Ketorolac and Pregabalin Effects on breaSt Cancer (KePreSt)

Free University of Brussels (ULB)

Status and phase: Enrolling; Phase 2

Conditions: Early-stage Breast Cancer; Estrogen-receptor-positive Breast Cancer

Treatments: Drug: Pregabalin 75mg; Procedure: Prospective data and sample collection; Drug: Omeprazole 20mg Capsule; Drug: Ketorolac 10 Mg Oral Tablet

Study type: Interventional

Funder types: Other

Identifiers

NCT06150898

IJB-KEPREST-2022

Details and patient eligibility

About

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

Full 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.

Enrollment: 112 estimated patients

Sex: Female

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

Subjects must meet all of the following criteria in order to be eligible for this study:

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 diagnostic 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 (1.31<INR) and platelet count (>100.10³/ml)
13. 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.
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

Subjects meeting one of the following criteria are not eligible for this study:

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 an NSAID
20. Subject 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 associated with a high risk of bleeding
23. 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.
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-years 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

Trial design

Primary purpose: Other

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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112 participants in 4 patient groups

No pre-operative treatment

Experimental group

Description:

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 )

Treatment:

Drug: Omeprazole 20mg Capsule

Procedure: Prospective data and sample collection

Pre-operative ketorolac

Experimental group

Description:

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 )

Treatment:

Drug: Omeprazole 20mg Capsule

Drug: Ketorolac 10 Mg Oral Tablet

Procedure: Prospective data and sample collection

Pre-operative pregabalin

Experimental group

Description:

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 )

Treatment:

Drug: Omeprazole 20mg Capsule

Procedure: Prospective data and sample collection

Drug: Pregabalin 75mg

Pre-operative ketorolac and pregabalin

Experimental group

Description:

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 )

Treatment:

Drug: Omeprazole 20mg Capsule

Drug: Ketorolac 10 Mg Oral Tablet

Procedure: Prospective data and sample collection

Drug: Pregabalin 75mg