Colorectal Metastasis Prevention International Trial 2

Официальное название

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

Обзор

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

Вмешательства

• Препарат Propranolol and etodolac
  A perioperative combined drug regimen
• Другое Placebo
  Placebo

Первичные конечные точки

• 5-year disease-free-survival [Срок оценки: From the date of surgery until malignant disease is identified, assessed up to 60 months post-surgery]]
• Biomarkers in extracted tumor tissue samples assessing pro- and anti-metastatic processes [Срок оценки: An average of one year following surgery]
• Biomarkers in blood samples assessing pro- and anti-metastatic processes [Срок оценки: An average of one year following surgery]

Вторичные конечные точки (3)

• Number of patients with treatment related adverse events [Срок оценки: 30 days following surgery]
• Depression, Anxiety, Global distress [Срок оценки: At baseline and at 30 days post-surgery]
• Fatigue [Срок оценки: At baseline and at 30 days post-surgery]

Критерии участия

Критерии включения

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

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Критерии исключения

• Patients with metastatic disease, known prior to surgery
• Patients in whom surgical resection is planned without curative intent
• 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, Bilirubin level>2)
• Patients currently suffering from asthma or Chronic Obstructive Pulmonary Disease (COPD)
• Patients treated pharmacologically for diabetes mellitus (type 1/2),
• Patients with peripheral vascular disease
• Patients with known allergy to one or more of the study medications.
• Patients with known allergy to any medication from the non-steroidal anti- inflammatory drug group or beta-blockers family
• Patients treated chronically with any type of a beta-adrenergic blocker or a COX inhibitor
• Patients with bradycardia or second or third degree AV block
• Patients with a history of CVA/TIA
• Patients with Printzmetal'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
• Pregnant women
• Patients who participate in another interventional study
• Patients with history or concomitant malignant disease of any type (except for the current colon/rectal cancer)
• 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.
• Patients who are treated with immunosuppressive medications
• Patients with Immunodeficiency Disorders, or autoimmune disease treated by immunosuppressive medications.
• Patients suffering from sick sinus syndrome

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Профилактика

Центры проведения

Израиль · 6 центров

• HaEmek Medical Center — Afula
• Rambam Health Care Campus — Haifa
• Rabin Medical Center — Petah Tikva
• Sourasky Medical Center — Tel Aviv
• Sheba Medical Center — Tel Litwinsky
• Asaf Harofeh Medical Center — Ẕerifin

Публикации

• 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 M PMID 29800703
• 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 1 PMID 28490464
• Sakis N, Sorski L, Asraf E, Ricon-Becker I, Shaashua L, Haldar R, Shvalbo BB, Shabat-Simon M, Gutman M, Nissan A, Nachmany I, Kent I, Pery R, Pencovich N, Shussman N, Wasserberg N, Reshef A, Quint E, Lishtzinsky YY, Kashtan H, Shabtai M, Brenner B, Sharon E, Allweis T, Shahar N, Eckerling A, Sandbank E, Zmora O, Ben-Eliyahu S. Favorable safety outcomes of a perioperative propranolol and etodolac r PMID 42088573

Идентификаторы

NCT: NCT03919461 · 0196-17-ASF

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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