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

Femara (Letrozole) Plus Ribociclib (LEE011) or Placebo as Neo-adjuvant Endocrine Therapy for Women With ER-positive, HER2-negative Early Breast Cancer

The purpose of this study is to determine if ribociclib in combination with letrozole for 24 weeks as neoadjuvant endocrine therapy increases the proportion of women with Pre-operative Endocrine Prognostic Index (PEPI) score of 0 at surgery compared to patients treated with letrozole alone therefore allowing more patients excellent outcomes without chemotherapy.

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