Inclusion Criteria:

- Adult women (≥ 18 years of age) with metastatic or locally advanced breast cancer not
amenable to curative treatment by surgery or radiotherapy

- Histological or cytological confirmation of estrogen-receptor positive (ER+) breast
cancer

- A representative tumor specimen must be available for molecular testing. An archival
tumor sample may be submitted; if one is not available, a newly obtained tumor
specimen must be submitted instead

- 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.

- Exception for Phase Ib patients: measurable disease is not required

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 CDK4/6 inhibitors, exemestane or mTOR inhibitors*.

- History of active or symptomatic brain or other CNS metastases.

- Impaired cardiac function or clinically significant cardiac diseases, including any
of the following:

- Left ventricular ejection fraction (LVEF) < 45% or less than the institution lower
limit of normal as determined by multiple gated acquisition scan (MUGA) or
echocardiogram (ECHO)

- Congenital long QT syndrome or family history of unexpected sudden cardiac death

- QT corrected with Fredericia's (QTcF) >470 ms for females on screening ECG

- Any other clinically significant heart disease such as angina pectoris, resting
bradycardia, left bundle branch block, ventricular tachyarrhythmia, unstable atrial
fibrillation, Right bundle branch block with left anterior hemiblock (bifascicular
block), acute myocardial infarction or any heart disease that requires the use of a
cardiac pacemaker or implantable cardioverter defibrillator ≤ 3 months prior to
starting study drug.

- Patients who are currently receiving treatment with agents that are known to cause
QTc prolongation in humans.

- Patients who are currently receiving treatment (within five days prior to
randomization) with agents that are metabolized predominantly through CYP3A4 and that
have a narrow therapeutic window. Agents that are known strong inducers or
inhibitors CYP3A4 are prohibited (Refer to Appendix 4) * Exceptions for Phase Ib
patients:

1. Patients who received more than two prior lines of chemotherapy are eligible

2. Patients who received CDK4/6 inhibitors, exemestane or mTOR inhibitors are
eligible