Letrozole Plus Ribociclib or Placebo as Neo-adjuvant Therapy in ER-positive, HER2-negative Early Breast Cancer

Subjects will be randomized (1:1:1) to either letrozole plus placebo vs. letrozole plus continuous dosing of ribociclib vs. letrozole plus intermittent dosing (3-weeks-on/1-week-off) of ribociclib.

The difference in clinical, pathologic and radiologic response as well as Pre-operative Endocrine Prognostic Index (PEPI) scores across the three treatments arms will be examined. Subjects will also be followed for 5 years post-treatment to determine if ribociclib in combination with letrozole for 24 weeks results in improved 5 year Relapse Free Survival (RFS) compared to letrozole alone.

Key Inclusion Criteria:

• Pathologically confirmed invasive breast cancer by core needle biopsy
• Female subjects, age ≥ 18 years
• Only postmenopausal women will be eligible.
• Performance Status: Eastern Cooperative Oncology Group (ECOG) score 0-2
• Invasive breast cancer must be ER+ in ≥66 % of the cells or ER Allred score 6-8
• Invasive breast cancer must be HER2 negative.
• Clinical Stage II or III (by clinical measurement and/or breast imaging)

Key Exclusion Criteria:

• Subjects meeting any of the exclusion criteria at baseline will be excluded from study participation.
• Current use of other investigational agents
• Inflammatory breast cancer defined as clinically significant erythema of the breast and/or documented dermal lymphatic invasion (not direct skin invasion by tumor or peau d'orange without erythema)
• An excisional biopsy of this breast cancer
• Surgical axillary staging procedure prior to study entry
• Hormone replacement therapy of any type, megestrol acetate, or raloxifene within four weeks prior to first study treatment
• Clinical or radiographic evidence of metastatic disease
• Clinically significant, uncontrolled heart disease
• Herbal preparations/medications as listed in Appendix B of the protocol