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

A Phase 1 Dose Escalation Study of LEE011 in Combination With Buparlisib and Letrozole for the Treatment of HR+, HER2-negative Post-menopausal Women With Locally Advanced or Metastatic Breast Cancer.

This is a multi-center, open-label, non-randomized, phase I study

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