BC-PC: Perioperative Intervention to Reduce Metastatic Processes in Pancreatic Cancer Patients Undergoing Curative Surgery

Sponsor

Assaf-Harofeh Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT03838029

Collaborator

Sheba Medical Center (Other)

210

Enrollment

Locations

Arms

73.4

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Neoplasms	Drug: Propranolol and etodolac Other: Placebo	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

210 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

Perioperative Use of a Beta-adrenergic Blocker and a COX-2 Inhibitor in Patients Undergoing Surgery With Primary Pancreatic Cancer: Intervention Aiming to Reduce Pro-metastatic Processes

Anticipated Study Start Date :

Nov 20, 2019

Anticipated Primary Completion Date :

Jan 1, 2026

Anticipated Study Completion Date :

Jan 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Propranolol and etodolac 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 A perioperative combined drug regimen Other Names: Deralin and etopan
Placebo Comparator: Placebo Same schedule as in the active comparator arm	Other: Placebo Placebo

Arm

Intervention/Treatment

Active Comparator: Propranolol and etodolac

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

A perioperative combined drug regimen

Other Names:

Deralin and etopan

Placebo Comparator: Placebo

Same schedule as in the active comparator arm

Other: Placebo

Placebo

Outcome Measures

Primary Outcome Measures

Rate of cancer recurrence [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
Biomarkers in extracted tumor tissue samples [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 [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)

Secondary Outcome Measures

Number of patients with treatment related adverse events [30 days following surgery]
According to the Clavien-Dindo classification system (7 grades of events depicting the severity of the event)
Depression, Anxiety, Global distress [At baseline and at 30 days post-surgery]
Assessed by changes on the brief symptom inventory 18 questionnaire (this questionnaire assess all three scales for depression, anxiety and global distress)
Fatigue [At baseline and at 30 days post-surgery]
4 items related to fatigue in the 36 item short-form survey questionnaire.

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

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
Patients with significant diagnosed cardiomegaly
Patients with (current) pheochromocytoma
Patients with chronic Digoxin treatment
Patients with active peptic disease
Patients with peripheral vascular disease
Pregnant woman
Special population with impaired judgment
Patients currently actively participating in any other clinical trial
contraindication for Whipple procedure
Patients suffering from sick sinus syndrome
Patients with borderline resectable tumors, as defined by one of the following:
an infiltration >180° of the portal vein
abutment of the tumor to the superior mesenteric artery
infiltration of the superior mesenteric artery or the celiac trunk