Alpelisib, Cetuximab, and Cisplatin in Treating Patients with HPV-Associated Oropharyngeal Cancer That Can Be Removed by Surgery

Inclusion Criteria

• Newly diagnosed, cytologically or histologically confirmed squamous cell carcinoma (and common variants, including poorly differentiated carcinoma; undifferentiated carcinoma; basaloid carcinoma) of the oropharynx; patients must have resectable oropharyngeal and nodal disease, including the following stages according to the American Joint Commission on Cancer Staging 7th edition: * T1N1-3 * T2N1-3 * T3N0-3 * T4aN0-3; note: eligible T4a tumors may include deep/extrinsic tongue muscle invasion and must be judged resectable by transoral laser microsurgery (TLM) or transoral robotic surgery (TORS), according to the surgeon-investigator; patients with T4a tumors with clear radiologic mandibular, hard palate or medial pterygoid invasion are not eligible
• Carcinoma must be HPV-associated, which is defined as positive for p16 protein by immunohistochemistry (IHC); p16 positivity is defined as >= 70% of tumor cells demonstrating diffuse cytoplasmic and nuclear staining for p16 by immunohistochemistry in a Clinical Laboratory Improvement Amendments (CLIA) certified pathology lab. p16 testing is standard at participating institutions and may be conducted locally
• No evidence of distant metastatic disease
• Patients must have a clinically measurable primary oropharyngeal tumor, defined as measuring >= 1 cm by spiral computed tomography (CT), per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, and/or by clinical examination
• No prior systemic chemotherapy, systemic biologic/molecular targeted therapy or radiation treatment for head and neck cancer
• Patients may have received chemotherapy or radiation for a previous, curatively treated non-HNSCC malignancy, provided at least 2 years have elapsed without evidence of recurrence
• Patients must be untreated with radiation above the clavicles
• Patients with a history of curatively-treated non-HNSCC malignancy must be disease-free for at least 2 years except for excised and cured: carcinoma-in-situ of breast or cervix; non-melanomatous skin cancer; T1-2, N0, M0 resected differentiated thyroid carcinoma; superficial bladder cancer; T1a or T1b prostate cancer comprising < 5% of resected tissue with normal prostate specific antigen (PSA) since resection
• Patient has signed the Informed Consent Form (ICF) prior to any screening procedures being performed and is able to comply with protocol requirements
• Patient has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) =< 1 that the investigator believes is stable at the time of screening
• Absolute Neutrophil Count (ANC) >= 1.5 x 10^9/L
• Platelets >= 100 x 10^9/L
• Hemoglobin >= 9.0 g/dL
• International normalized ratio (INR) =< 1.5
• Serum creatinine =< 1.5 x upper limit of normal (ULN)
• Creatinine Clearance >= 60 mg/mL as calculated by the modified Cockraft-Gault formula
• Total serum bilirubin =< 1.5 x ULN
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
• Fasting plasma glucose (FPG) =< 140mg/dL or =< 7.8 mmol/L
• Patient is able to swallow and retain oral medication

Exclusion Criteria

• Patient has a known hypersensitivity to any of the excipients of BYL719 (alpelisib)
• Patient has distant metastatic disease, including central nervous system (CNS) tumor involvement
• Patient with poorly controlled diabetes mellitus or documented steroid-induced diabetes mellitus (defined as FPG > 140 mg/dL or Hemoglobin A1C (HbA1C) > 7.8)
• Patient who has had systemic therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to study entry
• Prior systemic chemotherapy, molecularly targeted therapy, or radiation therapy for the current OPSCC diagnosis
• History of radiation to the head and neck (above the clavicles)
• Patient who has undergone major surgery =< 4 weeks prior to starting study treatment or who has not recovered from side effects of such procedure; note: core needle biopsy, diagnostic tonsillectomy or excisional lymph node biopsy do not constitute major surgery
• Patient has clinically significant cardiac disease or impaired cardiac function, such as: * Congestive heart failure (CHF) requiring treatment (New York Heart Association [NYHA] Grade >= 2), left ventricular ejection fraction (LVEF) < 50% as determined by multi-gated acquisition (MUGA) scan or echocardiogram (ECHO) * History or current evidence of clinically significant cardiac arrhythmias, atrial fibrillation and/or conduction abnormality, e.g. congenital long QT syndrome, high-grade/complete atrioventricular (AV)-blockage; patients with asymptomatic and rate-controlled atrial fibrillation are not excluded * Acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass graft (CABG), coronary angioplasty, or stenting), < 3 months prior to screening
• QT interval adjusted according to Fredericia (QTcF) > 480 msec on screening electrocardiogram (ECG)
• Patient who is currently receiving medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes (TdP) and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug treatment
• Patient who has participated in a prior investigational study within 30 days prior to enrollment
• Patient 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
• Patient is 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 and must have discontinued strong inhibitors before the start of treatment; switching to a different medication prior to randomization is allowed
• Patient with impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral alpelisib (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
• Patient with known positive serology for human immunodeficiency virus (HIV)
• Patient with any other condition 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 medication, social/psychological complications
• Pregnant or 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)
• 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: * Sexually active males should use a condom during intercourse while taking BYL719 and for 16 weeks 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; moreover, sexually active males should not father a child for 6 months after completion of radiation per standard clinical practice * 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 12 weeks after the final dose of BYL719; moreover, per standard clinical practice, women should not become pregnant for 12 months after completion of radiation; highly effective contraception is defined as either: ** 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] ** 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 ** 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] ** Use a combination of the following (both a+b): *** Placement of an intrauterine device (IUD) or intrauterine system (IUS) *** Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository *** Note: Hormonal contraception methods (e.g. oral, injected, and implanted) are not allowed as alpelisib 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
• Chronic treatment with corticosteroids or other immunosuppressive agents
• Grade >= 2 peripheral neuropathy
• Grade >= 2 sensorineural hearing loss