Study Locations (138 sites)
Clinique de l'Europe, Amiens, 80090 France
Institut de Cancérologie de l'Ouest - Site Paul Papin, Angers, 49055 France
CH Victor Dupouy, Argenteuil, 95107 France
CH Henri Mondor, Aurillac, 15000 France
Centre Hospitalier d'Auxerre, Auxerre, France
Sainte Catherine - Institut du Cancer Avignon Provence, Avignon, 84918 France
Centre Hospitalier de la Cote Basque, Bayonne, 64100 France
Centre Hospitalier Simone Veil de Beauvais, Beauvais, 60021 France
Centre Hospitalier Universitaire de Besancon, Besançon, 25000 France
Institut Bergonie, Bordeaux, 33076 France
Eligibility Criteria
Inclusion Criteria:
1. Patient must have signed a written informed consent prior to any trial-specific screening procedure.
Note: When the patient is physically unable to give their written consent, an impartial witness of their choice, independent from the investigator or the sponsor, can confirm in writing the patient's consent.
2. Patient is ≥ 18 years old.
3. Patient is female with known menopausal status at the time of randomization.
Post-menopausal status is defined as:
1. Patient underwent bilateral oophorectomy, or
2. Age ≥ 60 years, or
3. Age \< 60 years and either amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression) or Follicle-stimulating hormone (FSH) and plasma estradiol are in the postmenopausal ranges per local normal ranges.
4. If taking tamoxifen or toremifene and age \<60 years, then FSH and plasma estradiol level in postmenopausal ranges.
4. The following criteria must be met for histologically confirmed invasive breast carcinoma, as determined by the local pathologist:
1. Pathological stage (8th edition of the AJCC), including pT2 pN0 Grade 3 or pT2 pN0 Grade 2 with Ki67≥20% or pT0-2 pN1 or pT3-4 pN0
2. ER-positive (with tumor cells showing ≥10% ER staining) and HER2-negative according to the most recent ASCO/CAP guidelines.
Note: Multifocal and multicentric tumors are allowed if they meet the clinical stage II criteria of the 8th Edition of the AJCC. All tumors must be ER-positive and HER2-negative. Patients with bilateral invasive breast cancer (diagnosed simultaneously or within 6 months of each other) are eligible if all lesions tested on both sides are ER+ (ie, ≥10% positive stained cells) and HER2- AND adequate surgery has been performed in both breasts.
5. Chemotherapy eligible per investigator decision, based on clinicopathological findings or the results of any genomic signature.
6. Patient has no contraindication for the adjuvant endocrine therapy (ET) or chemotherapy in the trial and is planned to be treated with ET for 5 years (after randomization date) or more.
7. Curative surgery for the invasive disease must have been performed with negative surgical margins within 12 weeks before randomization. If positive surgical margins, patients are eligible if revision surgery or other adequate local treatment (i.e local radiotherapy) is planned.
8. Women of childbearing potential (CBP) must have a confirmed negative serum pregnancy test (β-hCG) before starting study treatment.
9. Women of childbearing potential must agree to use one effective form of contraception during trial treatment and up to 21 days after the last dose of study drugs or longer, if required per standard of care;
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 28 days prior to randomization.
11. Adequate hematological, renal, and hepatic function, as outlined below:
1. Absolute neutrophil count (ANC) ≥1.5 x 10⁹/L
2. Platelet count ≥100 x 10⁹/L
3. Hemoglobin ≥9 g/dL
4. Total bilirubin \< ULN. Patients with known Gilbert syndrome may be enrolled with total bilirubin ≤3 x ULN or direct bilirubin ≤1.5 x ULN
5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<2.5 x ULN
6. Serum creatinine ≤1.5 mg/dL or calculated creatinine clearance ≥60 mL/min/1.73m² (CKD-EPI equation (2021))
7. Potassium, total calcium (corrected for serum albumin), and magnesium should be within institutional normal limits or corrected to within normal limits using supplements before the first dose of study medication.
12. Standard 12-lead ECG values assessed, as:
1. QTcF interval (QT interval using Fridericia's correction) at screening \< 450 milliseconds (msec)
2. Resting heart rate 50-100 beats per minute (determined from the ECG)
13. Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures.
14. Absence of any psychological, familial or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
15. Patients must be affiliated to a Social Security System (or equivalent) based on local regulations.
Exclusion Criteria:
1. Patient has received any neoadjuvant chemotherapy since her breast cancer diagnosis or has received any prior CDK4/6 inhibitor.
2. Breast cancer diagnosed while patient was receiving tamoxifen, raloxifene or aromatase inhibitors (AIs) for reduction in risk ("chemoprevention") of breast cancer and/or treatment for osteoporosis within the last 2 years prior to randomization.
3. Patient with a known hypersensitivity to any of the excipients of ribociclib and/or ET (e.g. rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption, and soy or peanut allergy).
4. Patient with evidence or history of distant metastases of breast cancer beyond regional lymph nodes (stage IV according to AJCC 8th edition), inflammatory breast cancer, breast cancer recurrence (local or distant) or a different primary breast cancer.
5. Patient has a concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed within 2 years before randomization. Note: Patients with adequately treated basal or squamous cell skin carcinoma or curatively resected cervical cancer in situ are eligible.
6. Patients whose breast cancer is considered as endocrine therapy insensitive, as determined by investigator's opinion; this may include (but is not limited to) breast cancer classified as " basal like " by molecular signatures (if available in the patient file) and/or breast cancer with persistently high proliferation after pre-operative endocrine therapy.
7. Patient has had major surgery within 14 days prior to study treatment initiation.
8. Patient has known history of human immunodeficiency virus (HIV) infection (testing is not mandatory) whose antiretroviral therapy (ART) has a known strong CYP3A4 inhibitor with potential for DDI with ribociclib. Patients with HIV may be enrolled if they fulfil the criteria recommended by FDA and ASCO guidelines (FDA Guidance, Uldrick et al. 2017):
1. CD4+ T-cell (CD4+) counts ≥ 350 cells/µL, AND
2. No history of AIDS-defining opportunistic infections within the past 12 months (prophylactic antimicrobials allowed if no drug-drug interactions or overlapping toxicities), AND
3. On established ART which is not a strong CYP3A4 inhibitor, for at least 4 weeks and have an HIV viral load less than 400 copies/mL prior to enrolment. Effective ART is defined as a drug, dosage, and schedule associated with reduction and control of the viral load.
9. Patient has known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (testing is not mandatory).
10. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:
1. History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft within 6 months prior to trial entry.
2. Documented cardiomyopathy.
3. Left Ventricular Ejection Fraction (LVEF) \< 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) (testing not mandatory)
4. Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
* Risk factors for Torsades de Pointes (TdP) including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia.
* Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause TdP that cannot be discontinued or replaced by safe alternative medication (e.g. within 5 half-lives or 7 days prior to starting trial treatment).