- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03838029
Perioperative Intervention to Reduce Metastatic Processes in Pancreatic Cancer Patients Undergoing Curative Surgery (BC-PC)
November 19, 2019 updated by: Assaf-Harofeh Medical Center
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.
Study Overview
Status
Recruiting
Conditions
Intervention / Treatment
Study Type
Interventional
Enrollment (Anticipated)
210
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Contact
- Name: Oded Zmora, MD
- Phone Number: +97289779202
- Email: ozmora@post.tau.ac.il
Study Locations
-
-
-
Tel Hashomer, Israel, 45858
- Recruiting
- Sheba Medical Center
-
Contact:
- Talia Golan, MD
- Email: Talia.Golan@sheba.health.gov.il
-
Tel-Aviv, Israel, 6423906
- Not yet recruiting
- Sourasky Medical Center
-
Contact:
- Ido Nachmany, MD
-
Contact:
- Email: idon@tlvmc.gov.il
-
Tsrifin, Israel, 70300
- Recruiting
- Asaf Harofeh Medical Center
-
Contact:
- Oded Zmora, MD
- Phone Number: +97289779202
- Email: ozmora@post.tau.ac.il
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
20 years to 80 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
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
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: Placebo
Same schedule as in the active comparator arm
|
Placebo
|
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.
|
A perioperative combined drug regimen
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Rate of cancer recurrence
Time Frame: 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
|
From the date of surgery until malignant disease is identified, assessed up to 60 months post-surgery
|
Biomarkers in extracted tumor tissue samples
Time Frame: 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.
|
An average of one year following surgery
|
Biomarkers in blood samples
Time Frame: 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)
|
An average of one year following surgery
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of patients with treatment related adverse events
Time Frame: 30 days following surgery
|
According to the Clavien-Dindo classification system (7 grades of events depicting the severity of the event)
|
30 days following surgery
|
Depression, Anxiety, Global distress
Time Frame: 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)
|
At baseline and at 30 days post-surgery
|
Fatigue
Time Frame: At baseline and at 30 days post-surgery
|
4 items related to fatigue in the 36 item short-form survey questionnaire.
|
At baseline and at 30 days post-surgery
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Investigators
- Principal Investigator: Oded Zmora, MD, Asaf Harofeh Medical Center
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- 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.
- 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.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Anticipated)
November 20, 2019
Primary Completion (Anticipated)
January 1, 2026
Study Completion (Anticipated)
January 1, 2026
Study Registration Dates
First Submitted
January 23, 2019
First Submitted That Met QC Criteria
February 11, 2019
First Posted (Actual)
February 12, 2019
Study Record Updates
Last Update Posted (Actual)
November 20, 2019
Last Update Submitted That Met QC Criteria
November 19, 2019
Last Verified
November 1, 2019
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Digestive System Diseases
- Neoplasms
- Neoplasms by Site
- Endocrine System Diseases
- Digestive System Neoplasms
- Endocrine Gland Neoplasms
- Pancreatic Diseases
- Pancreatic Neoplasms
- Physiological Effects of Drugs
- Adrenergic beta-Antagonists
- Adrenergic Antagonists
- Adrenergic Agents
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Anti-Arrhythmia Agents
- Antihypertensive Agents
- Vasodilator Agents
- Peripheral Nervous System Agents
- Enzyme Inhibitors
- Analgesics
- Sensory System Agents
- Anti-Inflammatory Agents, Non-Steroidal
- Analgesics, Non-Narcotic
- Anti-Inflammatory Agents
- Antirheumatic Agents
- Cyclooxygenase Inhibitors
- Cyclooxygenase 2 Inhibitors
- Propranolol
- Etodolac
Other Study ID Numbers
- 0308-17-ASF
- MOH_2018-03-12_002226 (Registry Identifier: The Israeli Ministry of Health)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
No
Studies a U.S. FDA-regulated device product
No
product manufactured in and exported from the U.S.
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Pancreatic Neoplasms
-
Sidney Kimmel Cancer Center at Thomas Jefferson...CelgeneWithdrawnPancreatic Ductal Adenocarcinoma | Stage III Pancreatic Cancer | Stage IV Pancreatic Cancer | Stage IIA Pancreatic Cancer | Stage IIB Pancreatic Cancer | Stage IA Pancreatic Cancer | Stage IB Pancreatic CancerUnited States
-
Memorial Sloan Kettering Cancer CenterRecruitingPancreatic Cancer | Pancreatic Cancer Metastatic | Pancreatic Cancer Stage IV | Metastatic Pancreatic Carcinoma | Metastatic Pancreatic Adenocarcinoma | Pancreatic Carcinoma | Metastatic Pancreatic Cancer | Pancreatic Cancer Non-resectable | Metastatic Pancreatic Ductal Adenocarcinoma | Pancreatic Carcinoma... and other conditionsUnited States
-
Case Comprehensive Cancer CenterNational Cancer Institute (NCI)TerminatedPancreatic Adenocarcinoma | Resectable Pancreatic Cancer | Stage III Pancreatic Cancer | Stage IIA Pancreatic Cancer | Stage IIB Pancreatic Cancer | Stage IA Pancreatic Cancer | Stage IB Pancreatic Cancer | Poorly Differentiated Malignant Neoplasm | Undifferentiated Pancreatic CarcinomaUnited States
-
The First Affiliated Hospital with Nanjing Medical...RecruitingLocally Advanced Pancreatic Adenocarcinoma | Metastatic Pancreatic Cancer | Pancreatic NeoplasmChina
-
Case Comprehensive Cancer CenterNational Cancer Institute (NCI)WithdrawnStage IIA Pancreatic Cancer | Stage IIB Pancreatic Cancer | Stage IA Pancreatic Cancer | Stage IB Pancreatic Cancer
-
National Cancer Institute (NCI)CompletedStage IIA Pancreatic Cancer | Stage IIB Pancreatic Cancer | Stage IA Pancreatic Cancer | Stage IB Pancreatic CancerUnited States
-
University of UtahNovartis PharmaceuticalsRecruitingMetastatic Pancreatic Carcinoma | Unresectable Pancreatic Carcinoma | Stage III Pancreatic Cancer | Stage IV Pancreatic Cancer | Stage IIA Pancreatic Cancer | Stage IIB Pancreatic Cancer | Stage II Pancreatic CancerUnited States
-
University of OxfordNational Institute for Health Research, United Kingdom; ImunonWithdrawnPancreatic Cancer Metastatic | Pancreatic Ductal Adenocarcinoma | Pancreatic Cancer Stage IV | Pancreatic Cancer Non-resectableUnited Kingdom
-
Mayo ClinicNational Cancer Institute (NCI)CompletedAdvanced Pancreatic Carcinoma | Metastatic Pancreatic Carcinoma | Stage II Pancreatic Cancer AJCC v8 | Stage III Pancreatic Cancer AJCC v8 | Stage IV Pancreatic Cancer AJCC v8 | Unresectable Pancreatic Carcinoma | Pancreatic Neoplasm | Locally Advanced Pancreatic CarcinomaUnited States
-
Maria LiljeforsKarolinska University Hospital; Karolinska Institutet; CelgeneCompletedPancreatic Ductal Adenocarcinoma | Pancreatic Carcinoma MetastaticSweden
Clinical Trials on Placebo
-
SamA Pharmaceutical Co., LtdUnknownAcute Bronchitis | Acute Upper Respiratory Tract InfectionKorea, Republic of
-
National Institute on Drug Abuse (NIDA)CompletedCannabis UseUnited States
-
AstraZenecaParexel; Spandauer Damm 130; 14050; Berlin, GermanyCompletedMale Subjects With Type II Diabetes (T2DM)Germany
-
Heptares Therapeutics LimitedCompletedPharmacokinetics | Safety IssuesUnited Kingdom
-
GlaxoSmithKlineCompletedPulmonary Disease, Chronic ObstructiveUnited Kingdom, Netherlands
-
ItalfarmacoCompletedBecker Muscular DystrophyNetherlands, Italy
-
Shijiazhuang Yiling Pharmaceutical Co. LtdXuanwu Hospital, BeijingCompleted
-
GlaxoSmithKlineCompletedInfections, BacterialUnited States
-
West Penn Allegheny Health SystemCompletedAsthma | Allergic RhinitisUnited States