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

NCT ID: NCT06839144

Last Updated: 2025-07-11

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-03-12
• Study Completion Date: 2026-08-31

Brief Summary

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.

Conditions

Ovarian Cancer; Ovarian Cancer Metastatic Recurrent

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Intervention Arm

Patients receive propranolol + etodolac (active treatment)

Group Type: EXPERIMENTAL

Propranolol (Beta-Blocker) and Etodolac (COX-2 Inhibitor)

Intervention Type: DRUG

• 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.

Placebo Arm

Patients receive matching placebo for both drugs

Group Type: PLACEBO_COMPARATOR

Placebo (Matching for Propranolol & Etodolac)

Intervention Type: DRUG

\- Placebo Arm: Placebo (Matching for Propranolol \& Etodolac). Inert placebo tablets matching propranolol and etodolac in appearance and dosing schedule. Administration Route: Oral.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

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

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

The Chaim Sheba Medical Center

OTHER

Sponsor Role: collaborator

Tel-Aviv Sourasky Medical Center

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nadav Michaan, Prof.

Role: PRINCIPAL_INVESTIGATOR

Tel Aviv Sourasky Medical Center (Ichilov Hospital)

Anna Blecher, Dr.

Role: PRINCIPAL_INVESTIGATOR

The Chaim Sheba Medical Center (Tel Hashomer)

Shamgar Ben-Eliyahu, Prof.

Role: PRINCIPAL_INVESTIGATOR

Tel Aviv University

Locations

The Chaim Sheba Medical Center

Ramat Gan, , Israel

Site Status: RECRUITING

Tel Aviv Sourasky Medical Center (Ichilov Hospital)

Tel Aviv, , Israel

Site Status: RECRUITING

Countries

Israel

Central Contacts

Shamgar Ben-Eliyahu, Prof.

Role: CONTACT

shamgar@tauex.tau.ac.il

972-3-6407266

Facility Contacts

Anna Blecher, Dr.

Role: primary

anna.blecher@sheba.health.gov.il

972-52-9280101

Nadav Michaan, Prof.

Role: primary

nadavm@tlvmc.gov.il

972-52-7360283

References

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.

Reference Type: BACKGROUND

PMID: 28490464 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 32533792 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 29800703 (View on PubMed)

Other Identifiers

1R21CA291683-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

TLV-0199-24

Identifier Type: -

Identifier Source: org_study_id