A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Phase 3 Study of Denosumab as Adjuvant Treatment for Women with Early-Stage Breast Cancer at High Risk of Recurrence (D-CARE)

INTERVENTION: Product Name: Denosumab Product Code: AMG 162 Pharmaceutical Form: Solution for injection INN or Proposed INN: Denosumab CAS Number: 615258‐40‐7 Current Sponsor code: AMG 162 Other descriptive name: ABX 1‐6 CHO OPG Ligand mAb IgG2; Human Monoclonal Antibody to RANKL Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 70‐ Pharmaceutical form of the placebo: Solution for injection Route of administration of the placebo: Subcutaneous use CONDITION: Adjuvant treatment for women with early‐stage breast cancer at high risk of disease recurrence receiving standard of care adjuvant/neoadjuvant cancer therapy ; MedDRA version: 12.1 Level: LLT Classification code 10006187 Term: Breast cancer PRIMARY OUTCOME: Main Objective: To compare the treatment effect of denosumab with that of placebo on prolonging bone metastasis‐free survival (BMFS) in subjects with early‐stage breast cancer at high risk of recurrence Primary end point(s): Bone metastasis‐free survival (BMFS) Secondary Objective: To compare the treatment effect of denosumab with that of placebo on:; • Disease‐free survival (DFS); • Overall survival (OS); • Distant recurrence‐free survival (DRFS); Safety Objectives; • To assess the safety and tolerability of denosumab compared with placebo INCLUSION CRITERIA: Disease related • Histologically confirmed, AJCC stage II or III breast cancer See Appendix E of protocol for breast cancer grading and staging information. • High risk of breast cancer recurrence, defined as documented evidence of one or more of the following criteria: ‐ Biopsy evidence of breast cancer in regional lymph node(s) (LN) (node‐positive disease) ‐ Tumor size > 5 cm or locally advanced disease (T4) See Appendix E of protocol for breast cancer grading and staging information. • Documented pathological evaluation of the breast cancer for hormone receptor(estrogen receptor [ER] and progesterone receptor [PR]) status and HER‐2 status • Subjects must be receiving or be scheduled to receive standard of care adjuvant or neoadjuvant chemotherapy and/or endocrine therapy and/or HER‐2 targeted therapy • For subjects receiving adjuvant therapy only: ‐ Subjects must have undergone complete resection o