Alpelisib in Treating Participants With Transorally Resectable HPV-Associated Stage I-IVA Oropharyngeal Cancer

Inclusion Criteria: 1. Cytologic or histologic diagnosis of p16+ squamous cell carcinoma of oropharyngeal or unknown primary metastatic to the cervical met. 2. p16 positivity is defined as ≥70% of tumor cells demonstrating diffuse cytoplasmic and nuclear staining for p16 by immunohistochemistry in a CLIA certified pathology lab. 3. Clinical stage I-IVa p16+ oropharyngeal squamous cell carcinoma, based upon the AJCC staging manual, 7th edition. 4. No evidence of distant metastatic disease. 5. Appropriate candidate and planned for primary transoral resection and/or neck dissection. 6. ECOG performance status 0-1 at time of consent. 7. Clinically or radiologically measurable disease; the primary tumor and/or neck nodes may be measurable according to RECIST 1.1(tumor diameter ≥ 1 cm; short-axis lymph node diameter ≥ 1.5 cm) OR by caliper measurement (tumor diameter ≥ 1 cm). 8. Adequate hematologic, renal and hepatic function within 4 weeks of registration, as defined by: a) Absolute neutrophil count (ANC) ≥ 1,500/ul b) Creatinine ≤ 1.5 x institutional upper limit of normal (ULN). c) Bilirubin ≤ 1.5 x ULN, d) AST or ALT ≤ 2.5 x ULN. e) Fasting Serum amylase ≤ 2 × ULN f) Fasting Serum lipase ≤ ULN Note: A redraw is permitted within the 4 weeks for screening purposes. 9. Ability to swallow and retain oral study medication as a whole tablet 10. Have signed the written informed consent Exclusion Criteria: 1. Prior therapy for head and neck cancer is not allowed. 2. Established diagnosis of diabetes mellitus type I or not controlled type II. 3. Known hypersensitivity to alpelisib, or to any of the excipients of alpelisib. 4. Currently documented pneumonitis (Note: The chest CT scan performed at baseline for the purpose of tumor assessment should be reviewed to confirm that there are no relevant pulmonary complications present). 5. Any of the following cardiac abnormalities: 1. Symptomatic congestive heart failure within 12 months prior to the start of study treatment 2. History of documented congestive heart failure (New York Heart Association functional classification III-IV), documented cardiomyopathy 3. Left Ventricular Ejection Fraction (LVEF) \<50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO). 4. Myocardial infarction ≤ 6 months prior to start of study treatment 5. Unstable angina pectoris 6. Serious uncontrolled cardiac arrhythmia 7. History of angina pectoris, coronary artery bypass graft (CABG), symptomatic pericarditis prior to the start of study treatment 8. Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mmHg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without anti-hypertensive medication. (Initiation or adjustment of antihypertensive medication(s) is allowed during screening; hypertension must be controlled prior to administering the study drug.) QTcF \> 480 msec on the screening ECG (using the QTcF formula) 6. 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. 7. Currently receiving any of the following medications and cannot be discontinued at least 7 days prior to the start of the treatment: 1. Medications that have a known risk to prolong the QT interval or induce Torsade de Pointes (TdP) and the treatment cannot be discontinued or switched to a different medication prior to starting treatment with BYL719 (refer to list of prohibited QT prolonging drugs provided in in Appendix 3) 2. Herbal preparations/medications 8. Currently receiving treatment with drugs known to be moderate or strong inhibitors or inducers of isoenzyme CYP3A. The patient must have discontinued strong inducers for at least one week prior to the start of study treatment and must have discontinued strong inhibitors before the start of treatment. Switching to a different medication prior to randomization is allowed; (Refer to Appendix 2 and 3, Tables 1 and 2) for permitted and non-permitted medications). 9. History of acute pancreatitis within1 year of screening or past medical history of chronic pancreatitis 10. Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral BYL719 (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) 11. History of Stevens-Johnson-Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN). 12. Known positive serology for human immunodeficiency virus (HIV) 13. Any other condition, including severe and/or uncontrolled medical conditions, that would, in the Investigator's judgment, preclude patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g. infection/inflammation, intestinal obstruction, unable to swallow oral study medication as a whole tablet, social/psychological complications 14. Currently taking herbal preparations/medications and dietary supplements (except for vitamins) and unwilling to stop. 15. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (\> 5 mIU/mL) 16. Patient who does not apply highly effective contraception during the study and through the duration as defined below after the final dose of study treatment: 1. Sexually active males must use a condom during intercourse while taking BYL719 and for 1 week after the final dose of BYL719, and should not father a child in this period, but may be recommended to seek advice on conservation of sperm. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. 2. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during the study and through at least 1 week after the final dose of BYL719. Highly effective contraception is defined as either: i. Total abstinence: When this is in line with the preferred and usual lifestyle of the subject. \[Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception\]. ii. Female sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment iii. Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). \[For female study subjects, the vasectomized male partner should be the sole partner for that patient\] iv. Use a combination of the following (both 1+2): 1. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 2. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. 3. Note: Hormonal contraception methods (e.g. oral, injected, and implanted) are not allowed as BYL719 may decrease the effectiveness of hormonal contraceptives. NOTE: Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. 17\. Active systemic infection requiring systemic antibiotics or anti-fungals within 7 days prior to first dose of study drug. Note: Active topical infections (for example oral thrush) do not exclude a subject even if treated with systemic antibiotics or systemic antifungals. 18\. Chronic hepatitis 19\. Severely impaired lung function 20\. Unresolved osteonecrosis of the jaw 21\. Prisoners or individuals who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness.