Capivasertib Plus Fulvestrant vs. Fulvestrant in Primary High-risk Lobular Breast Cancer

Inclusion Criteria:

1. Written informed consent prior to beginning specific protocol procedures, includingexpected cooperation of the patients for the treatment and followup, and documentedaccording to the local regulatory requirements.

2. Postmenopausal women with age at diagnosis ≥ 18 years. Postmenopausal status is defined as:

• Age ≥60 years

• Age <60 years and amenorrhea for at least 12 continuous months with noidentified cause other than menopause

• Bilateral oophorectomy Negative pregnancy test (urine or serum) within 14 daysprior to randomization for all postmenopausal women 50 years of age or youngerwithout bilateral oophorectomy

3. Unilateral or bilateral primary untreated lobular invasive carcinoma of the breast.In case of bilateral breast cancer, both sides must be lobular; the lead tumor hasto be defined by the investigator based on the inclusion criteria for the respectivesubtype and the risk status. Lobular histology has to be centrally confirmed.

4. Willingness and ability to provide archived formalin fixed paraffin embedded (FFPE)tissue block from core biopsy before the start of neoadjuvant therapy.

5. Centrally confirmed HER2-negative (IHC score 0-1+ or ISH negative according toASCO/CAP guideline) and HR-positive (≥10% positive stained cells) disease, assessedon the core of diagnostic biopsy. Ki67% >10% is required. In case of bilateralbreast cancer, HER2-negative, HR-positive and lobular histology status has to beconfirmed for both sides.

6. Patients with invasive lobular breast cancer at high risk for recurrence defined ascT1c and clinical nodal involvement (cN+) or ≥ cT2 disease (irrespective of nodalinvolvement).

7. No clinical evidence of distant metastases.

8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.

9. Estimated life expectancy of at least 5 years irrespective of the diagnosis ofbreast cancer.

10. The patient must be accessible for scheduled visits, treatment, and followup.

11. Normal cardiac function must be confirmed according to local guidelines.

12. Laboratory requirements: Hematology

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

• Platelets ≥100 x 109 / L

• Hemoglobin ≥10 g/dL (≥6.2 mmol/L) Hepatic function

• Total bilirubin <1.25x ULN

• AST and ALT <=1.5x ULN

• Alkaline phosphatase <=2.5x ULN Glucose Metabolism

• HbA1c <8.0% (63.9 mmol/mol) Renal Function

• Creatinine <1.25x ULN or creatinine clearance ≥50 ml/min (if creatinine isabove ULN according to Cockroft-Gault)

13. Complete staging work-up prior to the initiation of neoadjuvant therapy as perstandard recommendations.

Exclusion Criteria:

1. Female patients of childbearing potential.

2. Excisional biopsy or lumpectomy performed prior to study entry.

3. Surgical axillary staging procedure including sentinel lymph node biopsy prior torandomization. Exceptions: FNA or core biopsy of an axillary lymph node.

4. Any previous treatment including endocrine therapy, chemotherapy, radiotherapy ortargeted therapy (including AKT inhibitor or PIK3 inhibitor) for the currentlydiagnosed breast cancer.

5. Concurrent use of herbal or natural products intended as treatment or prophylaxisfor any type of cancer.

6. Known hypersensitivity reaction to one of the compounds or substances used in thisprotocol.

7. Potent inhibitors or inducers of CYP3A4 within 2 weeks prior to the first dose ofstudy treatment (3 weeks for St John's wort).

8. Refractory nausea and vomiting, chronic gastrointestinal disease, inability toswallow the formulated product, or previous significant bowel resection that wouldpreclude adequate absorption, distribution, metabolism, or excretion ofcapivasertib.

9. Any contraindication for fulvestrant.

10. Patients with definitive clinical or radiologic evidence of stage IV cancer (metastatic disease) are not eligible.

11. Patients with a history of any malignancy are ineligible with the followingexceptions:

• Patient has been disease-free for at least 5 years and is at low risk forrecurrence of that malignancy except for breast cancer.

• CIS of the cervix, basal cell and squamous cell carcinomas of the skin.

12. History of type I or type II diabetes mellitus requiring insulin.

13. Severe and relevant co-morbidity that would interact with the application of studydrugs or the participation in the study, including cerebrovascular incidentincluding transient ischemic attack, or symptomatic pulmonary embolism, activeinfection requiring intravenous anti-microbial treatment (antibiotics, anti-fungal,and anti-viral drugs) within 1 week of enrolment. Patients with confirmed Gilbert'ssyndrome may be included in the study.

14. Known medically history of HIV infection, tuberculosis, or hepatitis B.

15. History of and/or active cardiac disease that would preclude the use of studytreatments. This includes but is not confined to any of the following cardiaccriteria:

• Clinically significant cardiac dysfunction including heart failure (NYHAII-IV), active ventricular arrhythmias requiring medication or arrhythmiasrequiring a pacemaker, and history of a myocardial infarction within 6 monthsprior to randomization, angina pectoris, atrial fibrillation of any grade,coronary/peripheral artery bypass graft, angioplasty, or vascular stent.

• Mean resting QT interval corrected by Fridericia's formula (QTcF) >470 msecobtained from 3 consecutive ECGs.

• Increased risk of QTc prolongation or risk of arrhythmic events such as heartfailure, uncontrolled electrolyte disorders (e.g., hypocalcemia, hypokalemia,or hypomagnesemia), potential for torsades de pointes, congenital long QTsyndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age, or any concomitant medication known to prolong the QTinterval.

16. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving therapy.

17. History of significant neurological or psychiatric disorders including psychoticdisorders, dementia, or seizures that would prohibit the understanding and giving ofinformed consent.

18. Any condition that, in the opinion of the investigator, would interfere withevaluation of study treatment or interpretation of patient safety or study results (such as severe or uncontrolled systemic diseases, including uncontrolledhypertension or hypotension (BP <50mmHg), significant aneurysm, renal transplant andactive bleeding diseases).

19. Major surgical procedure (excluding placement of vascular access) or significanttraumatic injury within 4 weeks of the first dose of study intervention or ananticipated need for major surgery during the study.

20. Participation in another clinical study with a study intervention or investigationalmedicinal device administered in the 4 weeks prior to first dose of studyintervention or concurrent enrolment in another clinical study unless it is anobservational (non-interventional) clinical study or during the follow-up period ofan interventional study.