Colorectal Metastasis Prevention International Trial 2

NCT03919461 | Recruiting Phase 2

• 1 other identifier: 0196-17-ASF
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 6

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

Conditions

Colorectal Neoplasms

Keywords

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

Outcome Measures

Primary Outcomes (3)

• 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]

• 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

• 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 Outcomes (3)

• Number of patients with treatment related adverse events

  30 days following surgery

• Depression, Anxiety, Global distress

  At baseline and at 30 days post-surgery

• Fatigue

  At baseline and at 30 days post-surgery

Study Arms (2)

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.

Drug: Propranolol and etodolac

Placebo

PLACEBO COMPARATOR

Same schedule as in the active comparator arm

Other: Placebo

Interventions

Propranolol and etodolac DRUG

A perioperative combined drug regimen

Also known as: Deralin and etopan

Propranolol and etodolac

Placebo OTHER

Placebo

Placebo

Eligibility Criteria

• Age: 20 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Assaf-Harofeh Medical Center: lead
• Sheba Medical Center: collaborator
• Rabin Medical Center: collaborator
• Tel-Aviv Sourasky Medical Center: collaborator
• Rambam Health Care Campus: collaborator
• HaEmek Medical Center, Israel: collaborator

Study Sites (6)

HaEmek Medical Center

Afula, 1834111, Israel

NOT YET RECRUITING

Rambam Health Care Campus

Haifa, 3109601, Israel

NOT YET RECRUITING

Rabin Medical Center

Petah Tikva, 4941492, Israel

NOT YET RECRUITING

Sourasky Medical Center

Tel Aviv, 6423906, Israel

NOT YET RECRUITING

Sheba Medical Center

Tel Litwinsky, 45858, Israel

NOT YET RECRUITING

Asaf Harofeh Medical Center

Ẕerifin, 70300, Israel

RECRUITING

Related 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 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.

  PMID: 29800703 BACKGROUND

• 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.

  PMID: 28490464 BACKGROUND

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Propranolol; Etodolac

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Indoleacetic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Oded Zmora, MD

  Asaf Harofeh Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Oded Zmora, MD

CONTACT

+97289779202; ozmora@post.tau.ac.il

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 28, 2019
• First Posted: April 18, 2019
• Study Start: February 28, 2019
• Primary Completion (Estimated): February 28, 2027
• Study Completion (Estimated): February 28, 2027
• Last Updated: April 18, 2019

Record last verified: 2019-04

Locations

IL (6)