Perioperative Intervention to Reduce Metastatic Processes in Pancreatic Cancer Patients Undergoing Curative Surgery

NCT03838029 | Unknown Phase 2

• 2 other identifiers: 0308-17-ASFMOH_2018-03-12_002226
• Study Type: interventional
• Target: 210
• Locations: 1 country
• Sites: 3

Brief Summary

In Israel, of the \~1000 patients diagnosed annually with pancreatic cancer (PC), approximately 250 (25 percent) will be eligible for curative surgery, of which 80 percent will succumb to post-surgical metastatic disease. A reduction in post-surgical metastatic disease will save dozens of patients in Israel annually, and tens-of thousands-around the world. 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, our animal studies 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. We recently conducted two clinical trials 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, we propose to conduct a double-blind placebo-controlled two-arm Phase II clinical trial in 210 pancreatic cancer patients undergoing curative surgery in Israel. A perioperative 35-day drug treatment will be initiated 5 days before surgery. Primary outcomes will include (i) 1-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

Pancreatic Neoplasms

Keywords

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

Outcome Measures

Primary Outcomes (3)

• Rate of cancer recurrence

  Data regrading post-surgical recurrence will be recorded at 1,3,6,12,18,24,36,48, and 60 following surgery

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

• Biomarkers in extracted tumor tissue samples

  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

  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 35 days as follows. Etodolac:400mg PO bid for the entire intervention period,Propranolol:20 mg PO bid for 5 preoperative days, 80 mg PO bid on the day of surgery and the following morning, 40 mg PO bid for following 6.5 days, and 20 mg PO bid for next 22 days.

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:

• Newly diagnosed Stage I or II adenocarcinoma of the head, neck, or uncinated- process of the pancreas.
• Surgically resectable disease (R0 or R1) by spiral CT chest and abdomen scan, No distant metastases
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1
• Signed informed consent form
• Willing and able to comply with study procedures
• Men and women from age 20 up to age 80

You may not qualify if:

• Patients with metastatic disease, known prior to surgery
• Patients with history or concomitant malignant disease of any type (except for the current pancreatic cancer
• Patients who were treated with chemotherapy in the last 10 years for any reason
• Patients in whom surgical resection is planned without curative intent
• Patients exhibiting levels Carbohydrate antigen (CA) 19-9 above 500
• 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)
• Patients suffering from active asthma
• Patients with known allergy to any medication from the non-steroidal anti- inflammatory or beta-blockers drug group
• Patients treated chronically with any type of a beta-adrenergic blocker or a cyclooxygenase (COX) inhibitor
• Patients with bradycardia or second or third degree atrioventricular block (AV) block
• Patients with a history of cerebrovascular accident (CVA) or established diagnosed transient ischemic attack (TIA)
• Patients with prinzmetal's angina
• Patients with right sided heart failure owing to pulmonary hypertension

Sponsors & Collaborators

• Assaf-Harofeh Medical Center: lead
• Sheba Medical Center: collaborator

Study Sites (3)

Sourasky Medical Center

Tel Aviv, 6423906, Israel

NOT YET RECRUITING

Sheba Medical Center

Tel Litwinsky, 45858, Israel

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 RESULT

• 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 RESULT

MeSH Terms

Conditions

Pancreatic Neoplasms

Interventions

Propranolol; Etodolac

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System 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: January 23, 2019
• First Posted: February 12, 2019
• Study Start: November 20, 2019
• Primary Completion: January 1, 2026
• Study Completion: January 1, 2026
• Last Updated: November 20, 2019

Record last verified: 2019-11

Locations

IL (3)