Clinical trial NCT03838029: Perioperative Intervention to Reduce Metastatic Processes in Pancreatic Cancer Patients Undergoing Curative Surgery
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Pancreatic Neoplasms
Keywords: Beta-blocker
Propranolol
COX-2 inhibitor
Etodolac
Lead sponsor: Assaf-Harofeh Medical Center
Sponsor class: OTHER_GOV
Collaborators: name: Sheba Medical Center
First posted: 2019-02-12
Enrollment: 210
Sex: ALL
Minimum age (years): 20
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.


Eligibility criteria: 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

Primary outcomes:
measure: Rate of cancer recurrence
timeFrame: From the date of surgery until malignant disease is identified, assessed up to 60 months post-surgery
measure: Biomarkers in extracted tumor tissue samples
timeFrame: An average of one year following surgery
measure: Biomarkers in blood samples
timeFrame: An average of one year following surgery
Secondary outcomes:
measure: Number of patients with treatment related adverse events
timeFrame: 30 days following surgery
measure: Depression, Anxiety, Global distress
timeFrame: At baseline and at 30 days post-surgery
measure: Fatigue
timeFrame: At baseline and at 30 days post-surgery
Other outcomes:
Locations:
city: Tel Hashomer
country: Israel
facility: Sheba Medical Center
city: Tel-Aviv
country: Israel
facility: Sourasky Medical Center
city: Tsrifin
country: Israel
facility: Asaf Harofeh Medical Center
Study officials:
affiliation: Asaf Harofeh Medical Center
name: Oded Zmora, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.