Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of Hormone Receptor Positive HER2 Negative Advanced Breast Cancer

Inclusion Criteria:

* Adult women (≥ 18 years of age) with metastatic or locally advanced breast cancer
* Histological or cytological confirmation of ER+ breast cancer in dose escalation and HR+ breast cancer in dose expansion
* A representative tumor specimen must be available for molecular testing.
* Postmenopausal women. Postmenopausal status is defined either by:
* Age ≥ 18 with prior bilateral oophorectomy
* Age ≥ 60 years
* Age \<60 years with amenorrhea for at least 12 months and both follicle-stimulating hormone (FSH) and estradiol levels are in postmenopausal range (according to the local laboratory)
* Recurrence while on, or within 12 months of end of adjuvant treatment with letrozole or anastrozole, or
* Progression while on, or within one month of end of letrozole or anastrozole treatment for locally advanced or metastatic breast cancer.
* Patients must have:

  * Measurable disease\*: At least one lesion that can be accurately measured in at least one dimension ≥ 20 mm with conventional imaging techniques or ≥ 10 mm with spiral CT or MRI or
  * Bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable disease as defined above.
* ECOG Performance Status 0-1.
* Fasting serum cholesterol ≤ 300 mg/dl or 7.75 mmol/L and fasting triglycerides ≤ 2.5 × ULN. In case one or both of these thresholds are exceeded, the patient can only be included after initiation of statin therapy and when the above mentioned values have been achieved
* Standard 12-lead ECG values defined as the mean of the triplicate ECGs and assessed by the central laboratory.

  * QTcF interval at screening \< 450 msec (using Fridericia's correction).
  * Resting heart rate 50-90 bpm

Exclusion Criteria:

* HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive).
* Patients who received more than one chemotherapy line for advanced breast cancer.
* Previous treatment with exemestane or mTOR inhibitors\* (Note:

Patients with disease refractory to prior LEE011 are excluded for dose expansion Group 3 only).

* History of brain or other CNS metastases.
* Clinically significant, uncontrolled heart disease and/or recent cardiac repolarization abnormality including any of the following:
* History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry
* Documented cardiomyopathy
* Left ventricular ejection fraction (LVEF) \< 50% as determined by Multiple Gated acquisition scan (MUGA) or echocardiogram (ECHO)
* Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, and etc.
* Clinically significant cardiac arrhythmias, complete left bundle branch block, high-grade AV block
* Systolic Blood Pressure (SBP) \>160 or \<90 mmHg
* Patients who are currently receiving treatment with agents that are known to cause QTc prolongation in humans
* Patients who are currently receiving treatment (within 7 days prior to starting study treatment) with strong and moderate inhibitors or inducers of CYP3A4/5, substrates of CYP3A4/5 with a narrow therapeutic index or Herbal preparations/medications (Refer to Section 6.4 and Appendix 3)

Inclusion Criteria Exceptions for Phase Ib Dose Expansion patients:

Dose Expansion part of the study has 3 groups, following are the Inclusion Criteria exceptions for these 3 groups

1. Group 1 - Patients must not have received prior treatment with any CDK4/6 inhibitors
2. Group 2 - Patients must have disease progression while on or within one month after CDK4/6 inhibitor based therapy
3. Group 3 - Patients must have disease progression while on or within one month after CDK4/6 inhibitor based therapy (except those patients who received prior LEE011 based therapy).

Other protocol-defined Inclusion/Exclusion may apply.