Inhibiting Beta-adrenergic and COX-2 Signaling During the Perioperative Period to Reduce Ovarian Cancer Progression

Official title

Inhibiting Beta-adrenergic and COX-2 Signaling During the Perioperative Period to Reduce Ovarian Cancer Progression: A Randomized Placebo-Controlled Clinical Trial

Overview

This study investigates the impact of perioperative inhibition of beta-adrenergic and COX-2 signaling in ovarian cancer patients undergoing debulking surgery. The trial aims to assess the feasibility, safety, and biological effects of a combination of propranolol and etodolac in reducing cancer metastasis and improving immune responses.

Detailed description

The study is a placebo-controlled randomized clinical trial (RCT) enrolling 60 women undergoing ovarian cancer debulking surgery. Participants will be assigned to receive propranolol (starting 5 days preoperatively, increased on the day of surgery, and continued postoperatively) and etodolac at a fixed dose. The primary outcomes include recruitment rate, drug safety, tolerability, adherence, and molecular tumor and blood characteristics. Secondary outcomes include 3-year recurrence rates.

Interventions

• Drug Propranolol (Beta-Blocker) and Etodolac (COX-2 Inhibitor)
  \- Intervention Arm: Propranolol (Beta-Blocker) and Etodolac (COX-2 Inhibitor). Name: Propranolol (slow-Release) and Etodolac. Propranolol Dosage Schedule: 5 days pre-surgery: 20mg twice daily (BID), Day of surgery: 80mg BID, 1-week Post-surgery: 40mg BID, week 2-11 post-surgery: 20mg BID. Etodolac Dosage Schedule: 5 days pre-surgery until 3 weeks post-surgery: 400mg BID. Administration Route: Oral.
• Drug Placebo (Matching for Propranolol & Etodolac)
  \- Placebo Arm: Placebo (Matching for Propranolol \& Etodolac). Inert placebo tablets matching propranolol and etodolac in appearance and dosing schedule. Administration Route: Oral.

Primary outcome measures

• Transcriptional Activity in Excised Tumors [Time frame: At the time of surgery (Day 0). Data will be reported through study completion, an average of 2 years.]
• Transcriptional Activity in Blood Samples [Time frame: Preoperative baseline (Informed consent day), Day 0 (surgery), postoperative Day 1, Week 3, and Week 11. Data will be reported through study completion, an average of 2 years.]
• Adverse Event Assessment [Time frame: From 5 days pre-surgery to 3 months post-surgery.]
• Patient Adherence to Drug Regimen [Time frame: From 5 days pre-surgery to 3 months post-surgery.]
• Recruitment Rate [Time frame: Study duration (estimated 2 years).]

Secondary outcome measures (1)

• Three-Year Recurrence Rate [Time frame: 3 years post-surgery.]

Eligibility criteria

Inclusion criteria

• Age 20-85
• ASA score 1-3 or ECOG Performance Status of 0 to 2
• Patients with a suspected high-grade ovarian epithelial cancer based on imaging, clinical examination, CA125, and/or tumor biopsy
• Patients planned for surgery for primary surgery, or interval debulking surgery for ovarian cancer
• Signed informed consent form
• Willing and able to comply with study procedures (physically and mentally)

Exclusion criteria

• Patients who participate in another interventional study
• Patients with known allergy to one or more of the study medications, or 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, except use of Aspirin, which will be discontinued at least 7 days prior to surgery, and until 3 weeks post-surgery
• Patients currently suffering from asthma (אסתמה פעילה בלבד), or required hospital admission or change in medical treatment for asthma within the past year
• Patients with active peptic disease
• Patients with a history of CVA/TIA
• Recent (within the last 5 years) or concurrent malignancies, with the exception of adequately treated in-situ carcinoma of the cervix or basal-cell carcinoma of the skin
• Patients with renal failure, measured by creatinine level >1.5
• Patients with significant liver dysfunction (known cirrhosis, Bilirubin level>2)
• Patients with significant heart failure (NYHA functional class 3 or Higher)
• Patients with bradycardia (heart rate of 50 or less) or second- or third-degree AV block
• Patients with right-sided heart failure owing to pulmonary hypertension
• Patients with chronic Digoxin treatment
• Patients with Printzmetal's angina
• Patients with significant diagnosed cardiomegaly
• Patients suffering from sick sinus syndrome
• Patients with peripheral vascular disease
• Patients with current (unresected) pheochromocytoma
• Pregnant women
• Patients who are treated with immunosuppressive medications, including chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial drug
• Patients with Immunodeficiency Disorders

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Israel · 2 centers

• The Chaim Sheba Medical Center — Ramat Gan
• Tel Aviv Sourasky Medical Center (Ichilov Hospital) — Tel Aviv

Publications

• 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
• Haldar R, Ricon-Becker I, Radin A, Gutman M, Cole SW, Zmora O, Ben-Eliyahu S. Perioperative COX2 and beta-adrenergic blockade improves biomarkers of tumor metastasis, immunity, and inflammation in colorectal cancer: A randomized controlled trial. Cancer. 2020 Sep 1;126(17):3991-4001. doi: 10.1002/cncr.32950. Epub 2020 Jun 13. PMID 32533792
• 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

Identifiers

NCT: NCT06839144 · TLV-0199-24 · 1R21CA291683-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗