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出境医 / 临床实验 / Colorectal Metastasis Prevention International Trial 2 (COMPIT-2)

Colorectal Metastasis Prevention International Trial 2 (COMPIT-2)

Study Description
Brief Summary:
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, animal studies conducted by the investigators 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. Two recently conducted clinical trials, conducted by the investigators, 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, the investigators propose to conduct a double-blind placebo-controlled two-arm Phase II clinical trial in 200 colorectal cancer patients undergoing curative surgery in Israel. A perioperative 20-day drug treatment will be initiated 5 days before surgery. Primary outcomes will include (i) 3-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
Colorectal Neoplasms Drug: Propranolol and etodolac Other: Placebo Phase 2

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Perioperative Use of a β-adrenergic Blocker, Propranolol, and a COX2 Inhibitor, Etodolac, in Patients Undergoing Resection With Curative Intent for Primary Colon and Rectal Cancer: Effect on Tumor Recurrence and Survival
Actual Study Start Date : February 28, 2019
Estimated Primary Completion Date : February 28, 2027
Estimated Study Completion Date : February 28, 2027
Arms and Interventions
Arm Intervention/treatment
Active Comparator: Propranolol and etodolac
Both study medications will be given orally for an intervention phase of 20 days as follows. Etodolac:400mg PO bid for the entire intervention period, Propranolol (slow release): 20 mg PO b.i.d. for 5 preoperative days; 80 mg PO b.i.d. on the day of surgery; 40 mg PO b.i.d. for the first post-operative week and 20 mg PO b.i.d. for the second post-operative week.
 Drug: Propranolol and etodolac
A perioperative combined drug regimen
Other Name: Deralin and etopan
Placebo Comparator: Placebo
Same schedule as in the active comparator arm
 Other: Placebo
Placebo
Outcome Measures
Primary Outcome Measures :
  1. 5-year disease-free-survival [ 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. Primary outcome 1 will be rate of recurrence/disease at 60 months.

  2. Biomarkers in extracted tumor tissue samples assessing pro- and anti-metastatic processes [ 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

  3. Biomarkers in blood samples assessing pro- and anti-metastatic processes [ 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)


Secondary Outcome Measures :
  1. 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)

  2. 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)

  3. Fatigue [ Time Frame: At baseline and at 30 days post-surgery ]
    4 items related to fatigue in the 36 item short-form survey questionnaire.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   20 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

1. Patients planned for surgery for primary resection of colon or rectal cancer with curative intent. 2. Single colonic or rectal carcinoma, proven by full colonoscopy and tumor biopsy. 3. No evidence of metastatic disease prior to surgery. Minimal workup would include abdominal CT with IV contrast (or CT+liver US) and chest XR. 4. ASA score of 1-3 or ECOG Performance Status of 0 to 1 5. Signed informed consent form 6. Willing and able to comply with study procedures (physically and mentally) 7. Men and women from age 20 to age 80

-

Exclusion Criteria:

  1. Patients with metastatic disease, known prior to surgery
  2. Patients in whom surgical resection is planned without curative intent
  3. Patients with renal failure, measured by creatinine level >1.5
  4. Patients with significant heart failure (NYHA functional class 3 or higher)
  5. Patients with significant liver failure (known cirrhosis, Bilirubin level>2)
  6. Patients currently suffering from asthma or Chronic Obstructive Pulmonary Disease (COPD)
  7. Patients treated pharmacologically for diabetes mellitus (type 1/2),
  8. Patients with peripheral vascular disease
  9. Patients with known allergy to one or more of the study medications.
  10. Patients with known allergy to any medication from the non-steroidal anti- inflammatory drug group or beta-blockers family
  11. Patients treated chronically with any type of a beta-adrenergic blocker or a COX inhibitor
  12. Patients with bradycardia or second or third degree AV block
  13. Patients with a history of CVA/TIA
  14. Patients with Printzmetal's angina
  15. Patients with right sided heart failure owing to pulmonary hypertension
  16. Patients with significant diagnosed cardiomegaly
  17. Patients with (current) pheochromocytoma
  18. Patients with chronic Digoxin treatment
  19. Patients with active peptic disease
  20. Pregnant women
  21. Patients who participate in another interventional study
  22. Patients with history or concomitant malignant disease of any type (except for the current colon/rectal cancer)
  23. Patients who were treated with chemotherapy in the last 10 years for any reason besides neo-adjuvant therapy for rectal cancer within the last six months.
  24. Patients who are treated with immunosuppressive medications
  25. Patients with Immunodeficiency Disorders, or autoimmune disease treated by immunosuppressive medications.
  26. Patients suffering from sick sinus syndrome
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Oded Zmora, MD +97289779202 ozmora@post.tau.ac.il

Locations
Layout table for location information
Israel
HaEmek Medical Center Not yet recruiting
Afula, Israel, 1834111
Contact: Doron Kopelman, MD       kopelman_d@clalit.org.il   
Rambam Health Care Campus Not yet recruiting
Haifa, Israel, 3109601
Contact: Simon D Duek, MD       d_duek@rambam.health.gov.il   
Rabin Medical Center Not yet recruiting
Petah-Tikva, Israel, 4941492
Contact: Nir Wasserberg, MD       nirw@clalit.org.il   
Sourasky Medical Center Not yet recruiting
Tel Aviv, Israel, 6423906
Contact: Hagit Tulchinsky, MD       hagitt@tlvmc.gov.il   
Sheba Medical Center Not yet recruiting
Tel HaShomer, Israel, 45858
Contact: Mordechai Gutman, MD       motti.gutman@sheba.health.gov.il   
Asaf Harofeh Medical Center Recruiting
Tsrifin, Israel, 70300
Contact: Oded Zmora, MD    +97289779202    ozmora@post.tau.ac.il   
Sponsors and Collaborators
Assaf-Harofeh Medical Center
Sheba Medical Center
Rabin Medical Center
Tel-Aviv Sourasky Medical Center
Rambam Health Care Campus
HaEmek Medical Center, Israel
Investigators
Layout table for investigator information
Principal Investigator: Oded Zmora, MD Asaf Harofeh Medical Center
Tracking Information
First Submitted Date  ICMJE February 28, 2019
First Posted Date  ICMJE April 18, 2019
Last Update Posted Date April 18, 2019
Actual Study Start Date  ICMJE February 28, 2019
Estimated Primary Completion Date February 28, 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 15, 2019)
  • 5-year disease-free-survival [ 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. Primary outcome 1 will be rate of recurrence/disease at 60 months.
  • Biomarkers in extracted tumor tissue samples assessing pro- and anti-metastatic processes [ 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
  • Biomarkers in blood samples assessing pro- and anti-metastatic processes [ 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)
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: April 15, 2019)
  • 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)
  • 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)
  • Fatigue [ Time Frame: At baseline and at 30 days post-surgery ]
    4 items related to fatigue in the 36 item short-form survey questionnaire.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Colorectal Metastasis Prevention International Trial 2
Official Title  ICMJE Perioperative Use of a β-adrenergic Blocker, Propranolol, and a COX2 Inhibitor, Etodolac, in Patients Undergoing Resection With Curative Intent for Primary Colon and Rectal Cancer: Effect on Tumor Recurrence and Survival
Brief Summary 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, animal studies conducted by the investigators 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. Two recently conducted clinical trials, conducted by the investigators, 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, the investigators propose to conduct a double-blind placebo-controlled two-arm Phase II clinical trial in 200 colorectal cancer patients undergoing curative surgery in Israel. A perioperative 20-day drug treatment will be initiated 5 days before surgery. Primary outcomes will include (i) 3-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
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Colorectal Neoplasms
Intervention  ICMJE
  • Drug: Propranolol and etodolac
    A perioperative combined drug regimen
    Other Name: Deralin and etopan
  • Other: Placebo
    Placebo
Study Arms  ICMJE
  • Active Comparator: Propranolol and etodolac
    Both study medications will be given orally for an intervention phase of 20 days as follows. Etodolac:400mg PO bid for the entire intervention period, Propranolol (slow release): 20 mg PO b.i.d. for 5 preoperative days; 80 mg PO b.i.d. on the day of surgery; 40 mg PO b.i.d. for the first post-operative week and 20 mg PO b.i.d. for the second post-operative week.
    Intervention: Drug: Propranolol and etodolac
  • Placebo Comparator: Placebo
    Same schedule as in the active comparator arm
    Intervention: Other: Placebo
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 β-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 β-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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 15, 2019) 		200
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 28, 2027
Estimated Primary Completion Date February 28, 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

1. Patients planned for surgery for primary resection of colon or rectal cancer with curative intent. 2. Single colonic or rectal carcinoma, proven by full colonoscopy and tumor biopsy. 3. No evidence of metastatic disease prior to surgery. Minimal workup would include abdominal CT with IV contrast (or CT+liver US) and chest XR. 4. ASA score of 1-3 or ECOG Performance Status of 0 to 1 5. Signed informed consent form 6. Willing and able to comply with study procedures (physically and mentally) 7. Men and women from age 20 to age 80

-

Exclusion Criteria:

  1. Patients with metastatic disease, known prior to surgery
  2. Patients in whom surgical resection is planned without curative intent
  3. Patients with renal failure, measured by creatinine level >1.5
  4. Patients with significant heart failure (NYHA functional class 3 or higher)
  5. Patients with significant liver failure (known cirrhosis, Bilirubin level>2)
  6. Patients currently suffering from asthma or Chronic Obstructive Pulmonary Disease (COPD)
  7. Patients treated pharmacologically for diabetes mellitus (type 1/2),
  8. Patients with peripheral vascular disease
  9. Patients with known allergy to one or more of the study medications.
  10. Patients with known allergy to any medication from the non-steroidal anti- inflammatory drug group or beta-blockers family
  11. Patients treated chronically with any type of a beta-adrenergic blocker or a COX inhibitor
  12. Patients with bradycardia or second or third degree AV block
  13. Patients with a history of CVA/TIA
  14. Patients with Printzmetal's angina
  15. Patients with right sided heart failure owing to pulmonary hypertension
  16. Patients with significant diagnosed cardiomegaly
  17. Patients with (current) pheochromocytoma
  18. Patients with chronic Digoxin treatment
  19. Patients with active peptic disease
  20. Pregnant women
  21. Patients who participate in another interventional study
  22. Patients with history or concomitant malignant disease of any type (except for the current colon/rectal cancer)
  23. Patients who were treated with chemotherapy in the last 10 years for any reason besides neo-adjuvant therapy for rectal cancer within the last six months.
  24. Patients who are treated with immunosuppressive medications
  25. Patients with Immunodeficiency Disorders, or autoimmune disease treated by immunosuppressive medications.
  26. Patients suffering from sick sinus syndrome
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Oded Zmora, MD +97289779202 ozmora@post.tau.ac.il
Listed Location Countries  ICMJE Israel
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03919461
Other Study ID Numbers  ICMJE 0196-17-ASF
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Assaf-Harofeh Medical Center
Study Sponsor  ICMJE Assaf-Harofeh Medical Center
Collaborators  ICMJE
  • Sheba Medical Center
  • Rabin Medical Center
  • Tel-Aviv Sourasky Medical Center
  • Rambam Health Care Campus
  • HaEmek Medical Center, Israel
Investigators  ICMJE
Principal Investigator: Oded Zmora, MD Asaf Harofeh Medical Center
PRS Account Assaf-Harofeh Medical Center
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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