BYL719 and Nab-Paclitaxel in Locally Recurrent or Metastatic HER-2 Negative Breast Cancer

Inclusion Criteria: 1. Ability to understand and the willingness to sign a written Informed Consent Form. 2. Age ≥ 18 years 3. Histologically proven HER-2 negative breast cancer (HER-2 negative defined as HER IHC 0 or 1+ and/or HER-2 FISH negative); HER-2 negative breast cancer includes hormone positive (ER and/or PR positive) breast cancer and TNBC 4. HER-2 negative breast cancer that at the time of study entry is either stage III (locally advanced) disease not amenable to curative therapy or stage IV disease. Histological confirmation of recurrent/metastatic disease is encouraged but not required if clinical evidence of stage IV disease is available 5. Have measurable (defined as at least one lesion that can be accurately measured in at least one dimension \[longest diameter to be recorded\] with minimum lesion size of ≥ 2 cm on conventional measurement techniques or ≥ 1 cm on spiral computed tomography (CT) scan 6. No limitations to number of prior chemotherapies for metastatic disease. Treatment with prior taxanes (except Nab-Paclitaxel) is allowed as long as it has been 6 months or more since exposure to prior taxane. NOTE: For subjects who are, or who have previously received endocrine therapy for breast cancer, the treating investigator will decide how many days should pass between the last dose of endocrine therapy and the first dose of study treatment. 7. All patients should have received at least one line of chemotherapy in either the advanced or adjuvant setting and hormonal therapy (where appropriate) 8. Performance status of 2 or better as per ECOG criteria (See Appendix A for details) 9. Subject is able to swallow and retain oral medicines 10. Adequate marrow and organ function as defined below (labs must be performed within 14 days of subject registration) * Absolute neutrophil count ≥ 1500/uL * Platelets 100,000/uL (no transfusion allowed within 2 weeks) * Hemoglobin \> 9 g/dL (which may be reached by transfusion) * Total bilirubin within normal range or ≤ 1.5X IULN if liver metastases are present or total bilirubin ≤ 3.0X IULN with direct bilirubin within normal range in subjects with well-documented Gilbert's Syndrome, which is defined as presence of unconjugated hyperbilirubinemia with normal results from CBC (including normal reticulocyte count and blood smear), normal liver function test results and absence of other contributing disease processes at the time of diagnosis * AST(SGOT)/ALT(SPGT) ≤ 2.5X IULN or ≤ 5X IULN if liver metastases are present * Serum creatinine ≤ 1.5X IULN * INR ≤ 1.5 * Fasting plasma glucose ≤ 140 mg/dL or 7.8 mmol/L (NOTE: Fasting whole blood glucose testing is acceptable if fasting plasma glucose is not feasible.) * HBA1c ≤ 8% * Potassium, calcium (corrected for serum albumin) and magnesium within IULN * Serum Amylase \< 2 x ULN and serum lipase within normal limits 11. IV bisphosphate and denosumab for bony metastatic disease will be allowed 12. Prior palliative radiation therapy to bony metastases is allowed. There should be a minimum of 14 days between the end of radiation treatment and start of study treatment 13. Subjects with previously treated brain metastases who are free of CNS symptoms and are \> 3 months from treatment of brain metastases are eligible Subjects should be \> 2 weeks from prior systemic chemotherapy for breast cancer AND should have recovered to Grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy prior to study entry NOTE: For subjects who are, or who have previously received endocrine therapy for breast cancer, the treating investigator will decide how many days should pass between the last dose of endocrine therapy and the first dose of study treatment. 14. Women of child bearing potential (WOCBP) and their partners must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. After confirmation of negative pregnancy test at screening, should a WOCBP become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician and the investigator immediately. * WOCBP are defined as any females (regardless of sexual orientation, having undergone tubal ligation, or remaining celibate by choice) who meet the following criteria: * Have not undergone a hysterectomy or bilateral oophorectomy OR * Have not been naturally postmenopausal for at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 consecutive months) Exclusion criteria: 1. Subject has any other medical or psychiatric disorder that, in the opinion of the treating physician, would contraindicate the use of drugs in this protocol or place the subject at undue risk for treatment complications 2. Subject is pregnant or lactating 3. Subject has previously been treated with Nab-Paclitaxel NOTE: Subjects who have had previous treatment with Nab-Paclitaxel will NOT be excluded if given in the adjuvant or neoadjuvant setting Only in the metastatic setting, will subjects previously treated with Nab-Paclitaxel be excluded from this trial. Exceptions may be made for subjects who discontinued treatment with a previous Nab-Paclitaxel inhibitor for reasons other than progression and as long as it has been \> 12 months since discontinuation of the previous Nab-Paclitaxel. This exception will require prior approval from the study PI at KUMC. 4. Subject has inflammatory breast cancer 5. Subject has a known hypersensitivity to any of the excipients of Nab-Paclitaxel or BYL719/alpelisib 6. Subject has a concurrent malignancy or malignancy within 3 years of study enrollment (with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer) 7. Subject has clinically manifest diabetes mellitus or documented steroid-induced diabetes mellitus 8. Subject has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) 9. Subject is classified into Child-Pugh class C 10. Subject has a known history of HIV infection (testing not mandatory) 11. Subject has active, uncontrolled infection 12. Subject has symptomatic/untreated CNS disease 13. Subject has ≥ Grade 2 peripheral neuropathy 14. Subject has active cardiac disease or a history of cardiac dysfunction including any of the following: * Unstable angina pectoris within 6 months prior to study entry * Symptomatic peritonitis * Documented myocardial infarction within 6 months prior to study entry * History of documented congestive heart failure (New York Heart Association functional classification III-IV) * Documented cardiomyopathy * Subject has a Left Ventricular Ejection Fraction (LVEF) \< 50% as determined by Multiple Gated Acquisition (MUGA) scan or echocardiogram (ECHO) * Subject has any of the following cardiac conduction abnormalities * Ventricular arrhythmias except for benign premature ventricular contractions * Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medicine * Conduction abnormality requiring a pacemaker * Other cardiac arrhythmia not controlled with medication 15. Subject has a QTcF \> 480 msec on the screening ECG (using the QTcF formula) 16. Subject is currently receiving treatment with a medication that has a known risk to prolong the QT interval or induce Torsades de Pointes and the treatment cannot be discontinued or switched to a different medication prior to randomization 17. Subject has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects 18. Subject is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug or who have not fully recovered from side effects of such treatment 19. Subject is currently receiving treatment with drugs known to be moderate or strong inhibitors or inducers of isoenzyme CYP3A. The subject must have discontinued strong inducers for at least one week and must have discontinued strong inhibitors before the start of treatment 20. Subject 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 21. Subject has received previous treatment with a PI3K inhibitor. Exceptions may be made for subjects who discontinued treatment with a previous PI3K inhibitor for reasons other than toxicity or progression and as long as it has been \> 12 months since discontinuation of the previous PI3K inhibitor. This exception will require prior approval from the study PI at KUMC. 22. Subjects who have received an investigational agent within 30 days OR within 5 half-lives of the investigational agent (whichever is shorter) prior to the possible enrollment date on this study. 23. Subject with history of acute within one year of study entry or past medical history of chronic pancreatitis.