Alpelisib And Sacituzumab Govitecan For Treatment Of Breast Cancer

Inclusion criteria:

1. Ability of participant OR Legally Authorized Representative (LAR) to understand thisstudy, and participant or LAR willingness to sign a written informed consent

2. Males and females age ≥ 18 years

3. ECOG Performance Status 0 - 2 (See Appendix A)

4. Histologically proven HER2-negative breast cancer (per current ASCO-CAP guidelines);HER2-negative breast cancer includes hormone receptor-positive (estrogen receptorand/or progesterone receptor-positive) breast cancer and TNBC.

5. HER2-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 notrequired if clinical evidence of stage IV disease is available.

6. Have measurable or evaluable disease.

7. Ability to swallow and retain oral medicines.

8. No limitations to number of prior chemotherapies or endocrine therapies formetastatic disease.

9. All patients should have received at least one line of chemotherapy and at least oneline of hormonal therapy (where appropriate) in either the advanced or neo/adjuvantsetting. Patients who are candidates for anti-PD-1 and/or anti-PD-L1 therapy shouldhave received at least one line of anti-PD-1 and/or anti-PD-L1 therapy in either theadvanced or neo/adjuvant setting.

10. Prior palliative radiation therapy to bony metastases is allowed. A minimum of 14days between the end of radiation treatment and start of study treatment isrequired.

11. Participants with previously treated brain metastases must be free of centralnervous system symptoms and be >21 days from treatment of brain metastases. CNSbrain metastasis should be clinically stable at the time of screening, andparticipant is not receiving steroids and/or enzyme inducing anti-epilepticmedications for brain metastases.

12. Participants must be >2 weeks or 5 half-lives (whichever is longer) from priorsystemic chemotherapy for breast cancer AND should have recovered to Grade 1 orbetter (except alopecia and neuropathy) from related side effects of any priorantineoplastic therapy prior to study entry.

13. Women of childbearing potential must have a negative serum pregnancy test 24 hoursprior to initiating treatment.

14. Women of child-bearing potential and men with partners of child-bearing potentialmust agree to practice sexual abstinence or to use approved forms of contraceptionfor the duration of study participation and for 6 months following completion oftherapy.

15. Fasting plasma glucose ≤140 mg/dL or ≤7.8 mmol/L

16. HbA1c ≤6.4%

17. Absolute neutrophil count ≥ 1500/uL NOTE: Patients with established diagnosis ofbenign neutropenia are eligible to participate with ANC between 1000-1500 if in theopinion of treating physician the trial treatment does not pose excessive risk ofinfection to the patient.

18. Platelets ≥ 100,000/uL (no transfusion allowed within 2 weeks)

19. Hemoglobin > 9 g/dL (which may be reached by transfusion)

20. Total bilirubin within normal range or ≤ 1.5x institutional upper limit of normal (IULN) if liver metastases are present, or total bilirubin ≤ 3.0x IULN with directbilirubin within normal range in patients with well-documented Gilbert's Syndrome,which is defined as presence of unconjugated hyperbilirubinemia with normal resultsfrom CBC (including normal reticulocyte count and blood smear), normal liverfunction test results and absence of other contributing disease processes at thetime of diagnosis.

21. AST(SGOT)/ALT(SPGT) ≤ 2.5x IULN or ≤ 5x IULN if liver metastases are present

22. Serum creatinine ≤ 1.5x IULN

23. Creatinine clearance ≥ 35 mL/min using Cockcroft-Gault formula

24. Potassium within institutional normal limits

25. Magnesium within institutional normal limits

26. Calcium (corrected for serum albumin) within institutional normal limits or ≤grade 1according to NCI-CTCAE version 4.03 if judged clinically not significant by theinvestigator

27. Serum amylase ≤ 2x IULN

28. Serum lipase within institutional normal limits

29. Albumin ≥ 2.5 g/dL

Exclusion criteria:

1. Simultaneously enrolled in any therapeutic clinical trial

2. Current or anticipating use of other anti-neoplastic or investigational agents whileparticipating in this study

3. Diagnosed with a psychiatric illness or is in a social situation that would limitcompliance with study requirements

4. Is pregnant or breastfeeding

5. Has a known allergic reaction to any excipient contained in the study drugformulation Active Grade 3 (per the NCI CTCAE, Version 5.0) or higher viral,bacterial, or fungal infection within 2 weeks prior to the first dose of studytreatment.

6. Patient has previously been treated with sacituzumab govitecan or alpelisib.

7. Patient 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).

8. Diabetes mellitus type I, or uncontrolled type II based on fasting plasma glucoseand HbA1c meeting either of the following:

• Fasting plasma glucose >140 mg/dL or >7.8 mmol/L

• HbA1c ≥6.5% Note: For patients with fasting plasma glucose ≥ 100 mg/dL and/orHbA1c ≥5.7% (i.e. threshold for pre-diabetes) at baseline, lifestyle changesaccording to American Diabetes Association guidelines were recommended

9. Patient has impairment of gastrointestinal (GI) function or GI disease that maysignificantly alter the absorption of the study drugs (e.g. ulcerative diseases,uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowelresection).

10. Patient is classified into Child-Pugh class B or C.

11. Patient has a known history of HIV infection (testing not mandatory).

12. Patient has active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV). In patientswith a history of HBV or HCV, patients with a detectable viral load will beexcluded.

13. Patient has symptomatic/untreated CNS disease.

14. Patient has active cardiac disease or a history of cardiac dysfunction including anyof the following:

• Uncontrolled hypertension defined by a systolic blood pressure (SBP) ≥ 160 mmHgand/or diastolic blood pressure (DBP) ≥ 100 mm Hg, with or withoutanti-hypertensive medication. Initiation or adjustment of antihypertensivemedication(s) is allowed prior to screening.

• Unstable angina pectoris within 6 months prior to study entry

• Symptomatic pericarditis

• Documented myocardial infarction within 6 months prior to study entry

• Coronary artery bypass graft within 6 months prior to study entry

• History of documented congestive heart failure (New York Heart Associationfunctional classification III-IV)

• Documented cardiomyopathy

• Patient has a left ventricular ejection fraction (LVEF) < 50% as determined bymultiple gated acquisition (MUGA) scan or echocardiogram (ECHO)

• Patient has any of the following cardiac conduction abnormalities:

• Ventricular arrhythmias, except for benign premature ventricularcontractions

• Supraventricular and nodal arrhythmias requiring a pacemaker or notcontrolled with medicine

• Conduction abnormality requiring a pacemaker

• Other cardiac arrhythmia not controlled with medication

15. Patient has a QTcF > 470 msec if female and >450 msec if male on the screening ECG (using the QTcF formula).

16. Patient is currently receiving treatment with a medication that has a known risk toprolong the QT interval or induce Torsades de Pointes and the treatment cannot bediscontinued or switched to a different medication prior to start of study drug.

17. Patient has had major surgery within 14 days prior to starting study drug or has notrecovered from major side effects.

18. Participant has received palliative radiation therapy ≤ 2 weeks prior to startingstudy drug, or has not recovered to grade 1 or better from related side effects ofsuch therapy (with the exception of alopecia).

19. Patient is currently receiving or has received high-dose systemic corticosteroids (≥20mg of prednisone or its equivalent) ≤ 2 weeks prior to starting study drug orhas not fully recovered from side effects of such treatment. Note: The following uses of corticosteroids are permitted: single doses, topicalapplications (e.g., for rash), inhaled sprays (e.g., for obstructive airwaysdiseases), eye drops or local injections (e.g., intra-articular).

20. Patient is currently receiving treatment with drugs known to be moderate or stronginhibitors or inducers of isoenzyme CYP3A. The patient must have discontinued stronginducers for at least one week before the start of treatment.

21. Patient is currently receiving treatment with inhibitor(s) of BCRP (see Appendix B,table with heading Prohibited BRCP inhibitors). The patient must have discontinuedBCRP inhibitors for at least one week before the start of treatment.

22. Patient is currently receiving warfarin or other coumarin-derived anti-coagulant fortreatment, prophylaxis or otherwise.

23. Patient has received previous treatment with a PI3K inhibitor or AKT inhibitor

24. Patient has a history of acute (within one year of study entry) pancreatitis or pastmedical history of chronic pancreatitis.

25. Patient has pneumonitis or interstitial lung disease.

26. Patient has unresolved osteonecrosis of the jaw.

27. Patient has inflammatory breast cancer.

28. Patient has a history of severe cutaneous reactions, such as Steven-Johnson Syndrome (SJS), erythema multiforme (EM), toxic epidermal necrolysis (TEM), or drug reactionwith eosinophilia and systemic syndrome (DRESS).

29. Patient has any other concurrent severe and/or uncontrolled medical condition thatwould, in the investigator's judgment, contraindicate patient participation in theclinical study (including, but not limited to: severe immune disease, certaindegenerative diseases, certain other acute or chronic concurrent illnesses).