Phase IIIb Study of Ribociclib + ET in Early Breast Cancer

The study consists of Screening, Treatment, and Follow-up periods.

* Treatment Period: all participants who complete screening will receive ribociclib 400 mg orally once daily on days 1 to 21 of a 28-day cycle, in combination with daily ET for 36 months (approximately 39 cycles) from the date of first dose. The Treatment Period starts when the patient receives their first dose of ribociclib and ends at the time of the 30-day Safety Follow-up. All treated participants should have a Safety Follow-up call conducted 30 days after the last dose of study treatment.
* Follow-up period: participants will be followed from 30 days after study treatment (i.e., ribociclib) completion/discontinuation (i.e. 30-day Safety Follow-up) until death, withdrawal of consent, lost to follow-up, or until 48 months after the last participant has received their first dose of study treatment (i.e. End of Study \[EOS\]), whichever occurs first.

• Ribociclib (Drug), also known as LEE011: Ribociclib 400 mg orally once daily on days 1-21 of a 28 day cycle followed by 7 days rest
• Letrozole (Drug): Letrozole 2.5 mg orally once daily continuously
• Ansastrozole (Drug): Anastrozole 1 mg orally once daily continuously.
• Goserelin (Drug): Goserelin administered subcutaneously at 3.6 mg once every 4 weeks if the one-month depot formulation is used or at 10.8 mg once every 3 months if the three-month depot formulation is used
• Leuprolide (Drug): Leuprolide administered subcutaneously at 3.75 mg once every 4 weeks if the one-month depot formulation is used or at 11.25 mg once every 3 months if the three-month depot formulation is used
• Exemestane (Drug): Exemestane 25 mg once daily continuously

Primary outcomes

• Invasive Breast Cancer Free Survival (iBCFS) rate at 3 years [At 3 years]: iBCFS is defined as the time from the date of first dose to the date of the first event of invasive ipsilateral breast tumor recurrence, local/regional invasive recurrence, distant recurrence, death (any cause), or contralateral invasive BC. iBCFS will be assessed using STEEP criteria version 2.0 (Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials), as assessed by Investigator. The iBCFS rate at 3 years will be assessed.

Secondary outcomes

• Incidence and severity of adverse events (AEs) using CTCAE v4.03 [Up to approximately 6 years]: To evaluate Safety of ribociclib + ET
• Invasive Disease-Free Survival (iDFS) [Up to approximately 6 years]: iDFS is defined as the time from the date of first dose of study treatment to the date of the first event of invasive ipsilateral breast tumor recurrence, local/regional invasive recurrence, distant recurrence, death (any cause), contralateral invasive BC, or second primary non-breast invasive cancer (excluding basal and squamous cell carcinomas of the skin). iDFS will be assessed using STEEP 2.0 as assessed by the investigator.
• Distant Disease-Free Survival (DDFS) [Up to approximately 6 years]: Distant Disease-Free Survival (DDFS) is defined as the time from the date of first dose of study treatment to the date of the first event of recurrence at a distant site, death (any cause), or second primary non-breast invasive cancer (excluding in situ/non-invasive cancers and basal and squamous cell carcinomas of the skin). DDFS will be assessed using STEEP 2.0 as assessed by the investigator.
• Distant Relapse-Free Survival (DRFS) [Up to approximately 6 years]: Distant Relapse Free Survival (DRFS) is defined as the time from the date of first dose of study treatment to the date of the first event of recurrence at a distant site or death (any cause). DRFS will be assessed using STEEP 2.0 as assessed by the investigator.
• Recurrence-Free Interval (RFI) [Up to approximately 6 years]: RFI is defined as the time from date of first dose to date of first event of invasive recurrence in the ipsilateral breast or locoregionally, at a distant site, or death from breast cancer. RFI will be assessed using STEEP 2.0 as per investigator assessment.
• Relative dose intensity (RDI) of ribociclib [Up to 3 years]: RDI is defined as the ratio of the dose intensity delivered to the planned dose intensity.
• Overall Survival (OS) [Up to approximately 6 years]: OS is defined as time from the start of study treatment to date of death due to any cause.
• Time To Discontinuation (TTD) of ribociclib [Up to 3 years]: TTD is defined as the time from starting ribociclib to the time to treatment discontinuation due to any cause.
• Changes from baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) score [Up to approximately 6 years]: The FACT-B is a questionnaire that consists of 37 items with items from FACT-General (FACT-G) questionnaire (27 items) and from the Breast Cancer Subscale (BCS, 10 items). FACT-B consists of five subscales that address different aspects of the participant's quality of life: physical well-being (PWB), social/family well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and BCS.
• Changes from baseline in Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES) score [Up to approximately 6 years]: The FACT-ES is a questionnaire that consists of 19 items which assesses endocrine complaints and adverse events.
• Changes from baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) score [Up to approximately 6 years]: The FACIT-F is a 13-item questionnaire designed to assess self-reported fatigue and its impact on daily activities and functions.
• Changes from baseline in European Quality of Life-5 Dimensions (EQ-5D-5L) score [Up to approximately 6 years]: EQ-5D-5L is a standardized participant completed questionnaire that measures health-related quality of life and translates that score into an index value or utility score. EQ-5D-5L consists of two components: a health state profile and an optional visual analogue scale (VAS). EQ-5D-5L health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression.
• Changes from baseline in Work Productivity and Activity Impairment Questionnaire (WPAI-GH) score [Up to approximately 6 years]: WPAI-GH measures the impact of health problems on the participant's productivity, in paid or unpaid activities, in the last 7 days. It is 6-item scale measuring absenteeism, presenteeism, and impairments in unpaid activity.

Sex: All, ages: 18 Years to 100 Years

Key Inclusion criteria:

* Participant is an adult, male or female ≥ 18 years of age at the time of informed consent form signature (IC).
* Participant has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer (BC) based on the most recently analyzed tissue sample tested by a local laboratory prior to enrollment.
* Participant has HER2- BC defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing based on the most recently analyzed tissue sample.
* Participants may have already received any standard neoadjuvant and/or adjuvant ET, including tamoxifen or toremifene at the time of informed consent signature, but enrollment should occur within 36 months of prior ET start date and participants should have at least 3 years remaining of endocrine adjuvant therapy.
* For participants with prior ET treatment > 12 months, restaging is highly recommended (unless contradictory to local regulations) to rule out disease recurrence prior to enrollment.
* The number of participants with prior ET between 12 and 36 months will be capped at 30%. The cap will not apply to Black or African American participants.
* Participant has no contraindication to receive adjuvant ET in the study.
* Participant after surgical resection where tumor was removed completely, with the final surgical specimen microscopic margins free from tumor, and belongs to one of the following categories:

  * Anatomic Stage Group III, or
  * Anatomic Stage Group IIB, or
  * A subset of Anatomic Stage Group IIA.
* Participant has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2.
* Participant has adequate bone marrow and organ function.
* ECG values assessed by KardiaMobile-6L device, or standard 12-lead ECG per local investigator where KardiaMobile-6L cannot be used, as:

  * QTcF interval at Screening < 450 msec (QT interval using Fridericia's correction).
  * Mean resting heart rate 50-99 beats per minute (determined from the ECG).

Key Exclusion criteria:

* Participant with distant metastases of BC beyond regional lymph nodes (Stage IV according to AJCC 8th edition) and/or evidence of recurrence after curative surgery.
* Participant is concurrently using other antineoplastic therapy with the exception of adjuvant ET.
* Participant has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator's judgment, cause unacceptable safety risks, contraindicate participant participation in the clinical study or compromise compliance with the protocol, or limit life expectancy to ≤5 years.
* Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality.
* Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breast-feed during the trial.
* Women of child-bearing potential (CBP), defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 21 days after stopping the treatment.

Other inclusion/exclusion criteria may apply

129 more sites not listed.

• Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals