Ketorolac and Pregabalin Effects on breaSt Cancer (KePreSt)

Early-stage Breast Cancer Clinical Trial

— KePreSt  

Official title:

Unravelling the Local and Systemic Effects of Primary Surgery and Perioperative Use of Ketorolac and Pregabalin in Primary Breast Cancer Patients According to Adiposity

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06150898
• Other study ID #: IJB-KEPREST-2022
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: February 20, 2024
• Est. completion date: December 2026

Study information

• Verified date: November 2023
• Source: Jules Bordet Institute
• Contact: Imane Bachir, MD
• Phone: +3225413601
• Email: imane.bachir[@]bordet.be
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 112
• Est. completion date: December 2026
• Est. primary completion date: July 20, 2026
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Weight = 35 kg

• 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

• Tumour size = 1.5 cm, determined by imaging.

• N0 or N1

• In case of multifocal, multicentric unilateral or bilateral breast: Adenocarcinoma tumours are allowed provided that all foci are ER+ according to local testing

• Subject scheduled for a primary breast cancer surgery at the Institut Jules Bordet

• Subject is willing to provide plasma/blood and tumour samples for translational research.

• If not available yet, 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

• Have an HEMSTOP score<2 (see appendix "2. HEMSTOP score") and conventional coagulation screening test within normal limits such as activated partial thromboplastin time (21.6< aPTT >28.7), international normalised ratio (1.31<INR) and platelet count (>100.10³/ml)

• 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.

• Negative serum pregnancy test

• Completion of all necessary screening procedures prior to randomisation

• Subject is willing and able to provide written informed consent for the trial

Exclusion Criteria:

• Subject planned for intraoperative radiotherapy

• Subject planned for immediate reconstruction

• Neoadjuvant BC therapy

• Allergy to NSAID or gabapentinoïd

• Hypersensitive to peanut or soya (related to propofol contraindications)

• Current use of the antidiabetic agent thiazolidinedione (related to interaction with pregabalin)

• Current NSAID (> twice a week the year prior to diagnosis) or pregabalin use

• Previous malignant pathology within 5 years prior to inclusion. Exceptions include basal cell carcinoma or squamous cell carcinoma of the skin that have undergone potentially curative therapy or in situ cervical cancer.

• Active or history of peptic ulcer disease or gastro-intestinal bleeding or perforation

• Pregnancy or lactating women

• 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

• 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)

• Inadequate liver function (defined as total serum bilirubin = 2 x upper limit of normal (ULN) - unless documented Gilbert syndrome- AND Aspartate and Alanine Aminotransferase (AST and ALT) = 2 x ULN AND Alkaline phosphatase = 2.5 x ULN)

• Renal impairment (defined as GFR<90ml/min/1.73m²) or single kidney or previous renal surgery 15) 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) 16) 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.

• Inadequate bone marrow function (defined as absolute neutrophil count <1000/µL and platelet count <100'000/µL)

• Systemic immunosuppressive treatment (defined as systemic corticotherapy or anti-rejection treatment or interferon therapy) within the 2-years prior diagnosis

• Psychiatric disease or antipsychotic/ antidepressant use

• Epilepsy or any current anti-epileptic drug use

• Obstructive sleep apnea

• ASA=3

Related Conditions & MeSH terms

• Breast Neoplasms
• Early-stage Breast Cancer

Intervention

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

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

Locations

Country	Name	City	State
Belgium	Imane Bachir	Brussels

Sponsors (3)

Lead Sponsor	Collaborator
Jules Bordet Institute	KU Leuven, University of Milan

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Body Mass Index	Calculated: body mass (kg) divided by height squared (m²)	The day before surgery
Other	Fat percentage	Calculated from multiple frequency bio-impedance measurements (in %, range [0 - 100])	The day before surgery
Other	Waist-to-hip ratio	Waist circumference (cm) divided by hip circumference (cm)	The day before surgery
Primary	To detect a reduced increase in systemic inflammation (from baseline to up to 24 hours after surgery) using peri-operative ketorolac	Plasma multiplex technology using cytometric bead arrays	Up to 24 hours after surgery
Primary	To detect a reduced increase in systemic neurotransmitters (from baseline to up to 24 hours after surgery) using peri-operative pregabalin	Liquid Chromatography coupled to tandem Mass Spectrometry (LC-MS/MS)	Up to 24 hours after surgery
Primary	Change in biomarkers of metastasis at surgery from baseline	Transcriptome profile and bioinformatic analysis	At surgery
Primary	Change in tumoral immune cells recruitment at surgery from baseline	Characterization of Tumour-infiltrating leukocyte subpopulations using RNA sequencing analysis from fresh frozen tissue sections	At surgery
Primary	Change in tumoral neurogenesis at surgery from baseline	Level of neurogenesis markers using RNA sequencing analysis from fresh frozen tissue section	At surgery
Primary	Change in tumoral neurotransmitters level at surgery from baseline	Using RNA sequencing analysis from fresh frozen tissue sections	At surgery
Primary	Change in Peripheral Blood Mononuclear Cells at surgery from baseline	Fluorescence activated cell sorting (FACS) analysis	At surgery
Primary	Change in systemic neuro-inflammatory mediators at surgery from baseline	Plasma multiplex technology using cytometric bead arrays	At surgery
Primary	Change in systemic neurotransmitters at surgery from baseline	Plasma multiplex technology using cytometric bead arrays	At surgery
Secondary	Change in anxiety level at surgery from baseline	Generalized Anxiety Disorder - 7 (GAD - 7) Anxiety score (natural number, range[0 - 21]. A score comprised between 0 - 4 indicates a minimal anxiety, 5-9 a mild anxiety, 10-14 a moderate anxiety and a 15-21 in a severe anxiety.	At surgery
Secondary	Post-operative pain	Consumption of morphine delivered by a programmable patient-controlled analgesia (PCA) infusion pump (number of requested and effectively delivered bolus/ 24h)	Up to 48 hours after surgery