A Phase Ib Dose De-escalation Study With BYL719 in Premenopausal Patients With Locally Advanced or Metastatic Breast Cancer

Exclusion Criteria

• •Patient is post-menopausal.
• •Patient has received previous endocrine treatments in the metastatic setting.
• •Patient has received previous treatment with PI3K inhibitors, AKT inhibitors, mTOR inhibitors
• •Patient has received more than one chemotherapy line for metastatic disease
• •Patient has symptomatic CNS metastases
• •Patient who has received wide field radiotherapy ≦ 4 weeks or limited field radiation for palliation ≦ 2 weeks prior to starting study drug or who have not recovered to grade 1 or better from related side effects of such therapy (with exception of alopecia alopecia)
• •Patient has not recovered to grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy
• •Patient is currently receiving increasing or chronic treatment (\> 5 days) with corticosteroids or another immunosuppressive agent, as chronic administration of corticosteroids (\> 5 days) can induce CYP3A4
• •Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed
• •Patient is currently receiving treatment with drugs known to be moderate or strong inhibitors or inducers of isoenzyme CYP3A. The patient must have discontinued strong inducers for at least one week and must have discontinued strong inhibitors before the treatment phase is initiated.
• •Patient has a score ≧ 12 on the PHQ-9 questionnaire
• •Patient selects a response of "1, 2 or 3" to question number 9 on the PHQ-9 questionnaire regarding potential for suicidal thoughts or ideation (independent of the total score of the PHQ-9)
• •Patient has a GAD-7 mood scale score ≧ 15
• •Patient has ≧ Common Terminology Criteria for Adverse Events (CTCAE) grade 3 anxiety
• •Patient has active cardiac disease or a history of cardiac dysfunction
• •Patient has a Left Ventricular Ejection Fraction (LVEF) \< 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)
• •Patient has any of the following cardiac conduction abnormalities
• •1. Ventricular arrhythmias except for benign premature ventricular contractions
• •2. Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication
• •3. Conduction abnormality requiring a pacemaker
• •4. Other cardiac arrhythmia not controlled with medication
• •5. Patient has a QTcF \> 480 msec on the screening ECG (using the QTcF formula)
• •Patient is currently receiving treatment with medication that has a known risk to prolong the QT interval or inducing Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to treatment start.
• •Patient has chronic pulmonary disease including dyspnea at rest from any cause or with interstitial lung disease.