Neoadjuvant Run-In Study With TAK-228 Followed by Letrozole/TAK-228 in Women With High-Risk ER+/HER2- Breast Cancer

Exclusion Criteria

• •1. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
• •2. Any other presurgical therapy for breast cancer.
• •3. Prior anti-estrogen therapy within the last 5 years.
• •4. Prior treatment with an mTOR, AKT, or PI3K inhibitor.
• •5. Treatment within the past two years with a bisphosphonate or a Rank ligand inhibitor.
• •6. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of TAK-228. In addition, subjects with enteric stomata are also excluded.
• •8. History of any of the following within the last 6 months prior to study entry:
• •1. Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures.
• •2. Ischemic cerebrovascular event, including TIA and artery revascularization procedures.
• •3. Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia).
• •4. Placement of a pacemaker for control of rhythm.
• •5. New York Heart Association (NYHA) Class III or IV heart failure (See Appendix B).
• •6. Pulmonary embolism.
• •9. Significant active cardiovascular or pulmonary disease at the time of study entry, including:
• •1. Uncontrolled high blood pressure (i.e., systolic blood pressure \>180 mm Hg, diastolic blood pressure \> 95 mm Hg)
• •2. Pulmonary hypertension
• •3. Uncontrolled asthma or O2 saturation \< 90% by ABG (Arterial Blood Gas) analysis or pulse oximetry on room air
• •4. Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement
• •5. Medically significant (symptomatic) bradycardia
• •6. History of arrhythmia requiring an implantable cardiac defibrillator
• •7. Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTc interval \> 480 milliseconds, or history of congenital long QT syndrome, or torsade de pointes) Confidential v03January2017 40
• •10. Treatment with strong CYP3A4 and CYP2C19 inhibitors and/or inducers must be discontinued at least 1 week before administration of the first dose of study drug.(see Appendix C)
• •11. Initiation of treatment with hematopoietic growth factors, transfusions of blood and blood products, or systemic corticosteroids (either IV or oral steroids, excluding inhalers) within 1 week before administration of the first dose of study drug (patients already receiving erythropoietin on a chronic basis for ≥ 4 weeks are eligible).
• •12. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise participation of the patient in the study.
• •13. Central nervous system (CNS) metastasis.
• •14. Known human immunodeficiency virus infection.
• •15. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.
• •16. Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug.
• •17. Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI within 7 days before receiving the first dose of study drug.