propranolol and etodolac in people with Colorectal Neoplasms, run by Assaf-Harofeh Medical Center at 6 sites in Israel.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 18 Apr 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in Israel. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Oded Zmora, MD (+97289779202, ozmora@post.tau.ac.il), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
5-year disease-free-survival (time frame: From the date of surgery until malignant disease is identified, assessed up to 60 months post-surgery]). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03919461, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Apr 2019.