A Phase 2 interventional study of Propranolol and etodolac and Placebo in Pancreatic Neoplasms, sponsored by Assaf-Harofeh Medical Center. Recruiting at 3 sites in Israel. Open to participants aged 20 Years to 80 Years. Per ClinicalTrials.gov, last updated 2019-11-20.
Sponsored by Assaf-Harofeh Medical Center · Phase 2, Interventional, and Prevention
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.
3,235 studies on the registry are indexed under Pancreatic Neoplasms; 899 are open to participants now.
This study's planned enrollment of 210 is above the median of 46 across 2,424 interventional studies indexed under Pancreatic Neoplasms.
Browse Pancreatic Neoplasms studies →Assaf-Harofeh Medical Center is the lead sponsor of 258 studies on the registry; 40 are open to participants now.
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Exclusion Criteria:
Patients with borderline resectable tumors, as defined by one of the following:
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
Same schedule as in the active comparator arm
Other: Placebo
A perioperative combined drug regimen
Also known as: Deralin and etopan
Placebo
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
Time frame: 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.
Time frame: 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)
Time frame: An average of one year following surgery
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)
Time frame: 30 days following surgery
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)
Time frame: At baseline and at 30 days post-surgery
Fatigue
4 items related to fatigue in the 36 item short-form survey questionnaire.
Time frame: At baseline and at 30 days post-surgery
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Assaf-Harofeh Medical Center