Ketorolac and Pregabalin Effects on breaSt Cancer (KePreSt)

Study Purpose

Out of all proportion to its short duration, the perioperative period is critical in determining the long-term outcome of cancer. To contribute to a better understanding of the neural and inflammatory mechanisms underlying this issue, we aim to implement a novel intervention based on the preoperative use of non-steroidal anti-inflammatory drugs (NSAIDs) with or without an anti-epileptic drug. Our goal is to understand and transform the perioperative window from being a facilitator of metastatic progression to arresting and/or eliminating residual disease using repurposing drugs

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years - 70 Years
Gender	Female

More Inclusion & Exclusion Criteria

Inclusion Criteria:

Subjects must meet all of the following criteria in order to be eligible for this study: 1. Age ≥ 18 years and ≤ 70 years old. 2. Female. 3. Weight ≥ 35 kg. 4. Histological diagnosis of invasive breast adenocarcinoma that is estrogen receptor positive as per the updated American Society of Clinical Oncology (ASCO)

- College of American Pathologists (CAP) guidelines according to local testing with ER-positive is defined as having an immunohistochemistry (IHC) of 1% or more and/or Allred score of 3 or more.

5. Tumour size ≥ 1.5 cm, determined by diagnostic ultrasound or MRI/CT scan. 6. Stage I, II or III disease (non-metastatic) 7. In case of multifocal, multicentric unilateral or bilateral breast: Adenocarcinoma tumours are allowed provided that all foci are ER+ according to local testing. 8. Subject scheduled for a primary breast cancer surgery. 9. Subject is willing to provide plasma/blood and tumour samples for translational research. 10. Subject is willing to provide tissue from a newly obtained core or excisional biopsy of the tumour that should be evaluable for central histological characterization and future molecular testing. 11. Subject is willing to take omeprazole and has no contraindication to omeprazole. 12. Have an HEMSTOP score<2 and conventional coagulation screening test within normal limits such as activated partial thromboplastin time (21.6< aPTT >28.7), international normalised ratio (1.31100.10³/ml) 13. Women of childbearing potential must agree to use of one highly effective method of contraception prior study entry, during the course of the study and at least one months after the last administration of study treatment. 14. Negative serum pregnancy test for women of childbearing potential (within 30 days before start of treatment) 15. Subject is willing and able to provide written informed consent for the trial.

Exclusion Criteria:

Subjects meeting one of the following criteria are not eligible for this study: 1. Subject planned for intraoperative radiotherapy. 2. Subject planned for immediate reconstruction. 3. Neoadjuvant BC therapy. 4. Allergy to any NSAID or gabapentinoïd. 5. Known hypersensitivity reactions to the investigational treatments, or any excipients or auxiliary medicinal products or concomitant medications. Hypersensitive to peanut or soya (related to propofol contraindications) 6. Current use of the antidiabetic agent thiazolidinedione (related to interaction with pregabalin), lithium salts, probenecid, pentoxifylline or intensive diuretic therapy. 7. Current NSAID (> twice a week the year prior to diagnosis) or pregabalin use. 8. Previous malignant pathology within 5 years prior to inclusion or currently undergoing maintenance therapy. Exceptions include basal cell carcinoma or squamous cell carcinoma of the skin that have undergone potentially curative therapy or in situ cervical cancer. 9. Active or history of peptic ulcer disease or gastro-intestinal bleeding or perforation. 10. Pregnancy or lactating women. 11. Chronic inflammatory disease as rheumatoid arthritis, uncontrolled asthma, chronic heart failure, chronic obstructive pulmonary disease, cystic fibrosis, inflammatory myopathies (e.g., idiopathic polymyositis, dermatomyositis, inclusion body myositis), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), McArdle's disease, multiple sclerosis, lupus, chronic inflammatory demyelinating polyneuropathy, psoriasis, autoimmune thyroiditis as Graves' disease or Hashimoto's thyroiditis (unless previous surgical ablation), myasthenia gravis, vasculitis. 12. Complete or partial nasal polyposis syndrome, Quincke's oedema, bronchospasm, asthma. 13. Known chronic infectious disease as active hepatitis B (defined as positive serology for Ac anti-HBc and IgM anti HBc OR Ac anti HBc and Ag HBs), active hepatitis C (defined as positive serology for anti-VHC and positive PCR-VHC) or active tuberculosis (included under treatment) 14. Uncontrolled HIV infection (defined as detectable viral loads by standard clinical assays) or controlled HIV infection (defined undetectable HIV viral loads by standard clinical assays) treated by one of following drugs: Nelfinavir, Atazanavir or Saquinavir (related to interaction with omeprazole). 15. Infection currently treated with one of the following drugs: posaconazole, voriconazole, ketoconazole and rifampicin, unless discontinuation of treatment is planned at least 10 days prior to the start of study treatment AND with complete resolution according to expert opinion (related to interaction with omeprazole) 16. Inadequate liver function (defined as total serum bilirubin ≥ 2 x upper limit of normal (ULN<1.2 mg/dl)

- unless documented Gilbert syndrome- AND Alanine Aminotransferase (ALT) ≥ 2 x ULN (ULN <32 UI/l and ULN <33 UI/l, respectively) AND Alkaline phosphatase (ALP) ≥ 2.5 x ULN (ULN=104 UI/l)) 17.

Cirrhosis or severe hepatitis. 18. Renal impairment (defined as GFR<90ml/min/1.73m² or serum creatinine > 442 μmol/l or > 5 mg/dL) or single kidney or previous renal surgery. 19. Subject with history of (severe) renal toxicity with an NSAIDSubject with a recent history of operations associated with a high risk of bleeding. 20. Previous, ongoing or suspected cardiovascular disease defined as history of ischemic heart disease or heart failure or uncontrolled high blood pressure (Systolic ≥160mmHg and/or diastolic ≥100mmHg) or peripheral arterial disease or cerebrovascular disease. 21. Subject with a recent history of surgery associated with a high risk of bleeding. 22. Hemostasis disorder as haemophilia, Von Willebrand disease, constitutional thrombopathies or thrombocytopenia (defined as platelet count < 100 000/mm³), current /planned anticoagulant or anti-platelet therapy. 23. Inadequate bone marrow function (defined as absolute neutrophil count <1000/μL and platelet count <100'000/μL) 24. Systemic immunosuppressive treatment (defined as systemic corticotherapy or anti-rejection treatment or interferon therapy) within the 2-years prior diagnosis. 25. Psychiatric disease or antipsychotic/ antidepressant use. 26. Epilepsy or any current anti-epileptic drug use. 27. Obstructive sleep apnea. 28. ASA≥3

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT06150898
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 2
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Jules Bordet Institute
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Christine Desmedt, PhDImane Bachir, MD
Principal Investigator Affiliation	KU LeuvenJules Bordet Institute
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Not yet recruiting
Countries	Belgium
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Early-stage Breast Cancer, Estrogen-receptor-positive Breast Cancer

Additional Details

The perioperative period presents a unique window of therapeutic opportunities to counteract minimal residual growth and dormancy escape of cancer cells. The main physiological disturbances induced by the surgery, that enhance the tumoral growth in the perioperative period, are due to the neuronal and inflammatory signaling. We propose a therapeutic modelling of the inflammatory and neurological pathways in a phase II trial using ketorolac and pregabalin, alone or in combination. Ketorolac, a non-selective NSAIDs will target cyclooxygenase (COX)-enzymes, while pregabalin, an anti-epileptic drug will regulates the release of neurotransmitters. Moreover, both drugs have an effect on the postoperative pain and pregabalin has anxiolytic property. Thanks to this study, and through specific blockade, we want to understand how nervous and inflammatory systems remodel the tumour and systemic characteristics. To ensure an integrative analysis of those factors, patient's adiposity as well as other confounding variable will be taken into account.

Arms & Interventions

Arms

Experimental: No pre-operative treatment

Control group: Standard of care Number of subjects: 28 (14 lean patients, defined as Body mass index <25 kg/m², and 14 overweight/obese patients, defined as BMI ≥25 kg/m² )

Experimental: Pre-operative ketorolac

Investigational Medicinal Product (IMP): Ketorolac Number of subjects: 28 (14 lean patients, defined as Body mass index <25 kg/m², and 14 overweight/obese patients, defined as BMI ≥25 kg/m² )

Experimental: Pre-operative pregabalin

Investigational Medicinal Product (IMP): Pregabalin Number of subjects: 28 (14 lean patients, defined as Body mass index <25 kg/m², and 14 overweight/obese patients, defined as BMI ≥25 kg/m² )

Experimental: Pre-operative ketorolac and pregabalin

Investigational Medicinal Products (IMPs): Ketorolac and pregabalin Number of subjects: 28 (14 lean patients, defined as Body mass index <25 kg/m², and 14 overweight/obese patients, defined as BMI ≥25 kg/m² )

Interventions

Procedure: - Prospective data and sample collection

Core-needle biopsy of the breast (pre-treatment), surgical sample collection (post-treatment), extra collection of blood samples (pre- and post-treatment), measurements of adiposity, lifestyle questionaire

Drug: - Ketorolac 10 Mg Oral Tablet

Patients will receive 10 mg film-coated tablets of ketorolac tromethamine three times a day, for five days before the surgery

Drug: - Pregabalin 75mg

Patients will receive 75 mg of pregabalin hard capsule twice a day, for seven days before the surgery

Drug: - Omeprazole 20mg Capsule

Patients will receive 20 mg of omeprazole once a day on an empty stomach, for five days before the surgery

Contact a Trial Team

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International Sites

Imane Bachir, Brussels, Belgium

Status

Address

Imane Bachir

Brussels, , 1170

Site Contact

Imane Bachir, MD

[email protected]

+3225413601

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