Dose Escalation Study of LEE011 in Combination With Buparlisib and Letrozole in HR+, HER2-negative Post-menopausal Women With Advanced Breast Cancer.

• LEE011 (Drug): 3 weeks on and 1 week off
• Buparlisib (Drug): daily
• Letrozole (Drug): 2.5 mg daily;

Primary outcomes

• Incidence of dose-limiting toxicities (DLTs) [28 days]: Dose Escalation Phase: Frequency of DLTs at each dose level associated with administration of LEE011, buparlisib, and letrozole in a 28 day cycle
• Safety and tolerability of the combination of LEE011, buparlisib, and letrozole [approximately 25 months]: Dose Expansion Phase: Incidence of AEs, SAEs (overal and severity), laboratory abnormalities, ECG, vital, dose interteruptions, dose reductions, and dose intensity as a measure of safety and tolerability.

Secondary outcomes

• Safety and tolerabiity of the combination of LEE011, buparlisib, and letrozole [approximately 25 months]: Dose Escalation Phase: Incidence of AEs, SAEs (overall and severity), laboratory abnormalities, ECG, vital, dose interterruptions, dose reductions, and dose intensity as a measure of safety and tolerability.
• Pharmacokinetic paramters such as AUClast and Cmax of LEE011, buparlisib, and letrozole in order to characterize the PK profiles [approximately 25 months]: Dose Escalation Phase: When given in combination as well any other clinically significant metabolites that may be identified
• Pharmacokinetic paramters such as AUClast and Cmax of LEE011, buparlisib, and letrozole in order to characterize the PK profiles [approximately 25 months]: Dose Expansion Phase: When given in combination as well as any other clinically significant metabolites that may be identified
• Disease control rate [approximately 25 months]: Dose Expansion Phase: Proportion of patients with the best overall response of CR (complete response), PR (partial response), or SD (stable disease)
• PFS (progression free survival) [approximately 25 months]: Dose Expansion Phase: Time from date of start of treatment to date of first documented progression or death due to any cause.

Sex: Female, ages: 18 Years to any

Inclusion Criteria:

1. Women with advanced (recurrent or metastatic) breast cancer who received no prior therapy for advanced disease.
2. Patient is postmenopausal.
3. Patient may have received ≤ 2 lines of chemotherapy for metastatic or recurrent breast cancer in the dose-escalation phase.
4. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory.
5. Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an 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.
6. Patient must have either:

   * Measurable disease, i.e., at least one measurable lesion as per RECIST 1.1 criteria or at least one predominantly lytic bone lesion

Exclusion Criteria:

1. Patient who received any CDK4/6 or PI3K inhibitor.
2. Patient has active cardiac disease or a history of cardiac dysfunction including any of the following:

   * History of angina pectoris, symptomatic pericarditis, or myocardial infarction within 12 months prior to study entry
   * History of documented congestive heart failure (New York Heart Association functional classification III-IV)
   * Documented cardiomyopathy
   * Patient has a Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)
   * History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality in the previous 12 months.
   * On screening, any of the following cardiac parameters: bradycardia (heart rate < 50 at rest), tachycardia (heart rate > 90 at rest), PR interval > 220 msec, QRS interval >109 msec, or QTcF >450 msec.

   Systolic blood pressure >160 or <90 mmHg
3. Patient is currently receiving any of the following medications:

   * That are known strong inducers or inhibitors of CYP3A4.
   * That have a known risk to prolong the QT interval or induce Torsades de Pointes.
   * That have a narrow therapeutic window and are predominantly metabolized through CYP3A4.
4. Certain scores on an anxiety and depression mood questionnaires

• Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals