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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Letrozole
* Drug: Ribociclib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Placebo + Letrozole<br>Placebo randomized to 3 capsules/day 3 weeks on/1week off or 2 capsules/day continuous dosing + Letrozole 2.5 mg PO daily | Drug: Letrozole<br>* Nonsteroidal aromatase inhibitor<br>* Other names: LTZ;Drug: Placebo<br>* Placebo for ribociclib<br>|
| Experimental: Ribociclib 600 mg + Letrozole<br>Ribociclib 600 mg PO daily 21 days on/7 days off + Letrozole 2.5 mg PO daily | Drug: Letrozole<br>* Nonsteroidal aromatase inhibitor<br>* Other names: LTZ;Drug: Ribociclib<br>* Oral cyclin-dependent kinase (CDK) inhibitor<br>* Other names: LEE-011;|
| Experimental: Ribociclib 400 mg + Letrozole<br>Ribociclib 400 mg continuous daily dosing + Letrozole 2.5 mg PO daily | Drug: Letrozole<br>* Nonsteroidal aromatase inhibitor<br>* Other names: LTZ;Drug: Ribociclib<br>* Oral cyclin-dependent kinase (CDK) inhibitor<br>* Other names: LEE-011;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Pre-operative Endocrine Prognostic Index (PEPI) score 0 at surgery between ribociclib containing arms (combined) vs letrozole alone arm |  | At Surgery (22 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of complete cell cycle arrest at 2 weeks between ribociclib containing arms (combined) vs letrozole alone arm: Complete cell cycle arrest is defined as Ki67 at day 14 of < 2.7% |  | Day 14 of Cycle 1 | 
| Pathologic complete response rate (pCR rate): pCR rate is defined as the proportion of patients with no histologic evidence of invasive tumor cells in the surgical breast specimen and the axillary lymph nodes |  | At Surgery (Days 8-15 of Cycle 6) | 
| Clinical complete response rate (cCR rate): cCR rate is defined as the proportion of patients with no residual tumor by clinical exam |  | Post-surgery (Once in the first 4 weeks of post-op, then once every 6 months for 5 years post-op) | 
| 5 Year Relapse Free Survival (RFS) |  | 5 years post-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ER+, HER2-negative breast cancer, Stage II or III, Letrozole, Femara, Ribociclib, LEE011, Neo-adjuvant