Pancreatic Neoplasms Clinical Trial
— BC-PCOfficial 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
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.
Status | Recruiting |
Enrollment | 210 |
Est. completion date | January 2026 |
Est. primary completion date | January 2026 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 20 Years to 80 Years |
Eligibility |
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 |
Country | Name | City | State |
---|---|---|---|
Israel | Sheba Medical Center | Tel Hashomer | |
Israel | Sourasky Medical Center | Tel-Aviv | |
Israel | Asaf Harofeh Medical Center | Tsrifin |
Lead Sponsor | Collaborator |
---|---|
Assaf-Harofeh Medical Center | Sheba Medical Center |
Israel,
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 ß-adrenergic and COX2 signaling in a clinical trial in breast cancer patients improves tumor Ki-67 e — View 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 ß-Adrenergic Blockade Improves Metastatic Biomarkers in Breast Canc — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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 | |
Primary | 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 | |
Primary | 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 | 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) | 30 days following surgery | |
Secondary | 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) | At baseline and at 30 days post-surgery | |
Secondary | Fatigue | 4 items related to fatigue in the 36 item short-form survey questionnaire. | At baseline and at 30 days post-surgery |
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