Ketorolac and Pregabalin Effects on breaSt Cancer (KePreSt)

Sponsor

Jules Bordet Institute (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06150898

Collaborator

KU Leuven (Other), University of Milan (Other)

112

Enrollment

Location

Arms

33.3

Anticipated Duration (Months)

3.4

Patients Per Site Per Month

Study Details

Study Description

Brief 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

Condition or Disease	Intervention/Treatment	Phase
Early-stage Breast Cancer Estrogen-receptor-positive Breast Cancer	Procedure: Prospective data and sample collection Drug: Ketorolac 10 Mg Oral Tablet Drug: Pregabalin 75mg	Phase 2

Detailed 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

112 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Other

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

Anticipated Study Start Date :

Feb 20, 2024

Anticipated Primary Completion Date :

Jul 20, 2026

Anticipated Study Completion Date :

Dec 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
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 )	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
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 )	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
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 )	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: Pregabalin 75mg Patients will receive 75 mg of pregabalin hard capsule twice a day, for seven days before the surgery
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 )	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 Drug: Pregabalin 75mg Patients will receive 75 mg of pregabalin hard capsule twice a day, for seven days before the surgery

Outcome Measures

Primary Outcome Measures

To detect a reduced increase in systemic inflammation (from baseline to up to 24 hours after surgery) using peri-operative ketorolac [Up to 24 hours after surgery]
Plasma multiplex technology using cytometric bead arrays
To detect a reduced increase in systemic neurotransmitters (from baseline to up to 24 hours after surgery) using peri-operative pregabalin [Up to 24 hours after surgery]
Liquid Chromatography coupled to tandem Mass Spectrometry (LC-MS/MS)
Change in biomarkers of metastasis at surgery from baseline [At surgery]
Transcriptome profile and bioinformatic analysis
Change in tumoral immune cells recruitment at surgery from baseline [At surgery]
Characterization of Tumour-infiltrating leukocyte subpopulations using RNA sequencing analysis from fresh frozen tissue sections
Change in tumoral neurogenesis at surgery from baseline [At surgery]
Level of neurogenesis markers using RNA sequencing analysis from fresh frozen tissue section
Change in tumoral neurotransmitters level at surgery from baseline [At surgery]
Using RNA sequencing analysis from fresh frozen tissue sections
Change in Peripheral Blood Mononuclear Cells at surgery from baseline [At surgery]
Fluorescence activated cell sorting (FACS) analysis
Change in systemic neuro-inflammatory mediators at surgery from baseline [At surgery]
Plasma multiplex technology using cytometric bead arrays
Change in systemic neurotransmitters at surgery from baseline [At surgery]
Plasma multiplex technology using cytometric bead arrays

Secondary Outcome Measures

Change in anxiety level at surgery from baseline [At surgery]
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.
Post-operative pain [Up to 48 hours after surgery]
Consumption of morphine delivered by a programmable patient-controlled analgesia (PCA) infusion pump (number of requested and effectively delivered bolus/ 24h)

Other Outcome Measures

Body Mass Index [The day before surgery]
Calculated: body mass (kg) divided by height squared (m²)
Fat percentage [The day before surgery]
Calculated from multiple frequency bio-impedance measurements (in %, range [0 - 100])
Waist-to-hip ratio [The day before surgery]
Waist circumference (cm) divided by hip circumference (cm)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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