Unravelling the local and systemic effects of primary surgery and perioperative use of ketorolac and pregabalin in primary breast cancer patients according to adiposity

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Jules Bordet

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 May 2025 → ongoing

Decision date (initial)

2025-01-24

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Les Amis de l’Institut Bordet

External identifiers

EU CT number

2023-507440-36-00

ClinicalTrials.gov

NCT06150898

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

To assess the inflammatory benefit of preoperative ketorolac (COX-blockade).
To assess the neuronal benefit of preoperative pregabalin (neurotransmitters blockade).

Secondary objectives 5

1. To assess the local neuro-inflammatory benefit of preoperative ketorolac (COX-blockade), pregabalin (neurotransmitters blockade) or the combination of both according to subject’s adiposity.
2. To assess the systemic neuro-inflammatory benefit of preoperative ketorolac (COX-blockade), pregabalin (neurotransmitters blockade) or the combination of both according to subject’s adiposity
3. To assess subject's perioperative satisfaction regarding pain and anxiety
4. To assess the association between the subject’s lifestyle with the baseline neuronal features and inflammation
5. To exclude the potential increase in harm and risk associated with the preoperative use of IMPs in breast cancer surgery.

Conditions and MedDRA coding

Estrogen receptor-positive early breast cancer (ER + BC).

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

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 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 study and at least one month 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 29

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 NSAID
20. Subjects with a recent history of operations associated with a high risk of bleeding
21. 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
22. Subject with a recent history of surgery assoiated with a high risk of bleeding
23. Hemostasis disorder as haemophillia, Von Wilebrand disease, constitutional thrombopathies or thrombocytopenia (defined as platelet count < 100 000/mm³), current /planned anticoagulant or anti-platelet therapy.
24. Inadequate bone marrow function (defined as absolute neutrophil count <1000/μL and platelet count <100’000/μL)
25. Systemic immunosuppressive treatment (defined as systemic corticotherapy or anti-rejection treatment or interferon therapy) within the 2-y prior diagnosis
26. Psychiatric disease or antipsychotic/ antidepressant use
27. Epilepsy or any current anti-epileptic drug use
28. Obstructive sleep apnea
29. ASA≥3

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. To detect a different increase in systemic inflammation using peri-operative ketorolac as assessed by Interleukin (IL) 6 in the blood in treated subjects versus observation arm using mean differences in percentage change of IL 6 between baseline and T4.
2. To detect a different increase in systemic neurotransmitters using peri-operative pregabalin as assessed by Norepinephrine (NE) in the blood in treated subjects versus untreated observation arm using mean difference in percentage change of NE from baseline to T4.

Secondary endpoints 16

1. At local level (tumour): To assess, in treated subjects versus untreated subjects, at the time of surgery (T3) compared to pre-treatment diagnosis biopsy (T0) and according to subject’s adiposity
2. Decrease of biomarkers of metastatic progression: Epithelial to Mesenchymal Transition (EMT) markers and pro-metastatic transcription factors
3. Increase in recruitment of specific immune cell subpopulations: Tumour-infiltrating leukocyte subpopulations (monocytes/macrophages, dendritic cells, NK, T and B lymphocytes)
4. Decrease in neurogenesis: Neurotrophins: Neuronal growth factor (NGF) and Brain Derived neurotrophic factors (BDNF), Neuronal marker for neuronal plasticity: Stathmin-2 (STMN2)
5. Decrease of neurotransmitters: Sensitive neurotransmitters: Calcitonine Gene Related Peptide (CGRP), Substance P (SP), Parasympathetic neurotransmitter: Acetylcholin (Ach), Sympathetic neurotransmitter: Norepinephrine (NE)
6. Modification in spatial -omics: Transcriptomics, Metabolomics/ Lipidomics, Proteomics
7. At systemic level (blood): • To assess perioperatively (T0, T2 to T5) and according to subject’s adiposity, the variations between treated and non-treated subjects: • Increased cytotoxic immunity o IL12, IFNɣ, classical monocytes, dendritic cells and NK cells activity
8. Decrease of surgery-induced humoral immunity: CRP, IL10, cortisol
9. To assess perioperatively (T2, T3, T4, T5) and according to subject’s adiposity, variations between treated and non-treated subjects and variations between pre-(T0) and post-(T2) treatment: • Decrease of neurotransmitter levels o Neurotransmitters: CGRP, SP, E and NE o Neurotrophin: NGF
10. To assess at clinical level: Decrease in anxiety level (T0 vs T1), in pregabalin treated versus non pregabalin treated subjects • Generalized Anxiety Disorder - 7 (GAD-7)
11. Decrease of perioperative pain, at time of surgery, between treated and non-treated subjects, and according to the type of treatment (T3, T4, T5) • NRS (Numeric Rating scale) • Morphine consumption
12. Subject’s lifestyle (to assess once before surgery, at T1) • Lifestyle questionnaire • Clinical measurement of adiposity • Evaluation of muscular strength
13. To detect a different increase in systemic inflammation using peri-operative ketorolac as assessed by Interleukin (IL) 6 in the blood in treated subjects versus observation arm using mean differences in percentage change of IL 6 at each timepoints, from T0 to T5.
14. To detect a different increase in systemic neurotransmitters using peri-operative pregabalin as assessed by Norepinephrine (NE) in the blood in treated subjects versus untreated observation arm using mean difference in percentage change of NE at each timepoints, from T0 to T5.
15. To exclude, in treated versus untreated subjects, a potential increase in harm and risk associated with the preoperative use of IMP in breast cancer surgery (T2 to 30 days after the planned surgery),
16. to assess: o Intensity of any Adverse Events (from T2 to 30 days after the planned surgery) ▪ NCI-CTCAE version 5.0 o Intensity of intraoperative Adverse Events (iAEs) (from T2 to T3) ▪ ClassIntra® v1.0 o Intensity of postoperative Adverse Events (poAEs) (from T2 to 30 days after the planned surgery) ▪ Clavien-Dindo classification

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Jules Bordet

Sponsor organisation

Institut Jules Bordet

Address

Mijlenmeersstraat 90

City

Brussels

Postcode

1070

Country

Belgium

Scientific contact point

Organisation

Institut Jules Bordet

Contact name

Clinical Trial Support Unit

Public contact point

Organisation

Institut Jules Bordet

Contact name

Clinical Trial Support Unit

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 25 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications