Ketorolac and Pregabalin Effects on breaSt Cancer (KePreSt)

Study Overview
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Brief Summary
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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

Detailed Description
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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.

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

Conditions
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Early-stage Breast Cancer, Estrogen-receptor-positive Breast Cancer

Intervention / Treatment
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* Procedure: Prospective data and sample collection
* Drug: Ketorolac 10 Mg Oral Tablet
* Drug: Pregabalin 75mg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: No pre-operative treatment<br>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 ) | Procedure: Prospective data and sample collection<br>* 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<br>|
| Experimental: Pre-operative ketorolac<br>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 ) | Procedure: Prospective data and sample collection<br>* 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<br>Drug: Ketorolac 10 Mg Oral Tablet<br>* Patients will receive 10 mg film-coated tablets of ketorolac tromethamine three times a day, for five days before the surgery<br>|
| Experimental: Pre-operative pregabalin<br>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 ) | Procedure: Prospective data and sample collection<br>* 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<br>Drug: Pregabalin 75mg<br>* Patients will receive 75 mg of pregabalin hard capsule twice a day, for seven days before the surgery<br>|
| Experimental: Pre-operative ketorolac and pregabalin<br>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 ) | Procedure: Prospective data and sample collection<br>* 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<br>Drug: Ketorolac 10 Mg Oral Tablet<br>* Patients will receive 10 mg film-coated tablets of ketorolac tromethamine three times a day, for five days before the surgery<br>Drug: Pregabalin 75mg<br>* Patients will receive 75 mg of pregabalin hard capsule twice a day, for seven days before the surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| Change in biomarkers of metastasis at surgery from baseline | Transcriptome profile and bioinformatic analysis | At surgery | 
| 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 | 
| Change in tumoral neurogenesis at surgery from baseline | Level of neurogenesis markers using RNA sequencing analysis from fresh frozen tissue section | At surgery | 
| Change in tumoral neurotransmitters level at surgery from baseline | Using RNA sequencing analysis from fresh frozen tissue sections | At surgery | 
| Change in Peripheral Blood Mononuclear Cells at surgery from baseline | Fluorescence activated cell sorting (FACS) analysis | At surgery | 
| Change in systemic neuro-inflammatory mediators at surgery from baseline | Plasma multiplex technology using cytometric bead arrays | At surgery | 
| Change in systemic neurotransmitters at surgery from baseline | Plasma multiplex technology using cytometric bead arrays | At surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Surgery, Inflammation, Breast cancer, Neuronal features, Ketorolac, Pregabalin, Adiposity, Neurotransmitter, Nerves