KETOROLAC for Estrogen receptor-positive early breast cancer

Inclusion criteria

• {"criterion_text":"- Age ≥ 18 years and ≤ 70 years old\n- 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\n- Subject is willing to take omeprazole and has no contraindication to omeprazole\n- 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)\n- 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\n- Negative serum pregnancy test for women of childbearing potential (within 30 days before start of treatment)\n- Subject is willing and able to provide written informed consent for the trial\n- Female\n- Weight ≥ 35 kg\n- 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\n- Tumour size ≥ 1.5 cm, determined by ultrasound or MRI/CT scan\n- Stage I, II or III disease (non-metastatic)\n- In case of multifocal, multicentric unilateral or bilateral breast: Adenocarcinoma tumours are allowed provided that all foci are ER+ according to local testing\n- Subject scheduled for a primary breast cancer surgery\n- Subject is willing to provide plasma/blood and tumour samples for translational research"}

Exclusion criteria

• {"criterion_text":"- Subject planned for intraoperative radiotherapy\n- Pregnancy or lactating women\n- 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\n- Complete or partial nasal polyposis syndrome, Quincke’s oedema, bronchospasm, asthma\n- 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)\n- 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).\n- 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)\n- 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))\n- Cirrhosis or severe hepatitis\n- 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\n- Subject with history of (severe) renal toxicity with NSAID\n- Subject planned for immediate reconstruction\n- Subjects with a recent history of operations associated with a high risk of bleeding\n- 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\n- Subject with a recent history of surgery assoiated with a high risk of bleeding\n- 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.\n- Inadequate bone marrow function (defined as absolute neutrophil count <1000/μL and platelet count <100’000/μL)\n- Systemic immunosuppressive treatment (defined as systemic corticotherapy or anti-rejection treatment or interferon therapy) within the 2-y prior diagnosis\n- Psychiatric disease or antipsychotic/ antidepressant use\n- Epilepsy or any current anti-epileptic drug use\n- Obstructive sleep apnea\n- ASA≥3\n- Neoadjuvant BC therapy\n- Allergy to any NSAID or gabapentinoïd\n- 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)\n- Current use of the antidiabetic agent thiazolidinedione (related to interaction with pregabalin), lithium salts, probenecid, pentoxifylline or intensive diuretic therapy\n- Current NSAID (> twice a week the year prior to diagnosis) or pregabalin use\n- 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\n- Active or history of peptic ulcer disease or gastro-intestinal bleeding or perforation"}

Primary endpoints

• {"endpoint_text":"- 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.\n- 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.","definition_or_measurement_approach":"Primary measures: IL-6 levels in blood (for ketorolac) and Norepinephrine (NE) levels in blood (for pregabalin); assessed using mean differences in percentage change from baseline to T4."}

Secondary endpoints

• {"endpoint_text":"- 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\n- Decrease of biomarkers of metastatic progression: Epithelial to Mesenchymal Transition (EMT) markers and pro-metastatic transcription factors\n- Increase in recruitment of specific immune cell subpopulations: Tumour-infiltrating leukocyte subpopulations (monocytes/macrophages, dendritic cells, NK, T and B lymphocytes)\n- Decrease in neurogenesis: Neurotrophins: Neuronal growth factor (NGF) and Brain Derived neurotrophic factors (BDNF), Neuronal marker for neuronal plasticity: Stathmin-2 (STMN2)\n- Decrease of neurotransmitters: Sensitive neurotransmitters: Calcitonine Gene Related Peptide (CGRP), Substance P (SP), Parasympathetic neurotransmitter: Acetylcholin (Ach), Sympathetic neurotransmitter: Norepinephrine (NE)\n- Modification in spatial -omics: Transcriptomics, Metabolomics/ Lipidomics, Proteomics\n- 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\n- Decrease of surgery-induced humoral immunity: CRP, IL10, cortisol\n- 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\n- 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)\n- 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\n- Subject’s lifestyle (to assess once before surgery, at T1) • Lifestyle questionnaire • Clinical measurement of adiposity • Evaluation of muscular strength\n- 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.\n- 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.\n- 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),\n- 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","definition_or_measurement_approach":"Secondary endpoints include local tumour biomarker comparisons (T3 vs T0), measurement of EMT markers and pro-metastatic transcription factors, immune cell subpopulation quantification, neurotrophin and neurotransmitter level assays (e.g., NGF, BDNF, CGRP, SP, Ach, NE), spatial -omics (transcriptomics, metabolomics/lipidomics, proteomics), systemic blood markers at specified perioperative timepoints (T0, T2–T5) including IL12, IFNɣ, CRP, IL10, cortisol, and clinical assessments: GAD-7 for anxiety, NRS for pain, morphine consumption, lifestyle questionnaire and adiposity/muscular strength measures. Safety assessed by NCI-CTCAE v5.0 (AEs), ClassIntra v1.0 (intraoperative AEs), and Clavien-Dindo (postoperative AEs); some endpoints evaluated as percentage changes from baseline across timepoints T0–T5."}

Belgium

Earliest CTIS Part Ii Submission Date

13-12-2024

Latest Decision Or Authorization Date

24-03-2025

Processing Time Days

101

Number Of Sites

1

Number Of Participants

120

Primary sponsor

Full Name

Institut Jules Bordet

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Belgium