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