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

Inclusion Criteria

• Female patients 18 years or older.
• Have a diagnosis of metastatic TNBC previously treated with standard anthracycline, cyclophosphamide, and taxane chemotherapy, unless there was a contraindication to doxorubicin, in which case prior treatment with this agent is not required.
• Have not received more than 3 prior chemotherapy regimens for metastatic disease. Prior platinum and/or taxane therapy in the adjuvant or metastatic setting is permitted.
• Androgen receptor-negative (less than 10% positive nuclei) on standard IHC performed at the local pathology laboratory.
• Have locoregional (eg, breast, chest wall, regional lymphatic) or pulmonary or hepatic metastatic disease that is amenable to core needle biopsy.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (See Appendix I)
• Female patients who:
• Are postmenopausal for at least 1 year before the screening visit, OR
• Are surgically sterile, OR
• If they are of childbearing potential, agree to practice 1 effective methods of contraception and 1 additional effective (barrier) method, at the same time, from the time of signing the informed consent through 90 days (or longer as mandated by local labeling [eg, USPI, SmPC, etc,]) after the last dose of study drug, OR
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
• Screening clinical laboratory values as specified below:
• Bone marrow reserve consistent with: absolute neutrophil count (ANC) ≥ 1.5 x 10^9; platelet count ≥ 100 x 10^9; hemoglobin ≥ 9 g/dL without transfusion within 1 week preceding study drug administration
• Hepatic: total bilirubin ≤ 1.5 x upper limit of normal (ULN), transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase-AST/SGOT and alanine aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present);
• Renal: creatinine clearance ≥60 mL/min based either on cockroft-Gault estimate or based on urine collection (12 or 24 hour);
• Metabolic: Glycosylated hemoglobin (HbA1c) 180 mm Hg, diastolic blood pressure > 100 mm Hg). Use of anti-hypertensive agents to control hypertension before Cycle1 Day 1 is allowed.
• Pulmonary hypertension
• Need for supplemental oxygen
• Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement
• Medically significant (symptomatic) bradycardia
• History of arrhythmia requiring an implantable cardiac defibrillator
• 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)
• Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) > 7%; patients with a history of transient glucose intolerance due to corticosteroid administration may be enrolled in this study if all other inclusion/exclusion criteria are met.
• 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).
• 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.
• 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