Study of Efficacy and Safety of LEE011 in Men and Postmenopausal Women With Advanced Breast Cancer. (MONALEESA-3)

• Overall Survival (OS) [ Time Frame: Up to approximately 58 months ]
  Time from date of randomization to the date of death from any cause.
• Progression Free Survival (PFS) per Blinded Independant Review Committee (BICR) [ Time Frame: Up to approximately 26 months ]
  The primary endpoint of the study is PFS, defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS will be assessed via a BICR according to RECIST 1.1
• Overall response rate (ORR) [ Time Frame: Up to approximately 26 months ]
  Overall response rate (ORR) is defined as the proportion of patients with the best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1.
• Time to definitive deterioration of ECOG performance status in one category of the score [ Time Frame: Up to approximately 26 months ]
  Time to definitive deterioration of ECOG performance status in one category of score is defined as the time from the date of randomization to the date of event, which is defined as at least one score lower than the baseline.
• Safety will be determined by type, frequency and severity of adverse events per CTCAE version 4.03 and type, frequency and severity of laboratory toxicities per CTCAE version 4.03. [ Time Frame: Up to approximately 26 months ]
  Safety will be determined by type, frequency and severity of adverse events per CTCAE version 4.03 and type, frequency and severity of laboratory toxicities per CTCAE version 4.03.
• Time to definitive 10% deterioration in the global health status/quality of life (QOL) scale score of the EORTC QLQ-C30 [ Time Frame: Up to approximately 26 months ]
  The time to definitive 10% deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10% relative to baseline worsening of the corresponding scale score (without further improvement above the threshold) or death due to any cause.
• Change from baseline in the global health status/QoL scale score of the EORTC QLQ-C30 [ Time Frame: Up to approximately 26 months ]
  Change from baseline in the domain scores, health states, overall health status, and index values at the time of each assessment will be summarized.
• Clinical benefit ratio (CBR) [ Time Frame: Up to approximately 26 months ]
  Clinical benefit rate (CBR), defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) or stable disease (SD) lasting 24 weeks or longer as defined in RECIST 1.1
• Time to response (TTR) [ Time Frame: Up to approximately 26 months ]
  Time from randomization to the first documented and confirmed response (complete response or partial response) as defined by RECIST 1.1
• Duration of response (DOR) [ Time Frame: Up to approximately 26 months ]
  Time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer as defined in RECIST 1.1

• Overall Survival (OS) [ Time Frame: Up to approximately 58 months ]
  Time from date of randomization to the date of death from any cause.
• Progression Free Survival (PFS) per Blinded Independant Review Committee (BICR) [ Time Frame: Up to approximately 26 months ]
  The primary endpoint of the study is PFS, defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS will be assessed via a BICR according to RECIST 1.1
• Overall response rate (ORR) [ Time Frame: Up to approximately 26 months ]
  Overall response rate (ORR) is defined as the proportion of patients with the best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1.
• Time to definitive deterioration of ECOG performance status in one category of the score [ Time Frame: Up to approximately 26 months ]
  Time to definitive deterioration of ECOG performance status in one category of score is defined as the time from the date of randomization to the date of event, which is defined as at least one score lower than the baseline.
• Safety will be determined by type, frequency and severity of adverse events per CTCAE version 4.03 and type, frequency and severity of laboratory toxicities per CTCAE version 4.03. [ Time Frame: Up to approximately 26 months ]
  Safety will be determined by type, frequency and severity of adverse events per CTCAE version 4.03 and type, frequency and severity of laboratory toxicities per CTCAE version 4.03.
• Time to definitive 10% deterioration in the global health status/quality of life (QOL) scale score of the EORTC QLQ-C30 [ Time Frame: Up to approximately 26 months ]
  The time to definitive 10% deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10% relative to baseline worsening of the corresponding scale score (without further improvement above the threshold) or death due to any cause.
• Change from baseline in the global health status/QoL scale score of the EORTC QLQ-C30 [ Time Frame: Up to approximately 26 months ]
  Change from baseline in the domain scores, health states, overall health status, and index values at the time of each assessment will be summarized.
• Clinical benefit ratio (CBR) [ Time Frame: Up to approximately 26 months ]
  Clinical benefit rate (CBR), defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) or stable disease (SD) lasting 24 weeks or longer as defined in RECIST 1.1
• Time to response (TTR) [ Time Frame: Up to approximately 26 months ]
  Time from randomization to the first documented and confirmed response (complete response or partial response as defined by RECIST 1.1
• Duration of response (DOR) [ Time Frame: Up to approximately 26 months ]
  Time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer as defined in RECIST 1.1

• Breast Neoplasms
• Breast Diseases
• Neoplasms
• Neoplasms by Site
• Fulvestrant
• Antineoplastic Agents
• Antineoplastic Agents, Hormonal
• Estrogen Receptor Antagonists
• Hormone Antagonists
• Hormones, Hormone Substitutes, and Hormone Antagonists
• Molecular Mechanisms of Pharmacological Action
• Pharmacologic Actions
• Therapeutic Use

• Drug: Ribociclib
  Riblociclib 600mg daily oral (days 1 to 21 in a 28-day Cycle)
  Other Name: LEE011
• Drug: fulvestrant
  Fulvestrant 500mg i.m. injections every 28 days (Cycle n Day 1) with 1 additional dose on Day 15 of Cycle 1
  Other Name: Faslodex
• Drug: Ribociclib placebo
  Riblociclib placebo 600mg daily oral (days 1 to 21 in a 28-day Cycle)
  Other Name: LEE011 placebo

• Experimental: Ribociclib + fulvestrant
  Riblociclib 600mg daily oral (days 1 to 21 in a 28-day Cycle) in combination with fulvestrant 500mg i.m. injections every 28 days (Cycle n Day 1) with 1 additional dose on Day 15 of Cycle 1
  Interventions:

  • Drug: Ribociclib
  • Drug: fulvestrant
• Placebo Comparator: Ribociclib placebo + fulvestrant
  Riblociclib placebo 600mg daily oral (days 1 to 21 in a 28-day Cycle) in combination with fulvestrant 500mg i.m. injections every 28 days (Cycle n Day 1) with 1 additional dose on Day 15 of Cycle 1
  Interventions:

  • Drug: fulvestrant
  • Drug: Ribociclib placebo

Inclusion Criteria:

1. Patient is an adult male/female ≥ 18 years old at the time of informed consent and has signed informed consent before any trial related activities and according to local guidelines. Female patients must be postmenopausal.
2. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory and has HER2-negative breast cancer.
3. Patient must have either measurable disease by RECIST 1.1 or at least one predominantly lytic bone lesion.

4. Patient has advanced (loco regionally recurrent not amenable to curative therapy, e.g. surgery and/or radiotherapy, or metastatic) breast cancer.

   Patients may be:

   • newly diagnosed advanced/metastatic breast cancer, treatment naïve
   • relapsed with documented evidence of relapse more than 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for advanced/metastatic disease
   • relapsed with documented evidence of relapse on or within 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for advanced/metastatic disease
   • relapsed with documented evidence of relapse more than 12 months from completion of adjuvant endocrine therapy and then subsequently progressed with documented evidence of progression after one line of endocrine therapy (with either an antiestrogen or an aromatase inhibitor) for advanced/metastatic disease
   • newly diagnosed advanced/metastatic breast cancer at diagnosis that progressed with documented evidence of progression after one line of endocrine therapy (with either an antiestrogen or an aromatase inhibitor)
5. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
6. Patient has adequate bone marrow and organ function

Exclusion Criteria:

1. Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's best judgment.
2. Patient has received prior treatment with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy), fulvestrant or any CDK4/6 inhibitor.
3. Patient with inflammatory breast cancer at screening .
4. Patient with CNS involvement unless they are at least 4 weeks from prior therapy completion to starting the study treatment and have stable CNS tumor at the time of screening and not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases
5. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality

6. Patient is currently receiving any of the following substances and cannot be discontinued 7 days prior to start the treatment:

   • Known strong inducers or inhibitors of CYP3A4/5,
   • That have a known risk to prolong the QT interval or induce Torsades de Pointes.
   • Those have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
   • Herbal preparations/medications, dietary supplements.