Neoadjuvant and Adjuvant Ribociclib and ET for Clinically High-risk ER+ and HER2- Breast Cancer

Inclusion Criteria:

1. Signed Informed Consent Form prior to any study-specific procedure. Patients must bewilling and able to comply with the protocol for the duration of the study includingscheduled visits, treatment plan, laboratory tests and other study procedures. Note: Candidate patients in France must be affiliated to a Social Security System (or equivalent)

2. Male (≥18 years old) or pre-menopausal women (≥40 years old) or post-menopausalwomen. Premenopausal/male patients will receive LHRH agonists 2 weeks before C1D1and during treatment. Post-menopausal status is defined as:

3. Age ≥60 years or

4. Age <60 years and 12 months of amenorrhea plus follicle stimulating hormone (FSH) and plasma estradiol (E2) levels within post-menopausal range by locallaboratory assessment or

5. Prior bilateral oophorectomy (≥7 days prior to Day 1 of treatment).

6. Histologically confirmed invasive breast carcinoma, confirmed by the localpathologist, with all the following characteristics:

7. Clinical stage II (Seventh Edition of the AJCC) which includes cT1cN1cM0,cT2cN0cM0, cT2cN1cM0 and cT3cN0cM0.

8. ER-positive/HER2-negative according to the most recent ASCO/CAP guidelinesassessed locally, tumor cells >10% ER staining, grade 2 or 3 breast cancer.

9. Ki-67 index by local analysis of ≥20% on untreated tumor tissue and/or highgenomic risk (defined by gene signature): Oncotype DX® RS ≥ 26, Mammaprint® =Risk of Recurrence High, Prosigna® ROR ≥ 60 or luminal B, or Endopredict® =Risk of Recurrence High. Note: Multifocal and multicentric tumors are permitted if they are consideredclinical stage II according to Seventh Edition of the AJCC. Biopsy of all lesions isnot necessary.

10. Breast cancer eligible for primary surgery.

11. Available pre-treatment FFPE core (tru-cut) biopsy evaluable for PAM50 orpossibility to obtain one. Minimal sample requirements are to have at least 1 tumorcylinder with a minimal tissue surface of 4 mm2 tissue, containing at least 10%tumor cells and having enough tissue to do at least 2 cuts of 10 μm each (thequality of the sample must be approved centrally prior to inclusion).

12. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.Evaluation of ECOG is to be performed within 14 days prior to the date of enrolment.

13. Adequate hematological, renal and hepatic function, as follows:

14. Absolute neutrophil count (ANC) ≥1.5 x 109/L

15. Platelet count ≥100 x 109/L

16. Hemoglobin ≥10 g/dL

17. Alkaline phosphatase (AP) ≤2.5x upper limit of normal (ULN)

18. Total bilirubin <ULN. Patients with known Gilbert syndrome may be enrolled withtotal bilirubin ≤3 x ULN or direct bilirubin ≤1.5 x ULN.

19. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5x ULN

20. Serum creatinine ≤1.5 mg/dL or calculated creatinine clearance ≥60 mL/min (Cockcroft-Gault Equation)

21. Potassium, total calcium (corrected for serum albumin), magnesium, and sodiumwithin institutional normal limits or corrected to within normal limits withsupplements before first dose of study medication. Male participants:

22. A male participant must agree to use a contraception as detailed in Appendix 1 ofthis protocol during the adjuvant chemotherapy period (only non-responder cohort)and for at least 21 days, corresponding to time needed to eliminate any studytreatments plus an additional 120 days (a spermatogenesis cycle) after the last doseof chemotherapy and refrain from donating sperm during this period. After the end oftrial treatment, patients should use effective contraception according to localguidelines. Female participants:

23. A female participant is eligible to participate if she is not pregnant, notbreastfeeding, and at least one of the following conditions applies (see Appendix 1):

24. Not a woman of childbearing potential (WOCBP) as defined in Appendix 1 OR

25. A WOCBP who agrees to follow the contraceptive guidance in Appendix 1 duringthe treatment period and for at least 21 days (corresponding to time needed toeliminate any study treatments) plus 30 days (a menstruation cycle) for studytreatments with risk of genotoxicity after the last dose of study treatment.After the end of trial treatment, patients should use effective contraceptionaccording to local guidelines.

Exclusion Criteria:

1. Any prior treatment for primary invasive breast cancer. Letrozole or other drugsused during the preservation of ovarian function are permitted if administered afterbaseline biopsy.

2. Inoperable breast cancer.

3. Patients with Stage I, III or IV breast cancer are not eligible. Baseline staging todocument absence of metastatic disease is not required, however is recommended asdetermined by institutional practice (in patients where there may be a reasonablesuspicion of advanced disease e.g., large tumors, clinically positive axillary lymphnodes, signs and symptoms). If performed, reports of these examinations must beavailable. Examination type for staging, i.e. X-ray, sonography, bone scan, CT, MRI,and/or PET-CT, is at the discretion of the investigator.

4. Bilateral invasive breast cancer.

5. Patients who have undergone sentinel lymph node biopsy prior to study treatment.

6. Inability or unwillingness to swallow pills.

7. Malabsorption syndrome or other condition that would interfere with entericabsorption of study drugs.

8. Participation in a prior investigational study within 30 days prior to enrolment orwithin 5 half-lives of the investigational product, whichever is longer.

9. Patient with a Child-Pugh score B or C.

10. Patient has active cardiac disease or a history of cardiac dysfunction including anyof the following:

11. History of acute coronary syndromes (including myocardial infarction, unstableangina, coronary artery bypass grafting, coronary angioplasty or stenting) orsymptomatic pericarditis within 12 months prior to screening.

12. History of documented congestive heart failure (New York Heart Associationfunctional classification III-IV).

13. Documented cardiomyopathy.

14. Patient has a Left Ventricular Ejection Fraction (LVEF) <50% as determined byMultiple Gated acquisition (MUGA) scan or echocardiogram (ECHO).

15. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia),complete left bundle branch block, high-grade AV block (e.g. bifascicularblock, Mobitz type II and third-degree AV block).

16. Long QT Syndrome or family history of idiopathic sudden death or congenitallong QT syndrome or any of the following:

17. Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia orhypomagnesemia, history of cardiac failure or history of clinicallysignificant/symptomatic bradycardia.

18. QTc >500 msec or conduction abnormality in the previous 12 months.

19. On screening 12-lead ECG, any of the following cardiac parameters: bradycardia (resting heart rate <50), tachycardia (resting heart rate >90), or QTcFinterval ≥450 msec (using Fridericia's correction).

20. Uncontrolled hypertension (Systolic blood pressure >160 mmHg or <90 mmHg and/ordiastolic >100 mmHg).

21. Active infection requiring intravenous (IV) antibiotics.

22. Prior story of pneumonitis of any cause.

23. Prior thromboembolic events not attributable to a clear trigger cause.

24. Known human immunodeficiency virus (HIV) infection.

25. Any other diseases, active or uncontrolled pulmonary dysfunction, metabolicdysfunction, physical examination finding, or clinical laboratory finding givingreasonable suspicion of a disease or condition that contraindicates the use of aninvestigational drug, that may compromise compliance with the protocol, that mayaffect the interpretation of the results, or renders the patients at high risk fromtreatment complications.

26. Significant traumatic injury within 3 weeks prior to initiation of study treatment.

27. Major surgical procedure (not including minor procedures such as lymph node biopsy,tumor core biopsy, fine needle aspiration or bilateral oophorectomy) within 3 weeksprior to initiation of study treatment or not fully recovered from any side effectsof previous procedures.

28. Any psychological, familial, sociological, or geographical condition potentiallyhampering compliance with the study protocol and follow-up schedule.

29. Patients with a history of any malignancy are ineligible except for the followingcircumstances:

• Patients with a malignancy history other than invasive breast cancer areeligible if they have been disease-free for at least 5 years and are deemed bythe investigator to be at low risk for recurrence of that malignancy.

• Patients with the following cancers are eligible, even if diagnosed and treatedwithin the past 5 years: ductal carcinoma in situ of the breast, cervicalcancer in situ, and non-metastatic non-melanomatous skin cancers.

20. Estrogen replacement therapy stopped less than 2 weeks before treatment start.

21. Known hypersensitivity to any of the excipients of ribociclib, letrozole, goserelinor decapapetyl (if men or pre-menopausal).

22. Live vaccines within 30 days prior to the first dose of study.

23. Patients currently on following medications, which cannot be interrupted 7 daysprior treatment start:

24. Any prohibited medication as per goserelin or decapapetyl (pre-menopasualpatients), letrozole or ribociclib label

25. Herbal preparations/medications, dietary supplements.

26. Medications that have a known risk to prolong the QT interval or cause Torsadesde Pointe.

27. Medications with a narrow therapeutic window and predominantly metabolizedthrough CYP3A4.

28. Strong inhibitors of CYP3A4, including grapefruit, grapefruit hybrids,pummelos, star-fruit and Seville oranges.

29. Strong inducers of CYP3A4.

30. Warfarin or other coumarin-derived anticoagulant for treatment, prophylaxis orotherwise. Therapy with heparin, low molecular weight heparin or fondaparinuxis allowed.

31. A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation (see Appendix 1). If the urine test is positive or cannot be confirmed as negative,a serum pregnancy test will be required. Note: in the event that 72 hours have elapsed between the screening pregnancy testand the first dose of study treatment, another pregnancy test (urine or serum) mustbe performed and must be negative in order for subject to start receiving studymedication.

32. Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the study, interfere with thesubject's participation for the full duration of the study, or is not in the bestinterest of the subject to participate, in the opinion of the treating investigator.

33. Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

34. Is pregnant or breastfeeding or expecting to conceive or father children within theprojected duration of the study, starting with the screening visit through 120 daysafter the last dose of trial treatment. Males who want to father children shouldconsider preserving the sperm before starting treatment with ribociclib.

35. Persons deprived of their liberty or under protective custody or guardianship.