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

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies how well alpelisib works in treating participants with human papillomavirus(HPV)-associated stage I-IVA head and neck cancer that can be removed by surgery. Alpelisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To assess the preliminary efficacy of neoadjuvant Alpelisib (BYL719) in patients with transorally-resectable, HPV+ head and neck squamous cell carcinoma (HNSCC), as measured by quantitative change in tumor size (change in T) following 14-21 days of treatment. II. To evaluate the relationship between genomic PIK3CA activation to change in T. SECONDARY OBJECTIVES: I. To describe the tolerability of brief neoadjuvant exposure to BYL719. II. To assess the effect of BYL719 on the tumoral Ki-67 proliferation index. III. To evaluate viral and molecular mediators of response and resistance to BYL719, including viral messenger ribonucleic acid (mRNA), E6 and E7 oncoproteins, and phosphorylated (p)HER3. OUTLINE: Participants receive Alpelisib orally (PO) once daily (QD) for 14-21 days in the absence of disease progression of unacceptable toxicity and then undergo surgery. Participants may receive Alpelisib for up to 28 days if surgery is delayed. After completion of study treatment, participants are followed up for up to 12 weeks.

Official Title
-----------------
Biomarker Modulation by Alpelisib (BYL719) in Transorally Resectable, HPV-Associated HNSCC: A Phase II Window Trial

Conditions
-----------------
CDKN2A-p16 Positive, Human Papillomavirus Positive Oropharyngeal Squamous Cell Carcinoma, Stage I Oropharyngeal Squamous Cell Carcinoma AJCC v6 and v7, Stage II Oropharyngeal Squamous Cell Carcinoma AJCC v6 and v7, Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7, Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7

Intervention / Treatment
-----------------
* Drug: Alpelisib
* Other: Laboratory Biomarker Analysis
* Other: Pharmacodynamic Study
* Procedure: Therapeutic Conventional Surgery


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Cytologic or histologic diagnosis of oropharyngeal squamous cell carcinoma Clinical stage I-IVa p16+ oropharyngeal squamous cell carcinoma, based upon the American Joint Committee on Cancer (AJCC) staging manual, 7th edition No evidence of distant metastatic disease 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 University Advising and Career Center (UACC) and Tucson community sites, and may be conducted locally Appropriate and planned for primary transoral resection and/or neck dissection Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Clinically or radiologically measurable disease; the primary tumor and/or neck nodes may be measurable according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (tumor diameter ? 1 cm; short-axis lymph node diameter ? 1.5 cm) OR by caliper measurement (tumor diameter ? 1 cm) Absolute neutrophil count (ANC) ? 1,500/ul Creatinine ? 1.5 x institutional upper limit of normal (ULN) Bilirubin ? 1.5 x ULN Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ? 2.5 x ULN Ability to swallow and retain oral study medication, either as a whole tablet or a drinkable suspension Have signed written informed consent Exclusion Criteria: Subjects who fail to meet the above criteria Prior therapy for head and neck cancer is not allowed Poorly controlled diabetes mellitus Patients with type II diabetes who have either a fasting plasma glucose (FPG) of ? 140 or a hemoglobin A1C (HgBA1C) of ? 6.4 will be excluded; type 1 diabetic patients will also be excluded Patient has any of the following cardiac abnormalities: Symptomatic congestive heart failure History of documented congestive heart failure (New York Heart Association functional classification III-IV), documented cardiomyopathy Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) Myocardial infarction ? 6 months prior to enrollment Unstable angina pectoris Serious uncontrolled cardiac arrhythmia Symptomatic pericarditis Fridericia's corrected QT (QTcF) > 480 msec on the screening electrocardiogram (ECG) (using the QTcF formula) currently receiving treatment with medication that has a known risk to prolong the QT interval or inducing Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to starting treatment with BYL719 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 BYL719 (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 study medication as a whole tablet or a drinkable suspension, social/psychological complications 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 human chorionic gonadotropin (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: 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 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 Severe and/or uncontrolled medical conditions such as infection requiring systemic antibiotics or anti-fungals; chronic hepatitis; severely impaired lung function Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (Alpelisib)<br>Participants receive Alpelisib PO QD for 14-21 days in the absence of disease progression of unacceptable toxicity and then undergo surgery. Participants may receive Alpelisib for up to 28 days if surgery is delayed. | Drug: Alpelisib<br>* Given PO<br>* Other names: Phosphoinositide 3-kinase Inhibitor BYL719;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacodynamic Study<br>* Correlative studies<br>* Other names: PHARMACODYNAMIC;Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantitative change in the sum of Response Evaluation Criteria in Solid Tumors (RECIST) - measurable index lesions on paired, pre-and post-treatment computed tomography scans (delta change in T) |  | Baseline up to 3 years | 
| Difference in quantitative change in tumor size (change in T) in patients with genomic PIK3CA pathway alteration (PIK3CA mutation, amplification, and fluorescence in situ hybridization [FISH] for PTEN loss) | Will compare quantitative change in tumor size (change in T) in patients with genomic PIK3CA pathway alteration (PIK3CA mutation, amplification, and fluorescence in situ hybridization [FISH] for PTEN loss) versus no genomic activation. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Will be reported descriptively, including tabulation of toxicities according to National Cancer Institut (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4. | Up to 3 years | 
| Surgical complications |  | Up to 3 years | 
| Length of hospital stay |  | Up to 3 years | 
| Changes in pre- and post-treatment tumor levels of human papillomavirus (HPV) messenger ribonucleic acid (mRNA) (quantitative polymerase chain reaction [qPCR]) |  | Baseline up to 3 years | 
| Changes in pre- and post-treatment tumor levels of E6 and E7 oncoproteins |  | Baseline up to 3 years | 
| Changes in pre- and post-treatment tumor levels of Phospho - human epidermal growth factor receptor 3 (HER3) |  | Baseline up to 3 years | 
| Changes in pre- and post-treatment tumor levels of HER3/PI3K dimers (monogram) |  | Baseline up to 3 years |