TAK-228 and TAK-117 Followed by Cisplatin and Nab Paclitaxel for Metastatic Triple Negative Breast Cancer

Exclusion Criteria

• •1. Leptomeningeal disease that is symptomatic or cytology-proven.
• •2. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise the patient's participation in the study.
• •3. Known human immunodeficiency virus infection.
• •4. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.
• •5. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
• •6. Diagnosed or treated for another malignancy within 2 years before administration of the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
• •7. Breast feeding or pregnant.
• •8. Treatment with any investigational products within 30 days before the first dose of study drug
• •9. Previous treatment with PI3K, AKT, dual PI3K/mTOR inhibitors, TORC1/2 inhibitors or TORC1 inhibitors.
• •10. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of PIKTOR. In addition, patients with enteric stomata are also excluded.
• •11. History of any of the following within the last 6 months before administration of the first dose of the drug:
• •1. Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures
• •2. Ischemic cerebrovascular event, including transient ischemic attack 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 f. Pulmonary embolism
• •12. Significant active cardiovascular or pulmonary disease including:
• •1. Uncontrolled hypertension (ie, systolic blood pressure \>180 mm Hg, diastolic blood pressure \> 100 mm Hg). Use of anti-hypertensive agents to control hypertension before Cycle1 Day 1 is allowed.
• •2. Pulmonary hypertension
• •3. Need for supplemental oxygen
• •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) (eg, repeated demonstration of QTc interval \> 480 milliseconds, or history of congenital long QT syndrome, or torsades de pointes)
• •14. Treatment with strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4, CYP2C19 or CYP2C19 within 1 week preceding the first dose of study drug (See Appendix IV).
• •15. 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.
• •16. 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