Biomarker Modulation by Alpelisib (BYL719) in Transorally Resectable, HPV-Associated HNSCC: A Phase II Window Trial
Phase: PHASE2
Conditions: CDKN2A-p16 Positive, HPV Positive Oropharyngeal Squamous Cell Carcinoma, Stage I Oropharyngeal Squamous Cell Carcinoma AJCC V7, Stage II Oropharyngeal Squamous Cell Carcinoma AJCC V7, Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7, Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7
Sponsor: University of Arizona

 
 
 
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Biomarker Modulation by Alpelisib (BYL719) in Transorally Resectable, HPV-Associated 
HNSCC: A Phase II Window Trial 
 
UA IRB Protocol #: 
 
1802258478 
IND#: 
 
137990 
Phase: 
 
II 
Version: 
 
V.6 
Version Date: 
 
05-20-2022 
Investigational Agent: 
 
Alpelisib (BYL719) 
 
National Clinical Trial (NCT):  
NCT03601507 
 
SPONSOR-INVESTIGATOR: 
Ricklie Julian, MD 
University of Arizona Cancer Center 
1515 N. Campbell Ave. 
Tucson, AZ 85724 
Phone: 520-694-2873 
Email: rickliej@arizona.edu 
 
 
 
 
 
Source(s) of Support: 
V Foundation Translational Grant  
 
Study Monitor: 
University of Arizona Cancer Center Data and Safety 
Monitoring Board 
 
 

 
 
 
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Title 
Biomarker Modulation by BYL719 in Transorally Resectable, HPV-
Associated HNSCC: A Window Trial 
Patient 
population 
Patients with de novo stage I-IVa HPV associated, resectable, 
oropharyngeal head and neck squamous cell carcinoma (HNSCC) who are 
planned for definitive surgery.  
Rationale 
for Study 
Head and neck squamous cell carcinoma (HNSCC) is the sixth leading 
incident cancer worldwide with 600,000 incident cases in 2012.  Five-year 
overall survival (OS) has increased incrementally in the past two decades. 
Improved prognosis is largely attributable to changing epidemiology; an 
increasing proportion of oropharyngeal HNSCC is infected with high-risk 
human papillomavirus (HPV), thought to confer sensitivity to conventional 
treatments. The PI3K/Akt/mTOR signaling network, a mitogenic pathway 
regulating cellular metabolism, proliferation and survival, plays a major role 
in HPV biology. Activation of the pathway is a nearly universal aspect of 
mammalian viral infection, and is of particular importance for dsDNA viruses 
such as HPV relying upon cap-dependent protein translation. The 
oncoproteins E5, E6 and E7 have direct roles in pathway activation: E5 
upregulates PI3K; E6 binds tuberin, a component of the TSC which 
negatively regulates mTORC1; and E7 prevents de-phosphorylation of Akt 
following activation by PI3K.  We would like to determine if PIK3CA 
mutations and/or gene amplification serve as predictive biomarkers for 
clinical responses to PI3K pathway inhibition in patients with transorally 
resectable HPV(+) HNSCC treated with the PI3K p110α-selective inhibitor 
BYL719. 
  
Primary 
Objective 
• To assess the preliminary efficacy of neoadjuvant BYL719 in patients with 
transorally-resectable, HPV+ HNSCC, as measured by quantitative change 
in tumor size (ΔT) following 10-21 days of treatment.  
• To evaluate the relationship between genomic PIK3CA activation to ∆T 
 
Secondary 
Objectives 
• 
To describe the tolerability of brief neoadjuvant exposure to 
BYL719 
• 
To assess the effect of BYL719 on the tumoral Ki-67 proliferation 
index 
• 
To evaluate viral and molecular mediators of response and 
resistance to BYL719, including viral mRNA, E6 and E7 
oncoproteins, and pHER3 
 

 
 
 
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Study Design This is a study designed to assess the effect of the PI3K inhibitor BYL719 on 
tumor proliferation, size, and biomarker expression. 
 
Number of 
patients 
Projected accrual is 20 patients for this study, for a total of 14 biomarker-
evaluable patients. 
Duration of 
Therapy 
Treatment will be during the pre-operative window of 10-21 days or up to 28 
days for delays in planned surgery.  
Duration of 
Follow up 
12-weeks post-operation, as deemed clinically necessary. 
Duration of 
study 
The study will complete accrual 24  months from the time the study opens 
and will close 36 months after the study opens. 
Note: Accrual to this study was significantly affected by the COVID-19 
pandemic. Thus, the accrual time will be extended to 64 months from the 
time study opened and will close 84 months after the study opens. 
Study Drugs 
BYL719/Alpelisib 350 mg PO daily as a pill  
Safety 
Assessments 
The safety of this window intervention will be reported descriptively, including 
tabulation of toxicities according to NCI CTCAE v.4, surgical complications, 
and length of hospital stay. 
Efficacy 
Assessments 
Preliminary efficacy of neoadjuvant BYL719 in patients with operable HPV+ 
HNSCC will determined by quantitative ΔTumor size. ΔTumor size will be 
measured using established RECIST v1.1 metrics for index lesions, however 
treated as a continuous variable. 
BYL719 350 mg/day 
Pre-Operative Window 
10-21 Days 

 
 
 
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Biomarker 
Assessments 
1) PIK3CA genomic alteration (gene mutation or amplification in tumor) 
2) Pre- and post-treatment tumor levels of:  
• 
HPV mRNA (qPCR) 
• 
E6, E7 protein 
• 
Phospho-HER2 
• 
HER3/PI3K dimers (monogram)   
 
 

 
 
 
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Table of Contents 
1 
Introduction .................................................................................................................................... 8 
1.1 
Background on Indication ................................................................................................................ 8 
1.2 
Background on BYL719 .................................................................................................................. 8 
1.3 
Rationale for Proposed Study ........................................................................................................ 11 
Human Papillomavirus (HPV) in HNSCC.................................................................................................. 11 
HPV and EGFR signaling ........................................................................................................................... 13 
HPV and the PI3-Kinase (PI3K) Pathway .................................................................................................. 14 
Preclinical Data, Grandis and Ozbun Laboratories ..................................................................................... 15 
2 
Objectives of the Study ................................................................................................................ 18 
2.1 
Primary Objective .......................................................................................................................... 18 
2.2 
Secondary Objectives..................................................................................................................... 18 
2.3 
Endpoints ....................................................................................................................................... 18 
2.3.1 
Primary Endpoint .................................................................................................................... 18 
2.3.2 
Secondary Endpoints ............................................................................................................... 18 
3 
Study Design ................................................................................................................................. 19 
3.1 
Characteristics ................................................................................................................................ 19 
3.2 
Number of Subjects........................................................................................................................ 19 
3.3 
Eligibility Criteria .......................................................................................................................... 19 
3.3.1 
Inclusion Criteria ..................................................................................................................... 19 
3.3.2 
Exclusion Criteria .................................................................................................................... 20 
3.4 
Duration of Therapy ....................................................................................................................... 23 
3.5 
Duration of Follow Up ................................................................................................................... 24 
3.5.1 
Procedures for discontinuation ................................................................................................ 24 
3.6 
Study Timeline ............................................................................................................................... 24 
3.6.1 
Primary Completion ................................................................................................................ 24 
Note: Accrual to this study was significantly affected by the COVID-19 pandemic. Thus, the accrual 
time will be extended to 64 months from the time study opened. ............................................ 24 
3.6.2 
Study Completion .................................................................................................................... 24 
4 
Study Drugs – BYL719 Description, Supply, and Storage ....................................................... 24 
4.1 
BYL719 (Alpelisib) Description .................................................................................................... 24 
4.2 
BYL719 dosing .............................................................................................................................. 25 
4.3 
Supply, receipt, and storage ........................................................................................................... 26 
4.3.1 
Drug compliance and accountability ....................................................................................... 26 
4.3.2 
Disposal and destruction ......................................................................................................... 26 
4.4 
Drug Accountability....................................................................................................................... 26 
4.5 
Drug Ordering ................................................................................................................................ 26 
4.6 
Packaging and Labeling of Study Drugs........................................................................................ 26 
5 
Treatment Plan ............................................................................................................................ 27 
5.1 
Dosage and Administration ............................................................................................................ 27 

 
 
 
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5.2 
Dose Modification ......................................................................................................................... 27 
5.3 
Treatment interruption and treatment discontinuation ................................................................... 28 
5.4 
Procedures in case of Overdose ..................................................................................................... 28 
5.5 
Procedures in Case of Pregnancy ................................................................................................... 28 
5.6 
Monitoring and Toxicity Management .......................................................................................... 29 
6 
Study Procedures and Assessments ............................................................................................ 37 
6.1 
Screening Period & Pre-treatment Procedures ............................................................................... 37 
6.1.1 
Screening Evaluations ............................................................................................................. 37 
6.1.2 
Registration ............................................................................................................................. 39 
6.1.3 
Mandatory Baseline Procedures Occurring Day -21 to -1 ...................................................... 39 
 
Treatment Period ............................................................................................................................ 40 
6.2 
40 
6.2.1 
Day 1 Study Visit .................................................................................................................... 40 
 
Study Drug Treatment - Days 1-21 and 22 (+/- 3 days) .......................................................... 40 
6.2.2 
40 
6.2.3 
Day 8, 15, and 22 (+/- 3 days) if patient is on BYL719 treatment .......................................... 40 
6.2.4 
Day 9-29 (inclusive of day of surgery).................................................................................... 40 
6.3 
Surgery and Post-treatment Tumor Tissue Collection ................................................................... 41 
6.3.1 
Days 11-22 (window of +7 days up to day 29, inclusive of day of surgery) .......................... 41 
6.3.2 
Post-operative therapy ............................................................................................................. 42 
6.4 
End-of-Treatment/Follow-up/Final Study Visit Procedures .......................................................... 42 
6.4.1 
4 week (+/- 2 weeks) follow-up visit ....................................................................................... 42 
6.4.2 
12 week (+/- 4 weeks) Final Study Visit ................................................................................. 42 
 
Other visits .............................................................................................................................. 42 
6.4.3 
42 
6.5 
Usage of Concurrent/Concomitant Medications ............................................................................ 46 
6.5.1 
Dietary Restrictions ................................................................................................................. 46 
6.5.2 
Permitted Concomitant Therapy Medications ......................................................................... 46 
6.5.3 
Prohibited concomitant therapy ............................................................................................... 48 
7 
Tumor Measurements ................................................................................................................. 49 
7.1 
Disease Parameter Definitions ....................................................................................................... 50 
7.2 
Methods for Evaluation of Measurable Disease ............................................................................ 50 
8 
Documentation and Reporting of Adverse Events & Unanticipated Problems ..................... 50 
8.1 
Definitions of Adverse Events ....................................................................................................... 51 
8.1.1 
Adverse Event ......................................................................................................................... 51 
8.1.2 
Adverse reaction ...................................................................................................................... 51 
8.2 
Recording of an Adverse Event ..................................................................................................... 53 
8.3 
Follow-up of Adverse Events ........................................................................................................ 54 
8.4 
Adverse Event Monitoring ............................................................................................................. 54 
8.5 
Serious Adverse Event Reporting .................................................................................................. 54 

 
 
 
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8.6 
Reporting Unanticipated Problems ................................................................................................ 56 
9 
Data and Safety Monitoring Plan: .............................................................................................. 56 
9.1 
Identification of the DSMB obligated for oversight responsibilities: ............................................ 56 
9.2 
Identification of the entity obligated for routine monitoring duties: .............................................. 57 
9.3 
Monitoring progress and data review process: .............................................................................. 57 
9.4 
Plan for assuring data accuracy and protocol compliance: ............................................................ 58 
10 
Statistical Considerations and Evaluation of Results ............................................................... 59 
10.1 
Study Endpoints ............................................................................................................................. 59 
10.2 
Determination of Sample Size and Accrual Rate ........................................................................... 59 
10.2.1 Sample Size and Power Estimate ............................................................................................ 59 
10.2.2 Replacement Policy ................................................................................................................. 60 
10.3 
Protocol Early Stopping Rules ....................................................................................................... 60 
10.3.1 Toxicity ................................................................................................................................... 60 
10.3.2 Delay in Surgery ...................................................................................................................... 61 
11 
Study Management ...................................................................................................................... 61 
11.1 
Pre-study Documentation ............................................................................................................... 61 
11.2 
Institutional Review Board Approval ............................................................................................ 62 
11.3 
Informed Consent .......................................................................................................................... 62 
11.4 
Changes in the Protocol ................................................................................................................. 62 
11.5 
Deviations ...................................................................................................................................... 62 
11.6 
Maintenance of Subject Specimens ............................................................................................... 62 
11.7 
Study Discontinuation and Closure ............................................................................................... 62 
11.8 
Handling and Documentation of Clinical Supplies ........................................................................ 63 
11.9 
Case Report Forms (CRFs) ............................................................................................................ 63 
11.10 Record Keeping and Record Retention .......................................................................................... 64 
11.11 Coordinating Center Documentation of Distribution [multi center studies] .................................. 64 
12 
Protection of Human Subjects .................................................................................................... 64 
12.1 
Protection from Unnecessary Harm ............................................................................................... 64 
12.2 
Protection of Privacy...................................................................................................................... 65 
REFERENCES .......................................................................................................................................... 66 
Appendices ................................................................................................................................................. 70 
Appendix 1 
Performance Status Criteria .......................................................................................... 70 
Appendix 2 
Permitted medications to be used with caution ............................................................ 71 
Appendix 3 
 Prohibited medications .................................................................................................. 73 
Appendix 4 
 Study Medication Instructions and Diary ................................................................... 75 
Appendix 5     Tumor Biomarkers ........................................................................................................... 79 
 
 

 
 
 
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1 Introduction 
1.1 Background on Indication 
Head and Neck Cancer 
 
Head and neck squamous cell carcinoma (HNSCC) is the most common cancer arising in 
the upper aerodigestive tract. HNSCC is the sixth leading incident cancer worldwide with 
600,000 incident cases in 2012.(1) Despite advances in multimodality therapy, 5-year overall 
survival (OS) is 40-60%, and has increased only incrementally in the past two decades.(2) 
The current standard of care for primary nonsurgical management of previously untreated, 
locally advanced (PULA) HNSCC is concurrent cisplatin-radiotheray (RT), which significantly 
improved overall survival (OS), progression-free survival (PFS), and locoregional control 
(LRC) compared with radiotherapy alone or the sequential administration of chemotherapy 
and RT. (3, 4) A developing standard is definitive radiotherapy with concurrent cetuximab, a 
chimeric monoclonal antibody against the epidermal growth factor receptor (EGFR), which 
improved survival relative to radiotherapy alone in patients with oropharyngeal, laryngeal, 
and hypopharyngeal HNSCC.(5) 
 
1.2 Background on BYL719  
 
Alpelasib or BYL719 (NVP-BYL719) is an oral α-specific class I phosphatidylinositol-3-
kinase (PI3K) inhibitor belonging to the 2-aminothiazole class of compounds. 
 
BYL719 inhibits p110α, in its wild-type form as well as when constitutively activated 
by somatic mutations, and is much less potent against the β, δ, and γ isoforms of PI3K, as 
well as Vps34 and mTOR. BYL719 shows significant antitumor activity and is well tolerated 
in relevant animal models. It also has good physico-chemical and pharmacological 
properties well-suited for drug development. 
 
Most of the current oncology drug discovery and development work has shifted towards 
molecularly targeted therapies. A key focus has been on identifying inhibitors against 
components of pathways that drive tumor cell proliferation, survival, and metastasis such as 
the PI3K/mTOR pathway. PI3Ks are lipid kinases that are important in controlling signaling 
pathways involved in cell proliferation, motility, cell death and cell invasion.   Class I PI3K 
contains four isoforms, p110α, p110β, p110δ and p110γ which carry out non-redundant 
signaling functions. The α and β isoforms are ubiquitously expressed, α is linked upstream 
mainly to receptor tyrosine kinases, whereas β can mediate signals from both G-protein-
coupled receptors and from receptor tyrosine kinases. The γ and δ isoforms are expressed 
primarily in lymphocytes and play important roles in the regulation of immune responses. 
 
A gain of function in PI3K signaling is common in many types of human cancer and include 
inactivation of the phosphatase and tensin homologue (PTEN) tumor suppressor gene, 
amplification/overexpression or activating mutations of some receptor tyrosine kinases (e.g. 

 
 
 
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ERBB3, ERBB2, epidermal growth factor receptor [EGFR]), amplification of genomic regions 
containing Akt, amplification of PIK3CA (the gene encoding p110α) and mutations in 
PIK3CA. More than 30% of various solid tumor types were recently found to contain 
mutations of PIK3CA. From these mutation frequencies, PIK3CA is one of the most 
commonly mutated genes identified in human cancers. As these mutations constitutively 
activate p110α kinase activity, the cancer-specific mutants of p110α appear to be ideal 
targets for drug development. p110α isoform-specific small molecular mass inhibitors, such 
as BYL719, could then have potential anti-cancer activity without causing the potential side 
effects that could be expected from interference with other isoforms or other members of the 
PI3K-related kinase (PIKK) family. 
 
Preclinical studies and pharmacodynamics 
 
In biochemical assays, BYL719 inhibits p110α (inhibitor concentration causing half maximal 
inhibition [IC50]=10 nM) much more potently than the p110δ and γ isoforms and PIK4β and 
has weak or no activity against p110β, Vps34 and mTOR. BYL719 is equipotent against the 
most common somatic mutations of p110α (H1047R, E545K) compared to wild type p110α, 
and is selective against a wide range of protein kinases with at least a 50-fold selectivity 
window compared to p110α. The potency and selectivity of BYL719 is confirmed at the cellular 
level in mechanistic and relevant tumor cell lines. BYL719 potently inhibits p110α cellular 
activity (IC50=74 nM) and shows significant selectivity against the p110β and p110δ isoforms 
(above 15-fold). BYL719 has no activity against mTOR (IC50> 10mM), and is not interfering 
with phospho-inositol 3 kinase-related kinases (PIKKs) involved in DNA-damage repair 
processes (IC50> 30mM on S15P-p53 and IC50> 10mM on S1981P-ataxia-telangiectasia 
mutation [ATM]). Its biological activity correlates with inhibition of various PI3K/Akt 
downstream signaling pathway components. In vitro, BYL719 inhibits the proliferation of 
cancer cell lines harboring gene alterations in PIK3CA. 
 
In vivo, BYL719 shows dose and time-dependent inhibition of the PI3K/Akt pathway in relevant 
tumor xenograft models (p110α-mechanistic model and p110α-mutant xenograft models) in 
nude mice. In vivo analyses of tumor tissues, upon acute dose or after multiple treatments, 
show a good correlation between compound exposure and PI3K pathway blockade. BYL719 
shows good tolerability and statistically significant dose-dependent antitumor efficacy in 
PIK3CA mutant and/or ERBB2 amplified tumor xenograft models in mice. Moreover, in nude 
mice, after in vivo efficacy studies, blood glucose levels remained normal at all tested doses 
and time points. Plasma insulin levels were significantly increased at all tested doses to 
maintain glucose homeostasis, indicating on-target effects of BYL719 on the regulation of 
metabolism.  
 
The combination of BYL719 with cetuximab was tested in vitro and in vivo. Superior anti-tumor 
effects were observed when BYL719 was combined with cetuximab compared to either agent 
alone. Combination of BYL719 and cetuximab led to tumor regression in two different 
xenograft models (FaDu and PIK3CA mutant HSC2 models), supporting the hypothesis of 
testing the combination of BYL719 with cetuximab in HNSCC cancer patients. In a phase II 

 
 
 
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clinical trial, BYL719 alone (n=32) or the combination of cetuximab plus BYL719 (n=5) was 
investigated in 37 patients with cetuximab-resistant, recurrent/metastatic HNSCC. With a 
confirmed response rate of 11% and a disease control rate of 51%, BYL719 was considered 
promising for further investigation, with or without cetuximab, in the cetuximab-resistant 
population(6). 
 
Preclinical Pharmacokinetics 
BYL719 had a low clearance (CL), a moderate volume of distribution at steady state (Vss) 
and a good absolute oral bioavailability in all preclinical species tests (Wistar rats, Beagle 
dogs, mice). The compound is moderately bound to plasma proteins independent of its 
concentration. BYL719 showed a rapid distribution to almost all rat tissues, except the brain 
(radiolabeled 14C-BYL719 study). BYL719 was found to be preferentially present in melanin 
containing tissues such as the choroid and ciliary body of the eye but declined with time. The 
highest tissue exposures after dosing were found in the liver, bile, harderian gland, hair 
follicles, tactile hair and in the preputial gland. 
The overall metabolic turnover was very low in dog and human hepatocytes followed by the 
rat. Cytochrome P450 CYP3A4 was found to be the major P450 enzyme involved in hepatic 
oxidative metabolism in vitro with small contribution by other enzymes. While UGT 
phenotyping showed that UGT1A9 enzyme could be involved in the glucuronidation of 
BYL719 in human liver microsomes, the turnover rate of phase II metabolism in vitro was low. 
The main biotransformation pathway that was observed consistently in vitro and in vivo across 
species was amide hydrolysis to BZG791. No covalent drug protein adduct formation was 
noted in human microsomes or hepatocytes. 
BYL719 is a substrate of breast cancer resistance protein (BCRP) and multidrug resistance 
(MDR)-1 protein (low affinity). It also showed little to no inhibition of the major uptake and 
efflux transporters (liver, kidney, and intestine). Uptake of BYL719 in human hepatocytes was 
found to be concentration-independent and was not influenced by inhibitors of the major 
transporter families OCT (organic cation transporters), OAT (organic anion transporters), 
OATP (organic anion transporting polypeptides) and NTCP (sodium/taurocholate 
cotransporting polypeptide). Assessment of the hepatobiliary disposition mechanisms of 
BYL719 in sandwich-cultured rat and human hepatocytes showed that it is actively transported 
into bile pockets. 
Reversible weak inhibition of CYP2C8, CYP2C9 and CYP2C19 was observed in vitro with 
unlikely clinical relevance. The compound is also both a time-dependent inhibitor of CYP3A4 
and inducer of CYP3A4 in vitro. Based on the current assessment both opposing effects seem 
to counterbalance each other. Refer to the IB, Sections 5.1.5 and 7.3 for a discussion of the 
transporter-based and metabolic drug-drug interaction potential. Results from 4-week and 13-
week Good Laboratory Practice (GLP)-toxicology studies in dog showed a roughly dose-
proportional increase in exposure. The rat exposure (in the GLP toxicology studies) increased 
until 30 mg/kg beyond which no further increase in exposure was noted following single dose 
administration. Increase in exposure up to doses of 50 mg/kg in rat was observed in a different 

 
 
 
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non-GLP rat toxicology study. The toxicology studies provided no clear evidence of increased 
exposures following multiple dosing (<2-3-fold). No gender differences were observed in rat 
or dog. 
 
Clinical Pharmacokinetics 
Currently, BYL719 pharmacokinetics as single agent was evaluated in the [CBYL719X2101] 
trial. The MTD was declared at 400 mg QD in escalating dose of single or repeated daily 
dosing regimens. Median Tmax at C1D8 ranged from 1.8 to 6.0 hours using QD dosing, and 
from 1.5 to 2.3 hours using BID dosing regimens. At clinically relevant doses (270-400 mg) 
between subject variability in the maximum plasma concentration (Cmax) at steady-state was 
moderate to high with 40-60% at C1D8. Plasma concentrations of BYL719 generally declined 
in a mono exponential manner, suggesting limited distribution towards the peripheral tissues. 
At steady state, the median terminal half-life generally appeared to be independent of dose 
and time and ranged between 6.8 and 9.4 hours. After dosing at 400 mg QD (MTD), the half 
life was approximately 7 to 8 hours. Steady state BYL719 plasma levels after daily dosing can 
be expected to be reached at 2 to 3 days following onset of therapy in most patients. Similar 
results are observed in the human ADME trial [CBYL719X2107]. Further description of the 
metabolism and excretion of BYL719 is described respectively in the IB, Section 5.1.3 and 
Section 5.1.4. In addition to these single-agent studies, preliminary pharmacokinetic results 
are presented for several studies using BYL719 in combination with fulvestrant, cetuximab, 
MEK162 and LGX818. The small size in these studies prevents making a conclusion at this 
time regarding potential interaction between BYL719 and these compounds. 
The ADME characteristics of BYL719 in-vivo were tested in healthy volunteers in a hADME 
trial [CBYL719X2107] where 4 subjects received a single 400 mg oral dose of radiolabeled 
BYL719. After this single dose, the total recovery of radioactivity was almost complete, 
between 92.3 and 95.1, excretion was mainly via feces with approximately 77% recovery of 
radioactivity when only 9.9 to 18.8% of total radioactivity was recovered in feces. The 
absorption of BYL719 was estimated around 59%. The elimination of radioactivity followed a 
similar decline than BYL719 with an estimated terminal half-life of 18.0 hours No specific 
affinity for blood cells was observed. In plasma, BYL719 represented approximately 60% of 
the total radioactivity. The exposure in plasma of BZG719, major metabolite, represented 
about 27% of the total radioactivity, no other major metabolite was observed. 
 
1.3 Rationale for Proposed Study  
Human Papillomavirus (HPV) in HNSCC 
Converging clinical, molecular and epidemiologic evidence now confirm that human 
papillomavirus (HPV) status is a critical determinant of prognosis in oropharyngeal HNSCC 
(OPSCC). HPV is an epitheliotropic, double-stranded DNA (dsDNA) virus with >100 
characterized genotypes; HPV genotype 16 has predilection for oropharyngeal mucosa 
representing >90% of isolated DNA in OPSCC.(7) HPV underlies the epidemiologic 

 
 
 
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observation that both incidence and survival of OPSCC are increasing, in contrast to cancer 
associated with tobacco and alcohol.(8) In the U.S., population registry data confirmed 
epidemic rise in the proportion of OPSCC cases infected with high risk HPV from 1984 to 
2004, from 16% to 72%.(9) Similar prevalence rates have been observed in Western Europe 
and Australia, although large regional, racial and ethnic variations are reflected by low 
reported rates in Central Europe, Latin America, and U.S. blacks.(10-13) In the U.S., 
approximately two-thirds of patients with oropharynx cancer have HPV-associated tumors. 
Hence, in 2012 approximately 4200 cases of OPSCC caused by tobacco and alcohol and 
8400 cases of new HPV-associated OPSCC presented for treatment. The incidence of HPV-
associated OPSCC in the U.S. is expected to surpass that of cervical cancer, universally 
associated with HPV, in 2020 – thus representing a major public health threat. Unlike 
cervical cancer, there is no established precursor lesion for OPSCC, and consequently no 
screening program for early detection or secondary prevention. 
 
Emerging evidence indicates that both HPV status and tobacco use are the major 
independent prognostic factors for patients with HNSCC. Ang and colleagues presented a 
retrospective analysis of HPV status and tobacco use in RTOG 0129, a randomized phase 
III trial originally designed to compare accelerated-fractionation to standard-fractionation 
radiotherapy when delivered with concurrent cisplatin.(14) In multivariate analysis, patients 
with HPV positive tumors had a 58% reduction in risk of death compared with patients with 
HPV-negative tumors (hazard ratio 0.42; 95% CI 0.27-0.66). Of note, analysis of tumoral 
p16 protein expression by immunohistochemistry performed numerically better than 
detection of HPV DNA in identifying the good prognostic group (hazard ratio 0.33; 95% CI 
0.21-0.53). Expression of p16 is upregulated when HPV E7 oncoprotein degrades 
Retinoblastoma, whereas p16 expression in HPV-negative tumors is usually silenced by 
epigenetic promoter methylation or genetic mutation.(15) Thus, tumoral expression of p16 
protein reflects biologically relevant HPV infection, is not genotype-specific, and represents 
an accepted surrogate for HPV status in current clinical trial design (RTOG 1016, ECOG 
1308). 
 
The emerging understanding of the HPV epidemic in OPSCC, including a favorable 
prognosis when treated with conventional chemoradiotherapy (CRT), has framed the 
national clinical trial framework in PULA HNSCC.(13) Specifically, deintensification 
strategies are being investigated in patients with HPV-associated HNSCC, where current 
paradigms are thought to represent overtreatment – creating unnecessary and significant 
late toxicities from radiotherapy including dysphagia, aspiration, feeding tube dependence, 
neck contractures, facial lymphedema, voice changes, osteonecrosis, dental decay, chronic 
pain syndromes and secondary malignancies. In Eastern Cooperative Oncology Group 
(ECOG) 1308, the first cooperative group de-intensification trial, 80 patients with HPV-
associated OPSCC were treated with induction cisplatin, paclitaxel and cetuximab.(16) 
Patients who experienced a clinical complete response at the primary site then underwent 
de-intensified radiation therapy (55 Gy). RTOG 1016 is comparing concurrent cisplatin to 
concurrent cetuximab with accelerated fractionation radiotherapy. This de-intensification 
model seeks to establish the non-inferiority of bioradiotherapy with cetuximab, given 

 
 
 
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cetuximab’s favorable toxicity profile, however preserves the model of full dose, accelerated 
fractionation radiotherapy. Finally, the development of transoral surgical resection 
techniques for OPSCC, which demonstrate comparable oncologic outcomes yet reduced 
morbidity compared to historical open procedures, has resulted in surging interest in 
minimally-invasive surgery as a primary modality.(17-19) This has resulted in the design of 
ECOG 3311, a randomized trial evaluating radiation de-intensification after primary transoral 
resection for HPV-associated OPSCC. To date, de-intensification trial models in HPV-
associated OPSCC have used available, U.S. FDA-approved agents initially developed in 
the era of HPV-negative HNSCC. As the biology of HPV-associated OPSCC is understood, 
investigators now have the opportunity to design trials exploiting targets unique to HPV 
biology. 
 
HPV and EGFR signaling 
Carcinogenesis by oncogenic HPVs is initiated predominantly via the two main 
oncoproteins, E6 and E7, with E5 also inducing proliferative activities.  HPV-induced 
cancers of the cervix, oropharynx, anus, penis and vulva lack many of the activating 
mutations in cellular oncogenes, or in tumor suppressors TP53 and RB1, that non-viral 
cancers typically possess.(20-22) Rather, HPV transformation begins as E6 and E7 
functionally inactivate tumor suppressor proteins, including, but not limited to, p53.(23-26)  
We recently showed that upon exposure of human keratinocytes to oncogenic HPV virus 
particles, signaling ensues from growth factor receptors (e.g., epidermal GFR, EGFR).(27) 
Subsequently, HPV induced signaling engages the downstream pathways of PI3K and 
MAPK that promote cell proliferation and survival.(28,29) Importantly, both of these 
cascades are activators of cellular AP1 transcription factors that stimulate HPV oncogene 
expression from four highly conserved AP1 binding sites in the HPV viral regulatory 
region.(30,31)  In persistently HPV infected (non-cancerous) cells that resemble 
preneoplasias, stimulating EGFR signaling results in enhanced transcription of HPV 
oncogenes, and inhibiting MEK1/2 signals impedes oncogene transcription and viral 
genome levels (Fig. 1).  This suggests that crosstalk between HPV and the EGFR pathway 
benefits the persistence of HPV infections.  Additionally, E5 increases EGFR signaling in a 
ligand-independent manner(31-34) leading to higher levels of AP1 transcription factors and 
increased HPV transcription.(35)  E6 and E7 proteins have multiple functions shown to 
positively interface with PI3K and MAPK signaling.(36-45)  These observations prompt us to 
hypothesize that the initiation and maintenance of oncogenic HPV infections establishes a 
feed-forward regulatory loop with the PI3K and MAPK pathways to promote proliferation and 
survival.  We further theorize that activating mutations or amplification of PIK3CA plays an 
essential role in driving progression of HPV-initiated lesions to malignancies. Extensive 
cross talk between PI3K and MAPK pathways and their common involvement in supports 
these ideas.(46, 47) 

 
 
 
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HPV and the PI3-Kinase (PI3K) Pathway 
 
The PI3K/Akt/mTOR signaling network, a mitogenic pathway regulating cellular metabolism, 
proliferation and survival, plays a major role in HPV biology. Starting with early infection, 
activation of PI3K suppresses autophagy and induces functional protein translational 
machinery.(28) Activation of the pathway is a nearly universal aspect of mammalian viral 
infection, and is of particular importance for dsDNA viruses such as HPV relying upon cap-
dependent protein translation.(48) The oncoproteins E5, E6 and E7 have direct roles in 
pathway activation: E5 upregulates PI3K; E6 binds tuberin, a component of the TSC which 
negatively regulates mTORC1; and E7 prevents de-phosphorylation of Akt following 
activation by PI3K.(49-51) 
Human cells contain three genes encoding the catalytic subunits of class IA PI3K enzymes: 
PIK3CA (encoding the p110α subunit, expressed in most tissues); PIK3CB (encoding 
p110β, expressed in most tissues); and PIK3CD (encoding p110δ, expressed primarily in 
leukocytes). Mutation in PIK3CA is the most common gain-of-function mutation in HNSCC, 
whereas mutations in PIK3CB and PIK3CD have not been observed.(21,22) Transformed, 
HPV-associated OPSCC demonstrates a strikingly high prevalence of genomic PI3K 
pathway activation, including activating PIK3CA mutations (27-31%), PIK3CA amplification 
(20%), and loss of PTEN (30%), the negative regulator of PI3K.(21, 22, 52) Overall genomic 
events hypothesized to result in PI3K pathway activation are present in approximately 45-
60% of HPV-transformed OPSCC(53,54), making this a naturally enriched population for the 
development of PI3K inhibitors. Moreover, HPV-associated OPSCC patient tumorgrafts 
bearing activating PIK3CA mutations are exquisitely sensitive to PI3K inhibitors, including 
Figure 1. The EGFR signaling pathway regulates viral gene expression and replication in HPV16-infected cells. 
(A) NIKS-HPV16+ cells were exposed to 10 ng/ml EGF for 0h (mock), 1 or 2 days, then analyzed for HPV 16 
early RNA levels normalized to β-actin RNA. (B,C) NIKS-HPV16+ cells were incubated in growth media with 
100 μg/mL anti-EGFR antibody (cetuximab), 25 μM MEK1/2 inhibitor (PD98059) for the number of days 
indiated; 0 = vehicle-treated. (B) mRNA was harvested at indicated time points; RT-qPCR targeting HPV 16 
E1^RNA normalized to β-actin RNAs. (C). Total cellular DNA was harvested at indicated time points and 
qPCR performed to quantify HPV16 genome levels. Error bars – SEM (n=2). Student’s t-test: p<0.05(*), 
p<0.001 (**). Mock/vehicle treated cells were normalized to 100%. 

 
 
 
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BYL719.(52);unpublished data BYL719 is an oral α-specific class I phosphatidylinositol-3-kinase 
(PI3K) inhibitor belonging to the 2-aminothiazole class of compounds. BYL719 is a 
particularly attractive molecule to develop in HPV-associated OPSCC. Due to its PI3K 
p110α isoform specificity, it may be particularly effective in PIK3CA mutant/amplified cancer 
and has demonstrated fewer toxicities as compared to pan-isoform inhibition during Phase I 
development.  
 
Preclinical Data, Grandis and Ozbun Laboratories 
PIK3CA genetic alterations enhance PI3K signaling 
and HPV(+) HNSCC growth.  
Activation of the PI3K signaling pathway by PIK3CA 
mutation or amplification drives tumor growth in many 
cancers.(55, 56) We showed that genes in the PI3K 
signaling pathway are frequently mutated in HNC. 
Although the majority of PIK3CA mutations (≈60%) occur 
at the known canonical hotspot loci (E542K, E545K, 
H1047R), about one-third arise elsewhere in p110α.(51) 
We developed an HPV(+) HNC cell model harboring 
unamplified WT PIK3CA to identify “driver” mutations. We 
employed this HPV(+) HNC platform to functionally screen 
PIK3CA mutations detected in human HPV(+) HNC 
tumors. Using this model, we have reported that a subset 
of novel PIK3CA mutations activate PI3K signaling.(51) 
 
PIK3CA mutations confer sensitivity to PI3K inhibition in HPV(+) HNSCC.  
PI3K pathway inhibitors are more efficacious in patients with breast and gynecologic 
malignancies whose tumors harbor PIK3CA mutations.(57) Thus, we hypothesized that 
activation of PI3K signaling through gain-of-function mutations in PIK3CA would increase 
PI3K activation and serve as biomarkers for treatment with a PI3K inhibitor in HPV(+) HNC 
models. Indeed, we found that an HPV(+) HNC cell line harboring mutant H1047R PIK3CA 
was more sensitive to two separate PI3K inhibitors compared to an HNC cell line with WT 
PIK3CA and no gene amplification. In addition, the PI3K inhibitor decreased proliferation of 
HPV(+) HNC cells engineered to express E542K mutant PIK3CA to a greater degree than its 
WT counterpart.(51) The p110α-selective PI3K inhibitor BYL719 would be predicted to be 
most effective in cells with p110α mutations. To test this hypothesis, we compared BYL719 
effects in PIK3CA mutant (Cal33), amplified (HSC2) or WT (PE/ CA-PJ34) HNC cells and 
found enhanced growth in HNC cells harboring mutant or amplified PIK3CA compared to 
those with unamplified, WT PIK3CA (Fig. 2). These findings support our hypothesis that 
PIK3CA mutations or amplification enhance sensitivity to PI3K pathway blockade. Prospective 
identification of patients whose tumors harbor these mutations will determine the biomarkers 
for treatment with agents that inhibit this pathway.  
Generation of heterotopic HPV(+) HNC tumor models. In vivo studies generally rely on 
 
 
Figure 2. PIK3CA alterations confer 
sensitivity to the p110α inhibitor BYL719. 
HNSCC cell lines were treated with BYL719 
at concentrations from 0-30 μM for 72 hours 
and then assessed by MTT assay (repeated 
2x, n=8).  

 
 
 
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xenograft tumors derived from inoculation of HNSCC cell lines into immunocompromised 
mice. In an attempt to generate a more clinically relevant in vivo platform to assess the 
antitumor effects of candidate therapies, we implant human HNC tumors directly into 
NOD/SCID gamma (NSG) mice. To date, we have successfully implanted tumors obtained 
from 53 HNSCC patients,(58) yielding tumors in mice at a median time of 16 weeks (range 6-
26 weeks). This model allows passage and tumor expansion to facilitate therapeutic studies 
(i.e., 20-40 tumors generated from one primary tumor implant). Treatment of tumorgrafts 
derived from a HPV(+) tumor harboring an E542K PIK3CA mutation with a PI3K/mTOR 
inhibitor (BEZ-235), revealed significant antitumor effects.(51) These results suggest that 
PIK3CA mutation may serve as a biomarker of enhanced sensitivity to PI3K pathway inhibition 
in HPV(+) HNSCC. 
 
PI3K inhibition and HER3 activation. 
We next evaluated the p110 alpha-specific PI3K inhibitor, BYL719, against a panel of 8 
HNSCC cell lines characterized by HPV status and PIK3CA mutation and found that 
endogenously mutated cells demonstrated the greatest sensitivity (data not shown). We next 
assessed the efficacy of BYL719 in vivo using 4 PDX models: 1 HPV(+) with WT PIK3CA; 1 
HPV(+)with PIK3CAE542K; 1 HPV(-) with WT PIK3CA; 1 HPV(-) with PIK3CAM1043V.  In all 4 
PDX models, BYL719 demonstrated measureable anti-tumor effects, with greatest efficacy in 
the HPV(+)PIK3CAE542K model (Figure 3). We also observed emergence of resistance after 
2-3 weeks in both HPV(+) models. We characterized the proteomic response by reverse 
phase protein array (RPPA), observing that HER3 was upregulated coincident with the 
emergence of in vivo resistance.  
Figure 3. BYL-719 Inhibits Patient-Derived HNSCC Xenografts (PDX) 

 
 
 
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To better characterize 
HER3 as a resistance 
mechanism 
to 
PI3K 
inhibition, and identify 
potential 
interactions 
between 
viral 
oncoproteins 
and 
resistance to BYL719, 
we 
first 
investigated 
cellular 
feedback 
mechanisms to BYL719 
in 
three 
PIK3CA-WT 
HPV(+) in vivo models: 
SCC47 xenograft; PDX-7; PDX-10. BYL719 upregulated HER3 and pHER3 in all models 
(Figure 4). Upregulation of HER3 was coincident with upregulation of the E6 and E7 
oncoproteins (Figure 5).  In a subsequent series of cell line models, we observed: 1) PIK3CA-
WT HPV(+) cell lines demonstrate greater 
endogenous resistance to BYL719 than their 
HPV(-) counterparts; 2) PIK3CA-WT HPV(+)  
cell lines were sensitized to BYL719 upon 
knockdown of the E6/E7 oncoproteins. We are 
currently studying this resistance mechanism in 
PIK3CA-mutant models.  
 
 
 
 
Figure 4. BYL719 Upregulates HER3 in PIK3CA Wild-type HPV(+) HNSCC 
Figure 5. BYL719 Upregulates E6 and E7 
Expression in PIK3CA-WT HPV(+) HNSCC 

 
 
 
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2 Objectives of the Study 
2.1  Primary Objective 
• 
To assess the preliminary efficacy of neoadjuvant BYL719 in patients with transorally-
resectable, HPV+ HNSCC, as measured by quantitative change in tumor size (ΔT) 
following 10-21 days of treatment.  
• 
To evaluate the relationship between genomic PIK3CA activation to ∆T 
 
2.2 Secondary Objectives 
• 
To describe the tolerability of brief neoadjuvant exposure to BYL719 
• 
To assess the effect of BYL719 on the tumoral Ki-67 proliferation index 
• 
To evaluate viral and molecular mediators of response and resistance to BYL719, 
including viral mRNA, E6 and E7 oncoproteins, and pHER3 
2.3 Endpoints 
2.3.1 
Primary Endpoint 
• 
Quantitative change in the sum of RECIST-measurable index lesions on paired, pre-
and post-treatment tumor measurement (∆T) with size treated as a continuous 
variable.  
• 
The difference in ∆T in patients with genomic PIK3CA pathway alteration (PIK3CA 
mutation, amplification, and FISH for PTEN loss) vs. no genomic activation 
2.3.2 
Secondary Endpoints 
• 
Safety. The safety of this window intervention will be reported descriptively, including 
tabulation of toxicities according to NCI CTCAE v.4.03, surgical complications, and 
length of hospital stay. 
• 
Mechanistic biomarker endpoints. Changes in pre- and post-treatment tumor levels 
of: 
o HPV mRNA (qPCR) – laboratory of Michelle Ozbun, PhD (UNM). We 
hypothesize that BYL719 will reduce HPV mRNA, and this will correlate with 
decrease in tumor size. 
o E6 and E7 oncoproteins – laboratory of Michelle Ozbun, PhD (UNM).  We 
hypothesize that BYL719 will decrease tumoral E6 and E7 oncoprotein levels, 
and this will correlate with decrease in tumor size 
o Phospho-HER3 – laboratory of Jennifer Grandis, MD (UCSF). We 
hypothesize that pHER3 is a resistance mechanism for BYL719, and that 
pHER3 will be upregulated in non-responders. 
o HER3/PI3K dimers (Monogram). We hypothesize that HER3/PI3K 
dimerization is a resistance mechanism for BYL719, and that dimers will be 
upregulated in non-responders. 
 

 
 
 
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3 Study Design 
3.1 Characteristics 
This is a single-arm, open label phase II window trial to assess the effect of the PI3K 
inhibitor, BYL719 on tumor proliferation, size, and biomarker expression following 10-21 
days (max 28 days for unexpected delays in planned surgery) of BYL719 monotherapy in 
patients with operable, HPV-associated oropharyngeal squamous cell carcinoma.  
 
The study design involves baseline tumor biopsy, collection of peripheral blood, and tumor 
size assessment via CT scan or MRI. After 10-21 days, CT scan or MRI and peripheral 
blood collection will be repeated, followed by planned oncologic surgery with collection of 
post-treatment tumor specimen. 
 
 
 
3.2 Number of Subjects  
20 patients will be accrued to achieve the target of 14 evaluable patients.  
 
3.3  Eligibility Criteria 
3.3.1 
Inclusion Criteria 
1) Cytologic or histologic diagnosis of p16+ squamous cell carcinoma of oropharyngeal 
or unknown primary metastatic to the cervical met. 
 
BYL719 350 mg/day 
Pre-Operative Window 
10-21 Days 

 
 
 
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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 (see Section 
4.1.1). 
 
10) Have signed the written informed consent  
 
3.3.2 
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. 

 
 
 
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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: 
a. Symptomatic congestive heart failure within 12 months prior to the start of study 
treatment 
b. History of documented congestive heart failure (New York Heart Association 
functional classification III-IV), documented cardiomyopathy 
c. Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple 
Gated acquisition (MUGA) scan or echocardiogram (ECHO). 
d. Myocardial infarction ≤ 6 months prior to start of study treatment 
e. Unstable angina pectoris  
f. Serious uncontrolled cardiac arrhythmia  
g. History of angina pectoris, coronary artery bypass graft (CABG), symptomatic 
pericarditis prior to the start of study treatment 
h. 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: 
a. 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) 
b. 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) 

 
 
 
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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: 
a. 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.  
b. 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): 

 
 
 
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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.  
3.4 Duration of Therapy 
Treatment will occur during the pre-operative window of 10-21 days or up to 28 days for delays 
in planned surgery or until: 
• 
Progressive disease at any time  
• 
Any clinical adverse event, laboratory abnormality or intercurrent illness which, in the 
opinion of the Investigator, indicates that continued treatment with study therapy is not in 
the best interest of the subject  
• 
Excessive toxicity  
• 
Withdrawal of informed consent (subject’s decision to withdraw for any reason)  
• 
Pregnancy  
• 
All women of child-bearing potential should be instructed to contact the 
Investigator immediately if they suspect they might be pregnant (e.g., missed or 
late menstrual period) at any time during study participation.  
• 
The Investigator must immediately notify Novartis in the event of a confirmed 
pregnancy in a patient participating in the study. 
• 
Study Closure or termination 
• 
Subject noncompliance with study procedures 
 

 
 
 
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3.5 Duration of Follow Up 
Patients will be followed for up to 12 weeks post-operation.  Patients removed from treatment 
for unacceptable treatment related adverse event(s) will be followed until resolution or 
stabilization of all treatment related adverse events. 
 
3.5.1 Procedures for discontinuation  
Subjects who discontinue prior to the end of treatment should, if possible, be seen and 
assessed by an investigator(s). The reason for withdrawal and the date of withdrawal must be 
documented. If possible, any diary cards and investigational products should be returned by the 
subject as soon as possible after study discontinuation.  
 
3.6 Study Timeline 
3.6.1 Primary Completion 
The study will reach primary completion 24 months from the time the study opens to accrual. 
 
Note: Accrual to this study was significantly affected by the COVID-19 pandemic. Thus, the 
accrual time will be extended to 64 months from the time study opened.  
3.6.2 Study Completion 
The study will reach completion 36 months from the time the study opens to accrual. 
 
Note: Accrual to this study was significantly affected by the COVID-19 pandemic. Thus, the 
accrual time will be extended to 64 months from the time study opened and will close 84 months 
after the study opens. 
 
4 Study Drugs – BYL719 Description, Supply, and Storage 
4.1 BYL719 (Alpelisib) Description 
Note: See the Investigator’s Brochure for detailed information. 
 
Classification 
BYL719 is an oral inhibitor that selectively targets the α-isoform of Class I PI3K, with in vitro 
IC50 values of 4.6, 1156, 250, and 290 nM for p110α, β, γ, and δ, respectively, as well as 4.0 
and 4.8 nM for the PIK3CA mutants E545K and H1047R. 
Mechanism of Action 
BYL719 (alpelisib) is a selective PI3Kα inhibitor equipotent against the wild-type and the most 
common somatic mutations of PI3Kα (inhibition concentration 50% [IC50]= 5 nM).  
 
Metabolism 

 
 
 
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BYL719 was eliminated predominantly by hepatobiliary excretion into feces and, to a lesser 
extent, via urine. Compounds identified in excreta mainly comprised of M4 and parent 
compound. Of the remaining metabolites, the most abundant are M3, M9, and M12. In vitro 
experiments suggested that M3 is formed by oxidation (Phase I, CYP3A4), and M12 is formed 
by glucuronidation (Phase II, UGT1A9). The primary metabolite M4 is pharmacologically 
inactive and not genotoxic.  
Contraindications 
In the absence of significant amounts of oxidation or glucuronidation, BYL719 is considered to 
have a low potential for interaction with other drugs—this is supported by clinical observations 
that inhibitors/inducers of CYP3A4 have a limited effect on the clearance of BYL719 in patients 
 
4.2 BYL719 dosing 
 
BYL719 will be administered orally once daily on a continuous dosing schedule and dosed 
on a flat-fixed dose and not adjusted by body weight or body surface area in a 21-28 day 
cycle. The recommended starting dose for single agent BYL719 studies is 350 mg/day. 
 
The investigator or responsible site personnel should instruct the patient to take BYL719 
as per protocol (promote compliance).  
 
The following general guidelines should be followed for BYL719 administration: 
   
• 
Patients should be instructed to take the dose of BYL719 once daily at approximately the 
same time each day after a meal (preferably in the morning after breakfast) except on the 
days blood collection is scheduled at the clinic, at which time the patients should take their 
doses at the clinic at any later point of time. 
• 
BYL719 must be taken within 1 hour after a meal or snack.  If, for any reason, a breakfast 
(or other meal) was not consumed, then the patient should take study treatment with a 
glass of water within 1 hour after a snack at any later point in time.  
• 
During treatment phase, the patient should record if the dose was taken or not in the 
alpelisib patient diary. 
• 
BYL719 should be taken with a glass of water. Patients should swallow the tablets as a 
whole and not chew them.  
• 
If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose. The occurrence and frequency of any vomiting during a 
treatment cycle must be noted in the adverse events section of the CRF. 
• 
If the patient forgets to take study treatment during the daytime, it should be taken in the 
evening at the latest within 1 hour after a meal, but not later than 6 pm. If not taken by this 
time, the dose should be withheld that day. Missed doses should not be made up the next 
day.  
• 
Patients must avoid concomitant intake of strong CYP3A inhibitors and inducers.  
 
NOTE: for current information, please see the most recent version of the Investigator Brochure 
 

 
 
 
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4.3 Supply, receipt, and storage 
 
Study drug must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
assistants have access. Upon receipt, BYL719 should be stored according to the instructions 
specified on the drug labels. Study medication will be dispensed by an authorized person at the 
investigator’s site.  
 
Patients will be provided with a 21-day supply of BYL719 for self-administration at home until at 
least their next scheduled study visit.  
4.3.1 Drug compliance and accountability 
 
Clinical drug supply must be accounted for and patients will be asked to return all unused study 
drug and packaging on a regular basis, at the end of the study or at the time of study drug 
discontinuation. 
 
At the conclusion of the study, and, as appropriate during the course of the study, the 
Investigator will return all used and unused study drug, packaging, drug labels, and a copy of 
the completed drug accountability ledger to Novartis.  
 
The University of Arizona Investigational Drug Service (IDS) pharmacy uses the National 
Cancer Institute (NCI) drug accountability logs for all studies at this institution. Control logs will 
be used for inventory and patient dispensing at the University of Arizona Cancer Center. 
 
4.3.2 Disposal and destruction  
 
The drug supply will be destroyed at a Novartis facility, or Novartis will provide guidelines for 
destruction, if investigational site is approved to destroy drug per prior agreement with Novartis.  
 
4.4 Drug Accountability 
The Investigational Pharmacist will manage drug accountability records. Damaged supplies will 
be destroyed at the study site and adequate records of the damaged supplies will be kept at the 
site. Study investigators will be responsible for drug accountability.  
4.5 Drug Ordering 
BYL719 will be supplied by Novartis Pharmaceuticals.   
4.6  Packaging and Labeling of Study Drugs 
Drugs will be packaged and labeled per University of Arizona institutional standards, adhering to 
applicable local and federal laws. 

 
 
 
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5 Treatment Plan 
5.1 Dosage and Administration 
Treatment will be administered on an outpatient basis. 
Table 5.1 
Regimen Description 
Study Drug 
Dose 
Route 
Schedule 
Cycle Length 
BYL719 
350 mg 
PO 
daily 
Pre-operative 
window (10-21 
days) or up to 
28 days for 
delayed 
surgery 
 
5.2 Dose Modification  
A continuous monitoring rule for safety will be instituted, to guard against excess toxicity from 
pre-operative treatment with BYL719 at a starting dose of 350 mg daily.  
 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments 
are permitted in order to allow the patient to continue the study treatment. All dose 
modifications must be based on the worst preceding toxicity as graded by the NCI Clinical 
Toxicity Criteria ([NCI-CTCAE version 4.03]).  
 
If the administration of BYL719 is interrupted for reasons other than toxicity, then treatment 
with BYL719 may be resumed at the same dose. 
 
A maximum of 2 dose reductions of BYL719 from the recommended starting dose may 
be allowed before considering discontinuation of BYL719 treatment. Table 5.2 below 
describes the dose reduction steps for BYL719.   
 
Table 5. 2 Dose reduction steps for BYL719 
 
A single agent dose levels and dose reductions* 
 
Starting dose level 
350 mg/day continuously 
Dose level – 1 
300 mg/day continuously 
Dose level – 2 
250 mg/ day continuously ** 
*Dose reduction should be based on the worst preceding toxicity.  
** = If a dose reduction below dose level –2 is required, the patient must be permanently 
discontinued from BYL719 
 

 
 
 
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5.3 Treatment interruption and treatment discontinuation 
 
All dose interruptions or discontinuations must be based on the worst preceding toxicity 
as graded by the NCI Clinical Toxicity Criteria (NCI-CTCAE version 4.03). 
 
Grade 4 adverse events will lead to permanent discontinuation, irrespective of recovery 
time, unless otherwise specified. Patients requiring > 2 dose reductions for BYL719 should 
be permanently discontinued. 
 
Patients should have weekly follow-up for 30 days if they develop an AE after 
discontinuation of study treatment or resolution of the AE to ≤ grade 1, whichever occurs 
first, that includes all study assessments appropriate to monitor the event. 
 
5.4 Procedures in case of Overdose 
There are no known antidotes for BYL719. Additionally, the dose which constitutes an overdose 
has not been defined. Doses of study treatment in excess of that specified (350 mg daily) in the 
clinical study protocol are considered to be an overdose. Patients experiencing toxicity upon 
overdosing must be treated at the discretion of the treating physician with adequate supportive 
care as indicated by the symptoms observed in the patient. Patients will have to be followed 
until full recovery or confirmed stabilization of the events. There is no clinical experience 
regarding the effect of hemodialysis on decreasing the plasma levels of BYL719 elimination thus 
far. There have been four events of accidental overdose reported with BYL719 and these were 
all cases in combination studies. Adverse events associated with the overdose were those 
expected with the BYL719 known safety profile and included hyperglycemia, nausea, 
hyperuricemia, hyponatremia, asthenia and rash. Patients fully recovered after some days and 
supportive medication to treat the associated adverse events experienced with the overdose. 
Overdose, with or without associated symptoms, should be handled in the same way as a SAE. 
Signs or symptoms of an overdose that meet the criteria of SAE should be reported as a SAE in 
the appropriate manner and be documented as clinical sequelae to an overdose. 
5.5 Procedures in Case of Pregnancy 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported 
to Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed 
up to determine outcome, including spontaneous or voluntary termination, details of the 
birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications. 
 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology (DS&E) department. 
Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the Novartis study treatment of any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported on the SAE Report 
Form. 

 
 
 
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Pregnancy outcomes must be collected for the female partners of any males who took 
study treatment in this study. Consent to report information regarding these pregnancy 
outcomes should be obtained from the mother. 
 
5.6 Monitoring and Toxicity Management 
Each patient receiving at least one dose of BYL719 will be evaluable for safety.  The safety 
parameters include all laboratory tests and hematological abnormalities, physical findings, and 
spontaneous reports of adverse events reported to the investigator by patients. 
Each patient will be assessed periodically for the development of any toxicity as outlined in 
Section 6 Study Procedures and Observations. Toxicity will be assessed according to the NCI 
CTCAE v4.03.  Dose adjustments will be made according to the system showing the greatest 
degree of toxicity.  
Table 5. Dose Modifications - Criteria for Interruption and Re-initiation of BYL719  
Worst toxicity CTCAE v.4.03 Grade  
Dose Modifications for BYL719 
Investigations (Fasting Plasma Glucose) 
Hyperglycemia 
Always consider consultation with a diabetologist and recommend/reinforce on lifestyle changes as per 
ADA, i.e. exercise and dietary advice (e.g. small frequent meals, low carb, high fiber, balancing carbs 
over the course of the day.  Three small meals and 2 small snacks rather than one large meal). 
Grade 1 (> ULN - 160 mg/dL) [> ULN - 8.9 
mmol/L] 
 
For patients with baseline values between >ULN – 
140 mg/dL (ULN – 7.7 mmol/L) this apply only for 
values > 140 mg/dL (7.7 mmol/L) 
Maintain dose level and remind patient on 
lifestyle changes*.  
• If FPG < 140 mg/dl, consider adding metformin 
as per guidance below or in cooperation with 
diabetologist 
• If FPG 140-160 mg/dl, start/intensify metformin 
as per guidance below or in cooperation with 
diabetologist 
 
Metformin 500 mg once daily with dinner. If no 
gastrointestinal (GI) intolerance after several days, 
increase to 500 mg bid, with breakfast and dinner. 
If tolerated, increase to 500 mg with breakfast, and 
1000 mg with dinner. If tolerated, 1000 mg bid with 
breakfast and dinner. If not tolerated, reduce to 
prior tolerated dose. 
 
Monitor FPG as clinically indicated and at least 
weekly for 8 weeks, then continue checking at 
least every two weeks until FPG is within baseline 
values. 
Grade 2 (>160 - 250 mg/dL) [> 8.9 - 13.9 mmol/L] 
Maintain dose level and remind patient on 
lifestyle changes*, exclude confounding factors 
like 
e.g. 
urinary 
tract 
infection, 
consider 

 
 
 
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consultation with a diabetologist and start oral-
antidiabetic treatment, e.g. metformin 500 mg bid 
with breakfast and dinner. If no GI intolerance, 
increase to 500 mg with breakfast, 1000 mg with 
dinner. If tolerated, 1000 mg bid with breakfast and 
dinner. If not tolerated, reduce to prior tolerated 
dose. Titrate to the maximum tolerated dose over 
a period of 3 weeks. 
 
If FPG is still rising on maximum tolerated dose of 
metformin 
or 
persistently 
>160mg/dl 
(>8.9 
mmol/L), 
add 
an 
insulin-sensitizer, 
e.g. 
pioglitazone 30 mg (max. dose). 
Monitor FPG as clinically indicated and at least 
weekly until FPG resolves to ≤ Grade 1 
• If FPG does not resolve to ≤ Grade 1 within 21 
days after institution of appropriate anti-diabetic 
treatment, reduce BYL719 by 1 dose level 
• Continue with anti-diabetic treatment and check 
FPG at least weekly for 8 weeks, then continue 
checking at least every 2 weeks, alert treating 
physician if FPG>250mg/dl 
 
Grade 3 (> 250 - 500 mg/dL) [> 13.9 - 27.8 
mmol/L] 
 
 
Omit BYL719 and confirm fasting status of the 
assessment. If non-fasting, re-check within 24 
hours.  
Exclude confounding factors like e.g. urinary tract 
infection 
and consider consultation with a 
diabetologist. 
 
Administer intravenous hydration and intervention 
for 
electrolyte/ketoacidosis/hyperosmolar 
disturbances as clinically appropriate. 
Start 
metformin and titrate as outlined for Grade 2, add 
pioglitazone as outlined for Grade 2.  Insulin may 
be used for 1-2 days until hyperglycemia resolves, 
however this may not be necessary in the majority 
of BYL719-induced hyperglycemia given the short 
half-life of BYL719. 
  
Monitor FPG as clinically indicated and at least 
twice weekly until FPG resolves to ≤ Grade 1. 
 
• If FPG resolves to ≤ Grade1 within 3-5 days, 
while off study treatment and on metformin,  
re-start BYL719 and reduce 1 dose level, 
continue with anti-diabetic treatment and 

 
 
 
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check FPG at least weekly for 8 weeks, then 
continue checking at least every 2 weeks, 
alert treating physician if FPG>250mg/dl 
• If FPG does not resolve to Grade1 within 3-5 
days while off study treatment and on 
metformin, consult a diabetologist for 
management of diabetes is strongly 
recommended. If FPG does not resolve to ≤ 
Grade 1 within 21 days after institution of 
appropriate anti-diabetic treatment in 
cooperation with diabetologist and exclusion 
of confounding factors e.g. urinary tract 
infection, permanently discontinue patient 
from BYL719 treatment 
 
Grade 4 (> 500 mg/dL) [≥ 27.8 mmol/L] 
 
 
Omit BYL719 confirm fasting status of the 
assessment. If non-fasting, re-check within 24 
hours.  
Exclude confounding factors like e.g. urinary tract 
infection. 
Administer intravenous hydration and intervention 
for 
electrolyte/ketoacidosis/hyperosmolar 
disturbances as clinically appropriate. 
Consider cooperation with diabetologist, initiate or 
intensify medication with appropriate anti-diabetic 
treatment (see Grade 3), re-check within 24 hours. 
• If grade improves then follow specific grade 
recommendations 
• If FPG is confirmed at Grade 4 and 
confounding factors could be excluded, 
permanently discontinue patient from BYL719 
A diabetologist consultation should always be considered. 
In case metformin is contraindicated or not tolerated even at low dose, another insulin-sensitizer (e.g., 
pioglitazone) may represent an alternative. 
For all grades: instruct patient to follow dietary guidelines according to local and/or institutional standards 
for management of diabetes mellitus (such as those provided by the American Diabetes Association) 
during the study, e.g., small frequent meals, low carbohydrate content, high fiber, balancing 
carbohydrates over the course of the day; three small meals and 2 small snacks rather than one large 
meal 
Investigations (Hematologic) 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 1.5 x 109/L) Grade 2 (ANC 
< 1.5 - 1.0 x 109/L) 
Maintain dose level 
Grade 3 (ANC < 1.0 - 0.5 x 109/L) Grade 4 (ANC 
< 0.5 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then: 
●   If resolved in ≤ 7 days, then maintain dose 
level 

 
 
 
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●   If resolved in > 7 days, then ↓ 1 dose level 
Febrile neutropenia 
(ANC < 1.0 x 109/L, with a single temperature of 
≥ 38.3 °C or a sustained temperature of ≥38 °C 
for more than one hour) 
Omit dose until resolved, then ↓ 1 dose level 
Thrombocytopenia 
Grade 1 (PLT < LLN - 75 x 109/L) Grade 2 (PLT < 
75 - 50 x 109/L) 
Maintain dose level 
Grade 3 (PLT < 50-25 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then: 
●   If resolved in ≤ 7 days, then maintain dose 
level 
●   If resolved in > 7 days, then ↓ 1 dose level 
Grade 4 (PLT < 25 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then ↓ 1 
dose level 
Investigations (Renal) 
Serum creatinine 
< 2 x ULN 
Maintain dose level 
2 – 3 x ULN 
Omit dose until resolved to ≤ grade 1, then: 
●   If resolved in ≤ 7 days, then maintain dose 
level 
●   If resolved in > 7 days, then ↓ 1 dose level 
Grade 3 (> 3.0 – 6.0 x ULN) 
Permanently discontinue patient from BYL719 
Grade 4 (> 6.0 x ULN) 
Permanently discontinue patient from BYL719 
 
 
Investigations (Hepatic) 
Bilirubin 
(*for patients with Gilbert Syndrome these dose modifications apply to changes in direct bilirubin 
only) 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level with LFTs* monitored as per 
protocol 
Grade 2 (> 1.5 - 3.0 x ULN) with ALT or AST 
≤ 3.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then: 
●   If resolved in ≤ 7 days, then maintain dose 
level 
●   If resolved in > 7 days, then ↓ 1 dose level 
Grade 3 (> 3.0 - 10.0 x ULN) with ALT or 
AST ≤ 3.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then: 
●   If resolved in ≤ 7 days, ↓ 1 dose level 
●   If resolved in > 7 days discontinue patient from 
BYL719 
Grade 4 (> 10.0 x ULN) 
Permanently discontinue patient from BYL719 
AST or ALT and concurrent Bilirubin 
AST or ALT > 3.0 x ULN and total bilirubin > 
2.0 x ULN 
Permanently discontinue BYL719 
*LFTs include albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN), alkaline 
phosphatase (fractionated if alkaline phosphatase is grade 2 or higher) and GGT. For patients with 

 
 
 
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Gilbert Syndrome: total and direct bilirubin must be monitored, intensified monitoring applies to 
changes in direct bilirubin only; the monitoring includes the following LFTs: albumin, ALT, AST, total 
bilirubin (fractionated if total bilirubin > 2.0 x ULN), alkaline phosphatase (fractionated if alkaline 
phosphatase is grade 2 or higher) and GGT). 
Patients with grade 0 or 1 at screening experiencing ALT/AST/bilirubin increase ≥ grade 2 the liver 
function tests must be monitored weekly or more frequently if clinically indicated until resolved to ≤ 
grade 1. In case of any occurrence of ALT/AST/bilirubin increase ≥ grade 3 the liver function tests 
must be monitored weekly or more frequently if clinically indicated until resolved to ≤ grade 1; 
hereafter the monitoring should be continued every other week or more frequently if clinically 
indicated until the end of treatment with study medication. Patients who discontinued study 
treatment should be monitored weekly, including LFTs or more frequently if clinically indicated until 
resolved to ≤ grade 1 or stabilization (no CTCAE grade change over 4 weeks). 
Investigations (Cardiac) 
Cardiac – QTc prolongation 
QTcF > 500 ms (≥ Grade 3, 4) 
or > 60 ms change from baseline on at least two 
separate ECGs 
First Occurrence: 
●   omit BYL719 
●   Perform an analysis of serum potassium 
and magnesium, and if below lower limit of 
normal, correct with supplements to within 
normal limits. Concomitant medication usage 
must be reviewed 
●   Perform a repeat ECG within one  
hour of the first QTcF of >500 ms or  
>60ms from baseline 
●   If QTcF remains > 500 ms or >60ms from  
baseline, repeat ECG as clinically indicated, but 
at least once a day until the QTcF returns to < 
480 ms. Seek cardiologist input. 
●   Once QTcF  prolongation has resolved, 
BYL719 may be restarted at a one lower dose 
level. 
Second Occurrence: Permanently discontinue 
patient from BYL719 
Isolated AST or ALT Elevation 
Confounding factors and/or alternative causes for increased transaminases like concomitant 
medications, infection, hepato-biliary disorders, obstruction, liver metastasis, etc. should be excluded 
before dose interruption/reduction 
Grade 1 (> ULN – 3.0 x ULN) 
Maintain dose level with LFTsb monitored per protocol 
Grade 2 (> 3.0 - 5.0 x ULN) 
• 
For patients with baseline value ≤ 
3.0 x ULN 
 
 
 
• 
For patients with baseline value > 
3.0 -5.0 x ULN 
 
• 
Maintain dose level. Repeat LFTsb as soon as possible, 
preferably within 48-72 hours from awareness of the 
abnormal results; if abnormal lab values are confirmed 
upon the repeat test, then monitor LFTsb weekly, or 
more frequently if clinically indicated, until resolved to ≤ 
3.0 x ULN 
• 
Maintain dose level 

 
 
 
V er si o n 0 5/ 2 0/ 2 0 2 2  
C o nfi d e nti al  
P a g e 3 4  of 7 9  
Gr a d e 3 ( > 5. 0 - 2 0. 0 x U L N)  
> 5. 0 - 1 0. 0 x U L N  
•  
F or p ati e nt s wit h b a s eli n e v al u e ≤ 
3. 0 x U L N  
 
 
 
 
•  
F or p ati e nt s wit h b a s eli n e v al u e > 
3. 0 -5. 0 x U L N  
 
 
•  
O mit d o s e. R e p e at L F T s b  a s s o o n a s p o s si bl e, 
pr ef er a bl y wit hi n 4 8 -7 2 h o ur s fr o m a w ar e n e s s of t h e 
a b n or m al r e s ult s; m o nit or L F T s b w e e kl y, or m or e 
fr e q u e ntl y if cli ni c all y i n di c at e d, u ntil r e s ol v e d t o ≤ 3. 0 x 
U L N T h e n  
If r e s ol v e d i n ≤ 1 4 d a y s, m ai nt ai n d o s e l e v el 
If r e s ol v e d i n > 1 4 d a y s,  1 d o s e l e v el  
•  
M ai nt ai n d o s e l e v el. R e p e at L F T s
b  a s s o o n a s p o s si bl e, 
pr ef er a bl y wit hi n 4 8 -7 2 h o ur s fr o m a w ar e n e s s of t h e 
a b n or m al r e s ult s; if a b n or m al l a b v al u e s ar e c o nfir m e d 
u p o n t h e r e p e at t e st, t h e n m o nit or L F T s b , w e e kl y, or 
m or e fr e q u e ntl y i f cli ni c all y i n di c at e d, u ntil r e s ol v e d t o ≤ 
5. 0 x U L N  
If r e s ol v e d i n ≤ 2 1 d a y s, m ai nt ai n d o s e l e v el 
If r e s ol v e d i n > 2 1 d a y s a n d c o nf o u n di n g f a ct or s h a v e 
b e e n e x cl u d e d,  1 d o s e l e v el  
 
> 1 0. 0 - 2 0. 0 x U L N  
O mit  d o s e.  R e p e at  L F T s b  a s  s o o n  a s  p o s si bl e,  pr ef er a bl y  
wit hi n 4 8 -7 2 h o ur s fr o m a w ar e n e s s of t h e a b n or m al r e s ult s; 
m o nit or  L F T s b  w e e kl y,  or  m or e  fr e q u e ntl y  if  cli ni c all y  
i n di c at e d, u ntil r e s ol v e d t o ≤ b a s eli n e. T h e n  1 d o s e l e v el.  
Gr a d e 4 ( > 2 0. 0 x U L N)  
•  
F or p ati e nt s d eri vi n g cli ni c al 
b e n efit u p o n i n v e sti g at or’ s 
j u d g e m e nt 
 
 
 
 
 
•  
F or all ot h er p ati e nt s  
 
•  
O mit d o s e. R e p e at L F T s b a s s o o n a s p o s si bl e, 
pr ef er a bl y wit hi n 4 8 -7 2 h o ur s fr o m a w ar e n e s s of t h e 
a b n or m al r e s ult s; m o nit or L F T s b w e e kl y, or m or e 
fr e q u e ntl y if cli ni c all y i n di c at e d, u ntil r e s ol v e d t o ≤ 3 x 
U L N ( or ≤ 5 x U L N f or p ati e nt s wit h b a s eli n e v al u e > 3. 0 
-5. 0 x U L N), t h e n r e s u m e tr e at m e nt at  1 d o s e l e v el. 
O nl y 1 d o s e r e d u cti o n i s all o w e d; if r e o c c ur s at > 5 x 
U L N, di s c o nti n u e p ati e nt fr o m al p eli si b.  
•  
Di s c o nti n u e p ati e nt fr o m al p eli si b  
R e p e at L F T s b  a s s o o n a s p o s si bl e, pr ef er a bl y wit hi n 4 8 -7 2 
h o ur s fr o m a w ar e n e s s of t h e a b n or m al r e s ult s; m o nit or L F T s b  
w e e kl y, or m or e fr e q u e ntl y if cli ni c all y i n di c at e d, u ntil r e s ol v e d 
t o b a s eli n e or st a bili z ati o n o v er 4 w e e k s 
C ar di a c  - L eft V e ntri c ul ar S y st oli c D y sf u n cti o n  
A s y m pt o m ati c,  
r e sti n g ej e cti o n fr a cti o n 40- 5 0 % or  1 0-2 0 % dr o p 
fr o m b a s eli n e 
-M ai nt ai n d o s e l e v el, a n d c o nti n u e B Y L 7 1 9 wit h 
c a uti o n  
-R e p e at  L V E F  wi thi n  4  w e e k s  or  a s  cli ni c all y  
a p pr o pri at e  
S y m pt o m ati c,  
r e s p o n si v e t o i nt er v e nti o n, 
ej e cti o n fr a cti o n 2 0- 3 9 %  
or > 2 0 % dr o p fr o m b a s eli n e  
-O mit B Y L 7 1 9 u ntil r e s ol v e d* ( a s d efi n e d b el o w), 
t h e n ↓ 1 d o s e l e v el  
-L V E F  m e a s ur e m e nt  t o  b e  r e p e at e d,  if  n ot 
r e s ol v e d* wit hi n 2 8 d a y s p er m a n e ntl y di s c o nti n u e 
p ati e nt fr o m B Y L 7 1 9 tr e at m e nt  
R efr a ct or y or p o orl y c o ntr oll e d, ej e cti o n fr a cti o n < 
2 0 %  
P er m a n e ntl y di s c o nti n u e p ati e nt fr o m B Y L 7 1 9  
*T h e  e v e nt i s c o n si d er e d r e s ol v e d w h e n t h e 
p at ie nt i s a s y m pt o m ati c, h a s a r e sti n g ej e cti o n 
 

 
 
 
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fraction ≥ 40% and ≤20% decrease from baseline. 
Other Cardiac Events 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then ↓ 1 
dose level 
Grade 4 
Permanently discontinue patient from BYL719 
Investigations (Gastrointestinal) 
Diarrhea 
 
Grade 1 
Maintain dose level 
Grade 2 
Omit dose until resolved to ≤ Grade 1, then restart 
at same dose 
≥ Grade 3 
Omit dose until resolved to ≤ Grade 1, then ↓ 1 
dose level 
Stomatitis/Oral mucositis  
Grade 1/Tolerable Grade 2 
Maintain dose level. 
Non-alcoholic or saltwater mouth wash. 
Intolerable Grade 2 or Grade 3 
First occurrence: hold until ≤ Grade 1 and ↓ 1 
dose level (if stomatitis is readily manageable 
with optimal management, re- introduction at 
the same level might be considered at the 
discretion of the investigator). 
Second occurrence: hold until ≤ Grade 1 and ↓ 1 
dose level. 
Grade 4 
Permanently discontinue patient from BYL719 
Skin and subcutaneous tissue disorders 
Consultation with a dermatologist is highly recommended for better assessment and management of 
BYL719-induced skin toxicity. Dermatologist consult is mandated for serious cutaneous reactions (i.e., 
fulfilling seriousness criteria for AE Reporting) and for severe cutaneous reactions like Stevens-Johnson-
Syndrome, Toxic Epidermal Necrolysis, Erythema Multiforme. 
Grade 1 (<10% body surface area (BSA) with 
active skin toxicity*) 
Maintain dose level 
• Initiate topical corticosteroids 3-4 x daily, 
preferred compounds to use are 
Triamcinolone, Betamethasone as long as 
skin toxicity is active, during maximum 28 
days 
 
For patients with symptoms like burning and/or 
pruritus add non-sedating anti-histamine, consider 
adding a sedating anti-histamine at night 
If active rash is not resolved within 28 days of 
appropriate treatment, consider adding low dose 
systemic corticosteroid (20-40 mg/d) 
Grade 2 (10-30% BSA with active skin toxicity*) 
Maintain dose level. 
• Initiate topical corticosteroids 3-4x daily, 
preferred compounds to use are 

 
 
 
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Triamcinolone or Betamethasone as long as 
skin toxicity is active, during max. 28 days 
• Consider adding systemic corticosteroids 20 
40mg/d   
If rash resolves to ≤ G1 within 10 days systemic 
corticosteroid may be discontinued 
 
For patients with symptoms like burning, stinging 
and/or pruritus add non-sedating anti-histamine, 
consider adding a sedating anti-histamine at night 
Grade 3(>30% BSA with active skin toxicity*) 
Omit BYL719 dose until rash /skin toxicity is no 
longer active but fading (G1), consider exploratory 
skin biopsy for central assessment 
• Initiate topical corticosteroids 3-4x daily, 
preferred compounds to use are 
Triamcinolone or Betamethasone for at least 
28 days 
• Add systemic corticosteroids  20-40mg/d   
If rash resolves to ≤ G1 within 10 days systemic 
corticosteroid may be discontinued 
For patients with symptoms like burning, stinging 
and/or pruritus add non-sedating anti-histamine 
during day time, consider adding a sedating anti-
histamine at night 
Re-start BYL719 dose once rash /skin toxicity is no 
longer active but  fading (G1): 
- at same dose in case of first occurrence, at 
reduced dose level in case of second occurrence 
- If rash/skin toxicity still active in up to 10% BSA 
after 
more 
than 
14 
days, 
continue 
oral 
corticosteroid for at least 48 hours upon re-
challenge with BYL719; if rash and/or pruritus do 
not reoccur within 48 hours after re-challenge with 
BYL719, 
systemic 
corticosteroid 
may 
be 
discontinued 
For patients with symptoms like burning, stinging 
and/or pruritus antihistamine regimen should be 
continued for a minimum of 28 days after re-
challenge with BYL719. 
Grade 4 (any % BSA associated with extensive 
superinfection, with IV antibiotics indicated; life-
threatening consequences) 
-Permanently discontinue patient from 
BYL719 and consider a dermatology 
consult, , ensure documentation by imaging 
like photographs, and obtain a skin biopsy. 
Treatment of rash may follow guidelines for 
Grade 3/ above with the exception of 
rechallenge. Additional measures may be taken 
as per local treatment guidance. 

 
 
 
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- 
Any Grade of Stevens-Johnson-
Syndrome/Toxic Epidermal Necrolysis or 
other SJS/TEN-like severe skin reactions 
• 
Permanently discontinue patient from 
alpelisib treatment 
• 
Consult dermatologist, ensure 
documentation by imaging like 
photographs and obtain skin biopsy for 
central assessment 
Follow local treatment guidelines for SJS/TEN 
Investigations (Pulmonary disorders) 
 
Pneumonitis 
• 
In patients who have new or worsening 
respiratory symptoms or are suspected to 
have developed pneumonitis, interrupt 
PIQRAY immediately and evaluate the 
patient for pneumonitis. 
• 
Permanently discontinue PIQRAY in all 
patients with confirmed pneumonitis. 
Investigations (any other) 
 
Other adverse events 
 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ grade 1, then↓ 1 
dose level 
Grade 4 
Omit dose and then discontinue from study 
drug treatment Omit dose for ≥ grade 3 
vomiting or grade 3 nausea only if the vomiting 
or nausea cannot be controlled with optimal 
antiemetic 
(as per local practice) 
6 Study Procedures and Assessments 
The study-specific assessments are detailed in this section. All on-study visit procedures are 
allowed a window of ±5 days unless otherwise noted.  Treatment or visit delays for public 
holidays or weather conditions do not constitute a protocol violation. 
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record.  The original will be kept on file with the study records.   
All patients who are consented will be registered in OnCore®, the Banner University Medical 
Center Clinical Trial Management System (CTMS). The system is password protected and 
meets HIPAA requirements. 
6.1 Screening Period & Pre-treatment Procedures 
6.1.1 Screening Evaluations 
Screening assessments must be performed within 28 days prior to the first dose of 
investigational product, unless otherwise specified.  Any results falling outside of the reference 

 
 
 
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ranges may be repeated at the discretion of the investigator.  
Note that all these procedures, with the exception of MUGA, are standard of care procedures for 
a patient with HNSCC. 
 
Required screening evaluations include:  
• 
Medical history assessment within 8 weeks prior to study registration. 
• 
 Physical examination, to include surgical and medical evaluation, within 8 weeks prior to 
study registration. 
o This is to include a careful description of the location and extent of the primary 
lesion and nodal spread.  Fiberoptic nasopharyngoscopy/laryngoscopy is 
recommended, unless fiberoptic exam is deemed unnecessary by the treating 
surgeon. Examination under anesthesia (EUA) is recommended, unless deemed 
unnecessary by the treating physician.   
• 
Vital signs, weight, height within 8 weeks prior to study registration 
• 
ECOG Performance Status within 8 weeks prior to study registration  
• 
Documentation of concomitant medications within 4 weeks prior to first dose of drug. 
• 
Note:  All medications taken within 28 days prior to first dose must be 
documented, including blood transfusions. 
• 
Laboratory studies including the following: 
• 
CBC with differential (to include total white blood cell count, absolute neutrophil 
count, hemoglobin, hematocrit and platelets), 
• 
Serum chemistries (to include sodium, potassium, chloride, carbon dioxide, BUN, 
creatinine, fasting glucose, magnesium, and calcium),  
• 
Liver function tests (LFTs; to include total bilirubin, AST, ALT, total protein, 
albumin and alkaline phosphatase),  
• 
Fasting amylase and lipase,  
• 
Coagulation studies (PT/INR and PTT) and  
• 
HbA1c. 
• 
Negative serum pregnancy test within 4 weeks of study registration in WOCBP.  
 
Note: the clinical research coordinator or treating investigator will document an additional 
negative serum or urine pregnancy test within 72 hours of starting BYL719 treatment. 
 
• 
Cross-sectional radiologic evaluation within 6 weeks of study registration (within 4 weeks 
is preferred).   
• 
The minimum cross-sectional evaluation is a diagnostic, contrasted computed 
tomography (CT) scan of the neck.   
• 
PET/CT is the preferred modality, provided it includes a diagnostic, 
contrasted CT scan of the neck – however is not mandatory.   
• 
For patients with severe allergy to iodinated contrast dye despite premedication, 
or in the case of physician preference, neck MRI may be substituted.   
• 
EKG.  The standard of care EKG performed for pre-surgical evaluation should be used.  
EKGs performed within 12 weeks prior to study registration may be substituted, provided 
the patient has not experienced an interval cardiac event. 
• 
Cardiac Multi Gated Acquisition (MUGA) or echocardiogram for determination of ejection 
fraction. MUGA or echocardiogram performed within 365 days prior to study registration 
may be substituted provided that the patient has not experienced an interval cardiac 
event.  
• 
Confirmation of positive p16 status 

 
 
 
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6.1.2 Registration 
• 
Questions regarding the eligibility of subjects must be directed to Ricklie Julian, MD. 
• 
After eligibility has been confirmed, registration will be submitted to the University of 
Arizona Cancer Center using the eligibility checklist. The following source documents must 
be submitted with the eligibility checklist. 
o Signed consent page with subject ID added, and PHI redacted 
• 
“Registration” is defined as the day Dr. Julian signs the Eligibility Checklist confirming that 
the subject is eligible to start the study drug. 
 
6.1.3 Mandatory Baseline Procedures Occurring Day -21 to -1 
These procedures must occur prior to the initial dose of study drug. They can occur any time 
after the subject signs informed consent.  
 
These Procedures are Mandatory. 
• 
Baseline, pre-treatment tumor biopsy   
o Note that a research biopsy of the primary tumor or malignant lymph node for 
biomarker studies is a condition for enrollment unless sufficient tissue is available 
to be repurposed for use in this trial. 
o The biopsy will be performed per standard-of-care procedure in the surgeon’s 
outpatient office, or during the standard of care examination under anesthesia 
(EUA), as preferred by the surgeon.  
o The tissue can be obtained during the standard-of-care surgical/medical 
evaluation of the extent of primary lesion and nodal spread.  
o 
  NOTE: Patients who have had research tissue procured under an omnibus 
tissue consent, who are determined to have sufficient fresh-frozen and paraffin 
tissue for biomarker analysis according to the PI, may substitute the archived 
tissue and do not need to undergo baseline research biopsy.  Such tissue must 
have been obtained within 16 weeks prior to registration, provided no interval 
anti-neoplastic therapy was given. 
o 
Collection and preparation of tissue for biomarker analysis will be processed 
according to procedures described in in the Laboratory Manual.  
• 
Baseline research blood collection 
o For logistical purposes, research labs may be drawn simultaneous with blood labs 
required for standard clinical management. 
o Blood for biomarker analysis will be collected and processed according to procedures 
described in the Laboratory Manual. 
 

 
 
 
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6.2 Treatment Period  
6.2.1 
Day 1 Study Visit 
 
• 
BYL719 will be dispensed. The BYL719 tablets are provided in 200 mg and 50 mg 
tablets.  
• 
Study diary will be provided and explained (see Appendix 6) 
• 
Adverse event assessment (and reporting of SAEs) will begin upon the first dose of study 
drug. 
o Prior to the first dose, active diagnosis and conditions will be considered medical 
history 
o For all grade 2 adverse events, treating investigator’s determination of tolerable or 
intolerable must be documented for determination of AEs to be entered into the 
AE CRF 
• 
Concomitant medication assessment (medications, herbal medications, and food or 
vitamin supplements taken within 28 days prior to Day 1 must be documented) 
6.2.2 Study Drug Treatment - Days 1-21 and 22 (+/- 3 days)  
NOTE: BYL719 treatment is planned for 10-21 days, however, may be administered up to 28 
days if required for logistical/scheduling purposes.  
 
• 
BYL719 will be administered at 350 mg orally once daily. This is one 200 mg tablet and 
three 50 mg tablets.  
• 
The last dose of BYL719 will be taken on the day prior to surgical resection. The interval 
between the last dose of BYL719 and surgery will be approximately 24 hours (+/- 8 
hours). 
• 
If surgery is delayed, BYL719 may be continued until the day prior to surgery, for a 
maximum of 28 days. If this is the case, additional drug may be dispensed at Day 22. 
• 
Subjects will be asked to indicate on a drug diary (see Appendix 6) when doses of BYL719 
are taken in order to monitor for compliance. Subjects may also use the drug diary for 
notations on side effects and other treatment related events. 
6.2.3 Day 8, 15, and 22 (+/- 3 days) if patient is on BYL719 treatment 
• 
Weekly fasting plasma glucose 
• 
Adverse event assessment. 
• 
Concomitant medication review. 
 
6.2.4 
Day 9-29 (inclusive of day of surgery) 
During treatment, pre-surgical  
Ideally, subjects will have the surgery on day 22 or later.  All efforts should be made to schedule 
these evaluations on the day prior to or the day of surgery, however a 5-day window is 
provided for logistical purposes, except for subjects with surgery on day 11 through 14. Subjects 
with scheduled surgery on day 11 through 14 should not have these procedures earlier than day 
9. Subjects will continue to take BYL719 until the day prior to planned surgery. The interval 

 
 
 
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between the last dose of BYL719 and surgery will be approximately 24 hours (+/- 8 hours).   
 
Compliance as evidenced by pill count and patient drug diary will be assessed when the 
subjects return the bottles and any leftover pills.  This may happen after their surgery at the first 
follow-up visit if they do not have a clinic visit the day before surgery. 
 
• 
History and Physical Examination (During treatment, Pre-operative):  Subjects will be 
evaluated by history and physical examination by the treating physician prior to planned 
surgery (including vital signs, weight, performance status).  This visit will also include 
adverse event assessment and compliance assessment as evidenced by pill count and 
patient drug diary.  For logistical convenience, this visit may be scheduled in conjunction 
with blood collection and imaging as specified below.   
NOTE: If surgery is unexpectedly delayed, subjects will continue to take BYL719, and this pre-
operative history and physical examination does not need to be repeated. 
 
• 
Clinical and Research Blood Collection: Subjects will undergo clinical labs including  
• 
CBC with differential,  
• 
serum chemistries including fasting glucose,  
• 
LFTs, and  
• 
coagulation studies prior to planned surgery.   
 
Research blood will be drawn simultaneously with these standard pre-operative labs. 
NOTE: If surgery is delayed, subjects will continue to take BYL719 and the clinical blood 
tests do not need to be repeated, but the research blood may be redrawn if the delay 
causes the research blood draw to be outside of the 5-day window prior to surgery. 
 
• 
Cross-sectional Imaging for Tumor Measurements (Research):  Subjects will undergo a 
repeat diagnostic CT scan of the neck with contrast prior to planned surgery as a part of 
the study.  For patients with severe allergy to iodinated contrast dye despite 
premedication, or in the case of physician preference, neck MRI may be substituted.   
NOTE: If surgery is delayed, subjects will continue to take BYL719, and this pre-
operative imaging does not need to be repeated. 
 
NOTE: in the event that a patient lacks a CT-measurable primary tumor or metastatic 
lymph node, measurable disease may be established by caliper measurement of an 
oropharyngeal tumor (≥ 1 centimeter). In this case, caliper measurement should be 
repeated and documented within 5 days prior to planned surgery, as a substitute for 
cross-sectional imaging. 
 
6.3 Surgery and Post-treatment Tumor Tissue Collection 
6.3.1 Days 11-22 (window of +7 days up to day 29, inclusive of day of surgery) 
• 
Oncologic head and neck cancer surgery 
o After 10-21 days of neoadjuvant treatment (+ 7 days if required for logistical and 
scheduling purposes), the patient will undergo the planned oncologic head and neck 
cancer surgery. The nature of complete resection of the primary head and neck 

 
 
 
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tumor, type of reconstruction, and levels of nodes to be dissected will be determined 
by the treating surgeon.   
o Prior to surgery, standard of care dental evaluation is recommended, to allow for any 
necessary dental extractions to be planned in conjunction with surgery. 
Consultations with a Nutritionist and Speech and Language Pathologist are strongly 
recommended prior to surgery and as ongoing support post-operatively. Placement 
of a nasogastric (eg. Dobhoff) or gastrostomy feeding tube is at the discretion of the 
subject and the study physicians.   
• 
Intraoperative tumor tissue for biomarkers (post-treatment tumor tissue collection) 
o Part of the tumor and/or lymph node specimen will be sent to the research laboratory 
for mandatory biomarker analyses. 
o If surgery is unexpectedly cancelled and the primary tumor or lymph node is 
accessible for in-office biopsy in the judgment of the surgeon-investigator, a tumor 
biopsy may be substituted for the intraoperative specimen. 
Tissue collection procedures are described in Section 9.0.    
 
6.3.2 Post-operative therapy 
After surgery, subjects may receive adjuvant radiation or radiation plus chemotherapy in 
accordance with appropriate standards, as determined by the subject’s treating physicians. 
6.4 End-of-Treatment/Follow-up/Final Study Visit Procedures 
6.4.1 4 week (+/- 2 weeks) follow-up visit 
• 
History and physical examination 
• 
Blood tests as clinically indicated (CBC, chemistries, liver function tests in accordance 
with investigator judgment) 
• 
If pill count and medication diary did not occur previously, it will be done at the 4-week 
follow-up visit 
• 
Adverse event follow up:   
o Events considered related to the study drug will be followed until return to 
baseline or stabilization. 
o During the post-treatment follow-up, only AEs considered related to the study 
drug need to be documented. 
o If a subject’s surgery is cancelled but they received study drug, they will be 
assessed for adverse events at the 4 weeks (+/- 2 week) follow-up visit. 
 
6.4.2 12 week (+/- 4 weeks) Final Study Visit 
• 
History and physical examination 
• 
Blood tests as clinically indicated (CBC, chemistries, liver function tests in accordance 
with investigator judgment) 
6.4.3 
Other visits 
Additional non-protocol visits may occur during the 12-week post-operative period as deemed 
clinically necessary. Patients will be referred for adjuvant chemotherapy and radiation per 
standard of care, based upon pathologic findings.  

 
 
 
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Once the first 12 weeks of follow-up have been completed, study follow-up will be discontinued, 
and subjects will continue standard treatment and surveillance in accordance with national 
guidelines.   
 
The standard post-operative visit which occurs 12 weeks post-op (+/- 4 weeks) will be 
considered the “final study visit.”  
 
 

 
 
 
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Table 6.1 
Schedule of Study Procedures and Assessments/Study Calendar 
Study Procedures 
Baseline 
Days 1 through 21 
Days 22 
through 28 (if 
surgery is 
delayed) k 
Day of 
Surgery 
4-Week 
Post-op 
Visit 
Final Study 
Visit 
(12-week 
post-op) l 
Informed consent 
X 
 
 
 
 
 
History & physical examination a 
X 
To be performed between days 9 
through 21 
 
 
X 
X 
Vital signs, weight 
X 
To be performed between days 9 
through 21 
 
 
X 
X 
ECOG-PS 
X 
 To be performed between days 9 
through 21 
 
 
X 
X 
Pregnancy test b 
X 
 
 
 
 
 
EKG c 
X 
 
 
 
 
 
Clinical blood tests d 
X 
To be performed between days 9 
through 21 
 
 
X 
X 
Cross-sectional imaging study e 
X 
To be performed between days 9 
through 21 
 
 
 
 
MUGA or echocardiogram f 
X 
 
 
 
 
 
p16 status  
X 
 
 
 
 
 
Adverse Event Assessment 
 
At each subject visit during treatment. 
 
X 
 
Concomitant Medication Assessment 
X 
At each subject visit during treatment. 
 
 
 
Fasting plasma glucose 
X 
Every 7 days (+/- 3 days) while on 
BYL719 
X 
 
 
 
Pill count/diary review 
 
Diary review to be done at each visit.  Pill count to be done when subject 
returns bottles and any extra pills. 
 
BYL719 g 
 
Take medication Days 1 through 21 
Continue 
BYL719 if 
surgery is 
delayed 
 
 
 
Surgery h 
 
Surgery is to be performed day 11 
or later.  
Surgery may be performed 
day 22 through day 29. 
 
 
Research blood collection i 
X 
Complete within 5 days prior to surgery 
 
 
 

 
 
 
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a. 
History and physical examination within 8 weeks prior to study entry. This should include surgical assessment of the primary tumor, including fiberoptic 
nasopharyngoscopy or examination under anesthesia as indicated per standard of care, and as determined by the treating surgeon.   
b. 
Pre-menopausal women of child-bearing potential (WOCBP) must have a negative serum pregnancy test within 4 weeks of registration. A negative pregnancy 
test, serum or urine, must then be documented within 72 hours of Day 1 of BYL719 treatment.  
c. 
The standard of care EKG performed for pre-surgical evaluation should be used.  EKGs performed within 12 weeks prior to study entry may be substituted, 
provided the patient has experienced no interval cardiac event. 
d. 
Clinical blood tests will be repeated once within 5 days prior to surgery, and at the 4 week and 12-week post-operative visits if clinically indicated according to 
the investigator.  Blood tests include, CBC with differential, serum chemistries including fasting glucose, LFTs, coagulation studies, except coagulation 
studies are not required at the 4 week or 12 week post-surgical visits.  Amylase, lipase, and HbA1c are done at baseline. 
e. 
Within 6 weeks of study entry (within 4 weeks preferred), and again within 5 days prior to planned surgery, patients will undergo cross-sectional radiological 
evaluation using diagnostic contrasted CT, PET/CT (with diagnostic contrasted CT), or MRI of regions with radiologically or clinically identifiable tumor.   
f. 
Cardiac imaging will be performed by Multiple Gated acquisition (MUGA) scan or Echocardiogram (ECHO) in order to assess the left ventricular ejection 
fraction (LVEF). MUGA or ECHO performed within 365 days prior to study entry may be substituted provided the patient has experienced no interval 
cardiac event. 
g. 
The first day of BYL719 treatment will be considered Day 1. BYL719 will be administered at 350 mg daily, for 10-21 days, and will be discontinued on the day 
prior to surgical resection.  If surgery is delayed, the study drug may be continued until surgery, for a maximum of 28 days.   
h. 
Surgery will be scheduled during days 11-22 of BYL719 treatment.  For logistical reasons, surgery may be delayed by up to 7 days (day 29).  Postoperative 
complications, hospital days, and ICU days will be noted for each patient.  
i. 
Research blood samples will be obtained at baseline (prior to study drug administration, within 3 weeks of registration) and within the 5 days prior to 
scheduled surgery. 
j. 
Research biopsies will be obtained at baseline (prior to study drug administration, within 3 weeks of registration) and during planned surgery for resection of 
the tumor. 
k. 
If surgery is delayed, subjects will continue to take BYL719 until the day prior to surgery (maximum 28 doses). The pre-operative history and physical 
examination, pre-operative clinical blood tests, vitals, assessment of ECOG status and pre-operative imaging do not need to be repeated. Research blood 
may be drawn again. 
l. 
Patients will be seen for a standard 4 week post-operative visit (+/- 2 weeks), and again for a standard 12-week post-operative visit (+/- 4 weeks). Clinical 
blood tests will be obtained as deemed clinically necessary. Thereafter, patients will be followed off study per standard of care. 
Biopsy for Research j 
X 
 
 
X 
 
 

 
 
 
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6.5 Usage of Concurrent/Concomitant Medications 
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the patient is permitted, except as specifically prohibited.  
Please refer to BYL719/alpelisib Investigator’s Brochure. 
All medications (excluding study treatment administered within 28 days prior to the 
administration of BYL) will be recorded in the Concomitant Medications log. Medications include 
not only physician prescribed medications, but also all over-the counter medications, herbal 
medications (prohibited, see Section 6.5.3 below) and food or vitamin supplements. The 
investigator should instruct the patient to notify the investigational site about any new 
medications he/she takes after the start of the study drug. 
 
6.5.1 Dietary Restrictions 
Patients will be instructed to avoid grapefruit products/juice, or Seville (sour) oranges/juice due 
to its potential for CYP3A4/5 interaction. 
6.5.2 Permitted Concomitant Therapy Medications 
In vitro metabolism studies performed to examine the reversible and metabolism-dependent 
inhibition of CYPP450 enzymes showed that BYL719, apart from the time-dependent inhibition 
of CYP3A4, is a weak, reversible inhibitor of CYP2C8, CYP2C9 and CPY2C19. Note that with 
the data available, it is not possible to confirm whether such interactions will occur in patients. 
Thus, caution should in principle be used in administering concomitantly drugs whose 
disposition is mainly dependent on these cytochrome P450 isoenzymes and whose therapeutic 
index is narrow. 
As it has been shown that BYL719 is a substrate of BCRP transporter in vitro and since the 
impact of this interaction has not been clinically investigated yet, BCRP inhibitors should also be 
used with caution to avoid a transport-related drug-drug-interaction. 
Patients receiving such medications must be monitored for potentiation of toxicity due to any 
individual concomitant medications and may require dose titration or reduction of the drug 
substrate. 
 
Permitted medications to be used with caution during treatment with BYL719: 
 
Antiemetics 
Use of anti-emetics is allowed. Prophylactic anti-emetics should be started only once the patient 
experiences nausea or vomiting, at the discretion of the investigator.  It is recommended that 
patients use drugs that do not cause QT prolongation. Please note that some anti-emetics have 
a known risk for TdP and are prohibited (refer to Appendix 3)  
 
Oral anti-diabetic Agents 
Patients who develop hyperglycemia during the study should be treated according to the ADA 
(American Diabetes Association) guidance. It is recommended to start treatment with metformin 
(or pioglitazone). Patients receiving oral antidiabetics which are predominantly  metabolized by 
CYP2C9 and CYP2C8, including but not limited to, repaglinide, rosiglitazone, glipizide and 

 
 
 
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tolbutamide, must be carefully monitored for hypoglycemia as BYL719 was found to be a 
moderate reversible inhibitor of these enzymes (refer to Table 1).  
 
Anticoagulation 
Anticoagulants other than warfarin/coumarin derivates or antiaggregation agents may be 
administered under the discretion of the investigator. However, caution is advised when BYL719 
is co-administered with anti-platelet pro-drugs such as clopidogrel, ticlopidine and prasugrel, 
which require metabolic activation by CYP3A4, CYP2C9 and CYP2C19.  BYL719 has the 
potential to inhibit these enzymes and may therefore decrease the metabolic activation and 
clinical efficacy of these pro-drugs.  Patients using anti-platelet pro-drugs should be carefully 
monitored (refer to Table 1). 
 
Contraceptives 
Hormonal contraceptives may be affected by cytochrome P450 interactions, and are therefore 
not considered effective for this study. For allowed contraception methods, refer to Exclusion 
Criteria. Highly effective contraception should be maintained throughout the study and through 
at least 1 weeks after the final dose of BYL719.  
 
CYP450 substrates 
In vitro studies demonstrate that BYL719 is a time dependent inhibitor of CYP3A4(Ki 5.6 μM, 
Kinact 0.011 min-1). Reversible inhibition of CYP2C8 (Ki 32 μM), CYP2C9 (Ki 22 μM) and 
CYP2C19 (IC50 75 μM) was also observed. BYL719 may inhibit metabolic clearance of co-
medications metabolized by CYP3A4, CYP2C8, CYP2C9 and CYP2C19, if sufficiently high 
BYL719 concentrations are achieved in vivo. Investigators, at their discretion, may administer 
concomitant medications known to be metabolized by or are substrates for CYP3A4/5, 
CYP2C8, CYP2C9 and CYP2C19. Patients receiving such medications and drugs which have a 
narrow therapeutic index must be carefully monitored for potential toxicity due to any individual 
concomitant medications. (Refer to Appendix 3). 
 
Caution is advised when BYL719 is co-administered with opioid analgesics. Inhibition of opioid 
metabolism by CYP3A4 can lead to opioid toxicity, including fatal respiratory depression, or an 
enhanced risk for QTc prolongation. Patients receiving BYL719 and opioid analgesics should be 
carefully monitored.  Synthetic opioids with clinically relevant interactions with CYP3A4 
inhibitors include, but are not limited to, propoxyphene, fentanyl, alfentanyl and sufentanil. Use 
of alfentanyl, a sensitive CYP3A4 substrate with narrow therapeutic window, should be full 
avoided whenever possible. The use of methadone and levomethadyl is prohibited (Refer to 
Appendix 3). 
 
Gastric protection agents  
BYL719 is characterized by a pH-dependent solubility. Medicinal products that alter the pH of 
the upper gastro-intestinal tract may alter the solubility of BYL719 and hence its bioavailability. 
These agents include, but are not limited to, proton-pump inhibitors (PPI) (e.g., omeprazole), H2-
antagonists (e.g., ranitidine) and antacids. Due to long pharmacodynamic effect of PPIs, i.e. 
long-lasting reduction of gastric acid production over 36 hours, H2-antagonists and antacids are 
recommend to be used over PPIs, whenever possible. Note that some proton pump inhibitors 
may possibly also inhibit BCRP (refer to Table 1). A drug-drug interaction study in human 
healthy volunteers confirmed that co-administration of alpelisib with the H2-antagonist ranitidine 

 
 
 
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after a meal lead to a decrease in exposure by only ~20%, considered to be not clinically 
relevant. Hence alpelisib can be co-administered with any ARAs. 
 
BYL719 should preferably be dosed in a staggered manner, i.e., at least 1 hour before or 10 
hours after dosing with a gastric protection agent. 
 
BCRP inhibitors 
BYL719 was identified as a substrate for the human BCRP. Co-administration of BYL719 with 
BCRP inhibitors may possibly increase systemic exposure and/or alter tissue uptake of oral 
BYL719. The treatment with BCRP inhibitors should be kept as short as possible or, if possible, 
fully avoided. See Appendix for Table of Permitted Medications. 
 
6.5.3 Prohibited concomitant therapy 
The following medications are prohibited during treatment in this study (see Appendix 3, this list 
is not comprehensive and is only meant to be used as a guide. Please contact the PI with any 
questions): 
• 
Medications with a known risk for TdP 
• 
Other investigational and antineoplastic therapies 
In addition, the use of herbal preparations/medications and dietary supplements (except for 
vitamins) are prohibited throughout the study, as a potential drug-drug interaction is possible. 
Herbal medications include, but are not limited to: St. John’s wort, Kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone, yohimbe, saw palmetto, black cohosh and ginseng. 
Patients should stop using all herbal medications and dietary supplements at least 7 days prior 
to first dose of study treatment. 
As far as possible avoid co-administering QT prolonging drugs (or any other drug with the 
potential to increase the risk of drug-related QT prolongation e.g. via a potential DDI increasing 
the exposure of the study drug or the exposure of the QT prolonging drug). If during the course 
of the study, concomitant administration of drugs with a known potential to cause Torsades de 
Pointe is required and cannot be avoided, study drug must be interrupted until an assessment of 
the potential safety risk has been performed. A definitive list of drugs associated with QT 
prolongation and/or TdP is available online at www.crediblemeds.org. If, based on the 
investigator assessment and clinical need study treatment is resumed, close ECG monitoring is 
advised. 
Metabolism studies in both human and animal liver preparations (microsomes, hepatocytes) 
showed a low metabolism of BYL719 by phase I and phase II metabolic enzymes. 
Phenotyping studies in human liver microsomes confirmed that biotransformation mainly takes 
place via CYP3A4 (minor involvement of CYP2J2) with no major participation of UGTs. In vitro 
metabolism studies performed to examine the reversible and metabolism-dependent inhibition 
of cytochrome P450 enzymes showed that BYL719 is a time-dependent inhibitor of CYP3A4. 
The following medications are therefore prohibited during treatment with BYL719: 
 
Other anticancer therapy 
If a patient, enrolled in the study, requires the concomitant use of any medication included in 
Appendix 3 entitled “List of Prohibited Medications during BYL719 Treatment” (i.e., drugs that 
are generally accepted by the Qtdrugs.org Advisory Board of the Arizona CERT to have a 

 
 
 
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known risk of causing TdP), B Y L 7 1 9  administration must be interrupted as long as the 
patient requires therapy with the QT prolonging agent. Note that Table2 also prohibits drugs 
that are substrates for CYP3A and CYP2C with a possible or conditional risk for TdP. If the 
patient requires long term therapy with such a QT prolonging agent, leading to study 
treatment interruption of > 28 days, the patient must be permanently discontinued from 
BYL719. 
 
Herbal medications 
 
Herbal preparations/medications are not allowed throughout the study. These herbal 
medications include, but are not limited to St. John’s wort, Kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. 
Patients should stop using these herbal medications 7 days prior to first dose of study drug. 
 
Warfarin and coumarin derivates 
 
Therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative 
anticoagulants are not permitted. Warfarin has a narrow therapeutic range and BYL719 is a 
possible inhibitor of CYP2C8 and 2C9, the major metabolizing enzyme of warfarin. Therapeutic 
anticoagulation may be accomplished using low-molecular weight heparin. 
 
Radiation therapy must not be given with BYL719 to patients while the patient is treated. If 
radiation therapy is required for a patient then the patient must be discontinued. 
 
 
7  Tumor Measurements 
  
The primary objective of this study is to evaluate ΔTumor size, which will be measured using 
established RECIST v1.1 metrics for target lesions, however treated as a continuous variable as 
previously described (23). Target lesions will be evaluated using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000].  Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter of metastatic lymph nodes are used in the RECIST 
v1.1 criteria.  
NOTE: Because this is a pre-operative window study with only brief exposure to study drug, and 
RECIST responses are not anticipated, target lesions will be measured bi-dimensionally and 
recorded quantitatively.  Quantitative change in the RECIST-defined baseline sum diameter 
(longest diameter of tumor + short axis diameter of up to three pathologic lymph nodes), 
expressed as a percent, will be the primary endpoint and will be correlated with biomarker 
modulation.  
All tumor measurements pre- and post-treatment will be performed independently by a single 
neuroradiologist.   
 
Evaluable for quantitative change in tumor size 
Only those patients who have measurable disease present at baseline, have received at least 
10 doses of BYL719, and have had their disease re-evaluated will be considered evaluable for 
change in tumor size.   
 

 
 
 
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7.1 Disease Parameter Definitions 
Measurable disease 
Primary Tumors. Measurable disease is defined as a primary tumor that can be accurately 
measured by one of the following techniques: 
• 
Cross-sectional imaging (spiral CT or MRI): the primary tumor can be measured in at 
least one dimension (longest diameter to be recorded) and measures at least 10 mm, 
when using spiral CT or MRI with slice thickness no thicker than 5 mm.  
• 
Caliper exam: the primary tumor measured at least 10mm in longest diameter by caliper 
measurement on clinical exam. Note: A photograph with superimposed caliper or ruler is 
strongly preferred for documentation of baseline and response. 
• 
PET/CT 
Lymph Nodes. Measurable disease is defined as a lymph node that can be accurately measured 
by cross-sectional imaging (spiral CT or MRI) and measures at least 15 mm in shortest diameter, 
when using spiral CT or MRI with slice thickness no thicker than 5 mm. 
All tumor measurements will be recorded in millimeters or decimal fractions of centimeters.   
Target lesions 
Only the following will be used as target lesions in this HNSCC window trial: 
• 
Primary tumor (long axis) 
• 
Up to two metastatic cervical lymph nodes (short axis) 
Non-target lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 
target lesions should be identified as non-target lesions and should also be recorded at 
baseline.   
Non-measurable disease (Tumor Markers) 
Non-measurable disease is all other lesions (or sites of disease), including small lesions 
(longest diameter < 20 mm with conventional techniques or < 10 mm using spiral CT scan).  
Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by reproducible imaging techniques are all non-
measurable. (e.g., PSA, CA-125, CA19-9, CEA) 
7.2 Methods for Evaluation of Measurable Disease 
All measurements will be taken and recorded in metric notation using a ruler or calipers.   
The same method of assessment and the same technique will be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the antitumor effect of a treatment. 
8 
Documentation and Reporting of Adverse Events & Unanticipated Problems 
All patients will be evaluable for toxicity from the time of their first treatment with the study drug. 
Analyses will be performed for all patients having received at least one dose of study drug using 
the CTCAE v4.03 for reporting of non-hematologic adverse events and modified criteria for 
hematologic adverse events. 

 
 
 
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8.1 Definitions of Adverse Events 
8.1.1 Adverse Event 
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related.  More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, without any judgment about causality.  An adverse event can arise from any use of the 
drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose.  
8.1.2 Adverse reaction 
An adverse reaction is defined as any adverse event caused by the use of a drug.  Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event. 
8.1.2.1 Suspected  
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship 
between the drug and the adverse event.  A suspected adverse reaction implies a lesser degree 
of certainty about causality than an adverse reaction. 
8.1.2.2 Unexpected  
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in 
the investigator brochure or package insert(s), or is not listed at the specificity or severity that 
has been observed, or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the current 
application.  
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or 
as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure.  For example, a certain number of non-acute deaths in a cancer trial 
would be anticipated as an outcome of the underlying disease, but such deaths would generally 
not be listed as a suspected adverse reaction in the investigator brochure. 
Some adverse events are listed in the Investigator Brochure as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not been observed with the drug under investigation.  Such events would be considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class 
effect, the first case of angioedema observed with the drug under investigation should be 
considered unexpected for reporting purposes. 
8.1.2.3 Serious 
Serious adverse event (SAE) is defined as one of the following: 

 
 
 
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• 
Is fatal or life-threatening 
• 
Results in persistent or significant disability/incapacity 
• 
Constitutes a congenital anomaly/birth defect 
• 
Is medically significant, i.e., defined as an event that jeopardizes the patient or 
may require medical or surgical intervention to prevent one of the outcomes 
listed above 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
unless hospitalization is for: 
o Note that hospitalizations for the following reasons might not be reported as 
serious adverse events: 
o Routine treatment or monitoring of the patient’s cancer indication, not associated 
with any deterioration in condition  
o Elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the patient’s cancer indication and has not worsened since the start of the 
treatment with alpelisib 
o Social reasons and respite care in the absence of any deterioration in the 
patient’s general condition 
o Is medically significant, i.e., defined as an event that jeopardizes the patient or 
may require medical or surgical intervention to prevent one of the outcomes 
listed above e.g. may require treatment on an emergency outpatient basis for an 
event not fulfilling any of the definitions of a SAE given above and not resulting in 
hospital admission 
o Transmission of infectious agent via medicinal product 
Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event. 
 
In the event of a serious adverse event, the PI, the institutional review board (per institutional 
reporting requirements), and Novartis Corporation will be notified using the FDA Form 3500 
MedWatch report.   
All events meeting the definition of a serious adverse event should be recorded on a MedWatch 
3500 Form 
(http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM163919.pdf ) and 
submitted to: 
1. DSMC 
2. Local IRB per institutional reporting requirements 
3. FDA 
4. Novartis 
 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include as applicable the following information that is available at the time of 
report within the Event Description (section 5) of the MedWatch 3500 form: 
• 
CTCAE term(s) and grade(s)  
• 
Current status of study drug 
• 
All interventions to address the AE (testing and result, treatment and response) 
• 
Hospitalization and/or discharge dates 
• 
Event relationship to study drug 
 

 
 
 
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8.1.2.4 Life-threatening 
An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death.  
8.2 Recording of an Adverse Event 
Only AEs meeting one of the following criteria will be entered into the OnCore CRM study 
database, whether or not the event is believed to be associated with use of the study drug. Data 
about these events and their severity will be recorded using the NCI CTCAE v4.0. 
 
• 
Any AE that is Grade 3 or higher, regardless of relationship to the study drug 
• 
Any intolerable Grade 2 AE 
• 
Any Grade AE resulting in holding or dose-reducing BYL719 
• 
Any Grade 2 laboratory or vital sign values that are deemed clinically significant by the 
treating investigator 
• 
Any Grade AE in the following categories of interest: 
o Rash 
o Diarrhea 
o Pneumonitis 
o Hyperglycemia 
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into OnCore® using the classification 
system listed below:  
Relationship  
Attribution  
Description  
Unrelated to investigational 
drug/intervention 
Unrelated 
The AE is clearly NOT related to the 
intervention  
Unlikely 
The AE is doubtfully related to the 
intervention  
Related to investigational 
drug/intervention 
Possible 
The AE may be related to the intervention  
Probable 
The AE is likely related to the intervention  
Definite 
The AE is clearly related to the intervention  
 
Grade 0: 
No AE (or within normal limits) 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2: 
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL) 

 
 
 
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Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE.  When specific adverse events are not listed in the CTCAE, the 
Investigator will grade as none, mild, moderate or severe according to the following grades and 
definitions. 
8.3 Follow-up of Adverse Events 
All adverse events will be followed with appropriate medical management until resolved.  
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  For selected adverse events for which administration of the 
investigational drug was stopped, a re-challenge of the subject with the investigational drug may 
be conducted if considered both safe and ethical by the Investigator. 
Subjects who end treatment due to an AE determined to be at least possibly related to the study 
must have weekly follow up to assess the AE until the AE is resolved, returns to baseline grade, 
or stabilizes, whichever occurs first. 
8.4 Adverse Event Monitoring  
Adverse events, whether or not unexpected, and whether or not considered to be associated 
with the use of the study drug, will be entered into OnCore®, as noted above. 
The Investigator will assess all adverse events and determine reportability requirements to the 
University of Arizona Data and Safety Monitoring Board (DSMB) and University of Arizona’s 
Institutional Review Board (IRB); and, when the study is conducted under an Investigational 
New Drug Application (IND), to the Food and Drug Administration (FDA) if it meets the FDA 
reporting criteria. 
All adverse events entered into OnCore® will be reviewed by the University of Arizona 
Comprehensive Cancer Center HNSCC Clinical Research Team (CRT) at minimum on a 
monthly basis.  The CRT will review and discuss at each monthly meeting the selected toxicity, 
the toxicity grade, and the attribution of relationship of the adverse event to the administration of 
the study drug(s), including all grade(s) 3-5 adverse events. 
In addition, all grade(s) 3-5 adverse events and all suspected adverse reactions considered 
“serious” entered into OnCore®, will be reviewed and monitored by the Data and Safety 
Monitoring Board on an ongoing basis and discussed at DSMB meetings, which take place 
every four weeks. 
8.5 Serious Adverse Event Reporting 
In the event of a serious adverse event, the PI, the institutional review board (if applicable, per 
institutional reporting requirements), and Novartis will be notified using the FDA Form 3500 
MedWatch report.  
SAEs must be reported within 24 hours of learning of its occurrence. Additional information must 
be provided in a follow-up SAE report and also reported within 24 hours after receiving the 
information. 
Grade 3: 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 
Grade 5: 
Death related to AE 

 
 
 
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ALL events meeting the definition of a serious adverse event must be reported using the current 
FDA MedWatch 3500 Form and submitted to: 
• 
UACC DSMB 
• 
Novartis 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include as applicable the following information that is available at the time of 
report within the Event Description of the MedWatch 3500 form: 
• 
CTCAE term(s) and grade(s)  
• 
Current status of study drug 
• 
All interventions to address the AE (testing and result, treatment and response) 
• 
Hospitalization and/or discharge dates 
• 
Event relationship to study drug 
Follow-up SAE Reports  
Additional information may be added to a previously submitted SAE report and submitted as 
follow-up SAE Report. 
Reporting to the UACC Data and Safety Monitoring Board 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient 
has taken the first dose of study drug and through the end of the study follow-up period must be 
reported to the DSMB Chair (or qualified alternate) within 24 hours of learning of its occurrence. 
If a death occurs during the treatment phase of the study or during the study follow-up period and 
it is determined to be related to the study drug or to a study procedure, the Investigator or his/her 
designee must notify the DSMB Chair (or qualified alternate) within 1 business day of knowledge 
of the event. The contact may be by phone or e-mail.  
Reporting safety information to Novartis 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. Any 
SAEs experienced after this 30 day period should only be reported to Novartis if the investigator 
suspects a causal relationship to the study treatment. Recurrent episodes, complications, or 
progression of the initial SAE must be reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one should 
be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department. 
The telephone and telefax number of the contact persons in the local department of Drug Safety 
and Epidemiology (DS&E), specific to the site, are listed in the investigator folder provided to 
each site. The original copy of the SAE Report Form and the fax confirmation sheet must be 
kept with the case report form documentation at the study site. 

 
 
 
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Follow-up information is sent to the same contact(s) to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. Each re-occurrence, complication, or progression 
of the original event should be reported as a follow-up to that event regardless of when it 
occurs. The follow-up information should describe whether the event has resolved or continues, 
if and how it was treated, whether the blind was broken or not, and whether the patient 
continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Drug Safety and Epidemiology (DS&E) department associate may urgently require further 
information from the investigator for Health Authority reporting. Novartis may need to issue an 
Investigator Notification (IN), to inform all investigators involved in any study with the same drug 
that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) 
will be collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in participating 
countries. 
8.6  Reporting Unanticipated Problems 
Adverse events, serious adverse events, and deviations may be considered “unanticipated 
problems.” Unanticipated problems, as defined below, will be reported to oversight entities 
including the IRB and FDA as required by regulation and/or policy. 
Note: Treatment or visit delays for public holidays or weather conditions do not constitute a 
protocol violation/deviation. 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all of the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
9 Data and Safety Monitoring Plan: 
 
9.1 Identification of the DSMB obligated for oversight responsibilities: 
Dr. Julian at the University of Arizona Cancer Center (UACC) will assume the role of Sponsor. 
The UACC Data and Safety Monitoring Board (DSMB) will provide ongoing oversight of safety 
monitoring for this trial.  Based on the UACC DSMB Charter, this is a high-risk study. 
 

 
 
 
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9.2  
Identification of the entity obligated for routine monitoring duties: 
 
This trial will undergo real-time monitoring by the PI and study team, including documentation of 
real-time monitoring of any new or ongoing safety issues.     
 
The PI and study team will meet monthly to review the data and CRFs.  
 
Routine monitoring will be provided monthly by the University of Arizona Cancer Center 
Compliance and Quality Assurance (CQA) Program to ensure that the investigation is 
conducted according to protocol design and regulatory requirements. Affiliate sites that 
participate in this trial will choose, through a reciprocal agreement with UACC, either to: 
1) Perform monitoring per the sites’ Data and Safety Monitoring Plan, only if the site has 
fully approved NCI Data and Safety Monitoring Plan.  
2) Allow UACC to conduct remote and on-site monitoring for this trial in accordance with 
the UACC’s approved NCI Data and Safety Monitoring Charter/Monitoring Plan. 
3) Perform monitoring per the UACC’s Data and Safety Monitoring Charter/Plan.  
If a site-specific monitoring plan will be used, the UACC DSMB must review the sites’ Data and 
Safety Monitoring Plan and approve that the plan is acceptable.  If the UACC DSMB finds that a 
plan is not acceptable, the UACC or the site’s internal monitors will perform monitoring per the 
UACC Data and Safety Monitoring Plan.  
Elements that are required to be included within each site-specific DSM plan are: 
• 
A process to verify eligibility by the local monitoring team. 
• 
Documented timelines in which serious adverse events are reported to the sponsor. 
• 
Frequency and extent of monitoring activities for this trial at the site 
• 
Monitoring reports will be provided to the PI, UACC DSMB, and UA IRB. The PI is 
responsible to follow up on any action items and/or findings in a timely manner. 
• 
Monitoring reports will be provided to the PI, UACC DSMB, and UA IRB. The PI is 
responsible to follow up on any action items and/or findings in a timely manner. 
• 
Monitoring reports will be provided to the PI, UACC DSMB, and UA IRB. The PI is 
responsible to follow up on any action items and/or findings in a timely manner. 
 
 
9.3  
Monitoring progress and data review process: 
Routine monitoring of subject data will be conducted at least every month.  
The first routine monitoring visit will include at a minimum: 
• 
Informed consent – 100% of cases enrolled;  
• 
Subject eligibility – 100% of cases, up to three subjects; 
• 
Data review – 100% of cases, up to three subjects. 
 
All subsequent monitoring visits will consist of randomly selected subject cases based 

 
 
 
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on current enrollment and include continuing review of previously selected cases, as 
applicable.  
 
Routine monitoring of regulatory documents and test article will be conducted every 
three months. 
 
A monitoring visit report and follow-up letter will be completed approximately two weeks 
after the routine monitoring visit; a copy will be maintained in the study file. The monitor 
will request additional source documentation, clarification, information, or corrections to 
the CRF and/or regulatory records from the Clinical Research Coordinator (CRC) or 
other applicable staff responsible for the study and resolution of queries/findings.  
Documentation of such a request will be maintained with a copy of the monitor’s visit 
report for follow-up at the next monitoring visit. Electronic records will be available in the 
institutional database or provided by the CQA Program staff.   
 
All monitoring reports must be completed and submitted to the local site PI, the Sponsor-
Investigator, and UACC DSMB. All submitted serious adverse events will be submitted 
to the UACC DSMB Coordinator monthly and then reviewed by the DSMB Chair. Any 
identified SAE trends will be made available for review at the investigator 
teleconferences.  
 
A teleconference will occur on a regular schedule to review study progress and any 
safety, or other, issues. Minutes of these teleconference meetings will be submitted to 
UACC DSMB for review. 
 
At each site, the Principal Investigator will ensure the accuracy, completeness, legibility 
and timeliness of the data reported in the OnCore electronic Case Report Form (eCRF), 
and other data formats. Source documentation supporting the study data should indicate 
the subject’s participation in the trial and should document the dates and details of study 
procedures, adverse events, and patient status.  
 
Case report forms, which include adverse event forms, serious adverse event forms, and 
protocol or patient deviations must be completed via the RedCap database 
 
9.4 Plan for assuring data accuracy and protocol compliance: 
Any identified safety issue will be submitted to the UA IRB, DSMB or other oversight entity as 
applicable.  Each month the DSMB will perform a review of study activity and safety information 
at each site.  A summary of activity at all sites will be reviewed including the following: 
 
• 
Study activity, cumulative and for the period under review; 
• 
Safety information (non-serious and serious adverse events);  
• 
Status of study in relationship to stopping rules;  
• 
Routine monitoring and protocol compliance (describe the monitoring process and 
identify the status of the monitoring);  
• 
Attachments (AE data reviewed by the PI to compile the report, SAE reports, results of 
any review(s), applicable correspondence with the IRB or other regulatory agencies. 
Data and Safety Monitoring Board determinations will be reported to the University of 

 
 
 
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Arizona IRB at least annually. DSMB determinations will be distributed to the sites 
contemporaneously. 
 
 
Data, safety and study progress will be reported to: 
• 
Human Subjects Protection Program (IRB) at least annually; 
• 
Sponsor (if applicable) at least quarterly. 
 
10 Statistical Considerations and Evaluation of Results 
10.1 
Study Endpoints 
This is a phase II open label study to identify baseline and/or pharmacodynamics biomarkers of 
clinical response to BYL719 based on quantitative change in tumor size following 10-21 days of 
neoadjuvant BYL719 in patients with operable HNSCC. ΔTumor size will be treated as a 
continuous variable, based upon the percent change in RECIST-determined index lesions pre 
and post-treatment. 
10.2 
Determination of Sample Size and Accrual Rate 
10.2.1 Sample Size and Power Estimate 
The primary objective of the study is to identify baseline and/or pharmacodynamic biomarkers 
that might have predictive utility to determine the clinical response to BYL719.  The overall 
sample size is 14 evaluable patients. Accrual will continue until 14 evaluable patients have 
enrolled If patient had baseline tissue samples obtained, has taken at least 10 doses of drug, 
and has undergone response assessment that is of sufficient quality to assess the primary 
clinical and biomarker endpoints, they are evaluable. Based upon prior window trials, up to 20 
patients will be enrolled to meet these criteria. The sample size is based upon the following 
considerations: half of enrolled patients will demonstrate genomic PI3K pathway activation, 
defined as PIK3CA mutation or amplification, or PTEN deletion. We expect those with 
genomically activated PI3K to demonstrate a median ΔTumor size of (-)20%, whereas those 
with no genomic PI3K activation to demonstrate a median increase of (+)5%. Alpha is set to 
0.03  and beta is set to 0.20. 
 
As a biomarker study, the statistical design is to accrue a sufficient number of patients and 
provide 80% power to test one or any of 5 key hypotheses with individual alphas of 0.03:  1) 
relationship between ΔTumor size and baseline genomic PIK3CA activation; 2) relationship 
between ΔTumor size and change in expression of HPV mRNA (qPCR); 3) relationship between 
ΔTumor size and change in expression of E6, E7 oncoprotein (immunoblotting); 4) relationship 
between ΔTumor size and change in expression of phospho-HER3 (immunoblotting and RPPA); 
5) relationship between ΔTumor size and change in expression of HER3/PI3K dimers 
(Monogram).  14 patients with complete biomarker data are needed to achieve 80% power for 
the 5 primary hypothesis and limit overall family wise error rate (FWER) to 15%. Based upon 
prior window trials, accounting for treatment compliance and quality paired tumor specimens, 
this will require enrollment of 20 patients.  
 
As an example, to justify the sample size for the first key hypothesis (relationship between 
ΔTumor size and baseline genomic PIK3CA activation), the standard deviation of ΔTumor size 

 
 
 
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was estimated from the erlotinib arm of Dr. Bauman’s previously completed study of erlotinib 
and dasatinib or both versus placebo (Bauman JE et al, JCI Insight 2017).  In this study, the 
quantitative change in tumor size after 10-21 days of targeted therapy ranged from -30% to 
55%.  Assuming the same standard deviation for the change in tumor size after BYL719 
treatment as observed for the erlotinib arm (sd = 8%), the study will have > 90% statistical 
power to detect the mean difference of -20% versus +5% in those with and without PIK3CA 
activation, assuming an alpha level of 0.03.  The power was calculated based on a two-sample t 
test with equal variances, assuming an alpha level of 0.03 with n = 7 per group. 
10.2.2 Replacement Policy 
Because this is an open label study with limited number of patients, 14 accrued eligible patients 
with clinical tumor assessments and biomarkers measurements at baseline and the end of study 
window are required for the study. Additional patients will be enrolled to replace patients without 
clinical tumor assessments and completed biomarker measurements for both timepoints and at 
least one of the five biomarkers of interest. However, all patients will be followed and included 
for safety assessments.  
10.3 
Protocol Early Stopping Rules 
10.3.1 Toxicity 
A continuous monitoring rule for safety will be instituted, to guard against excess toxicity from 
pre-operative treatment with BYL719 at 350 mg po daily, the RP2D for this agent. All patients 
will be treated at the dose of BYL719 350 mg po daily. After enrollment of the 6th patient, we will 
continuously monitor the number of patients who discontinue BYL719 and come off study for 
BYL719-attributable toxicity. A qualifying toxicity must be at least possibly related to BYL719, as 
judged by the treating investigator, and fulfill one of the following definitions: 
 
• 
Grade ≥ 3 non-hematologic toxicity, with the exception of asymptomatic electrolyte 
abnormalities manageable with repletion.  
• 
Intolerable non-hematologic toxicities of any grade, which persist despite optimal 
medical management. 
• 
Grade ≥ 3 thrombocytopenia or neutropenia. 
• 
Any grade toxicity that results in a significant delay of surgery, defined as more than 42 
days from the start of BYL719 protocol treatment. 
 
If the posterior probability of ≥ 33% toxicity rate exceeds 50% for patients having to discontinue 
window treatment due to qualifying toxicity, this would be considered unacceptable. The study 
would be placed on hold and would be referred to the UACC DSMB for evaluation of excess 
toxicity and recommendations for design change or study closure. 
 
Table 8 below describes the number of toxicity events per number of treated patients required to 
trigger referral to the UACC DSMC.  Table 8 also shows the posterior probability that the rate 
exceeds 33%, and the binomial probability associated with the decision for an assumed 33% 
discontinuation rate.  The prior probability has a beta distributions with parameters a = 1 and b = 
9, assumes a 10% mean with an approximate 80% mid-range of .0 to .22. 
 
Table 8. Boundaries for the Excess Toxicity Rule 

 
 
 
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Subjects Treatment-Related 
Discontinuations 
PP(π > 33%)* Pr(X ≥ r|p = .33) 
6 
5 
.629 
.017 
8 
6 
.685 
.019 
11 
7 
.673 
.037 
14 
8 
.664 
.054 
17 
9 
.657 
.071 
20 
10 
.650 
.087 
*π is the discontinuation rate. The minimum acceptable upper bound of a treatment-related 
discontinuation is 33%. PP(π > 33%) is the posterior probability that the discontinuation rate 
exceeds this 33% upper bound. This posterior probability of discontinuation is calculated from 
the prior distribution, the number of subjects treated and the observed number of treatment-
related discontinuations. 
 
10.3.2 Delay in Surgery 
Because the protocol enrolls patients who will undergo potentially curative surgery, a 
conservative stopping rule is in place to guard against unacceptable delays in surgery.  An 
unacceptable delay in surgery is defined as surgery occurring more than 42 days after the start 
of BYL719 protocol treatment, AND is due to a toxicity that is at least possibly related to BYL719 
as judged by the treating investigator. Among the first 14 patients, if the number of patients with 
an unacceptable delay in surgery ever exceeds 3, then enrollment will be stopped and the study 
will be referred to the UACC DSMC for evaluation of unacceptable delays in surgery, and 
recommendations for study redesign or closure. 
11 Study Management 
11.1 
Pre-study Documentation 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects.   
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements.  
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements. 

 
 
 
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11.2 
Institutional Review Board Approval 
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) will be reviewed and 
approved by the UA CHR (UA Institutional Review Board).  Prior to obtaining CHR approval, the 
protocol must be approved by the University of Arizona Comprehensive Cancer Center Site 
Committee and by the Protocol Review Committee (PRC).  The initial protocol and all protocol 
amendments must be approved by the IRB prior to implementation.   
11.3 
Informed Consent 
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants 
must sign the CHR-approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  
The original signed copy of the consent document must be retained in the medical record or 
research file.  
11.4 
Changes in the Protocol 
Once the protocol has been approved by the IRB, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the Investigator 
and approved by the IRB prior to implementation.   
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to CHR approval.  In this circumstance, however, the 
Investigator must then notify the CHR in writing within five (5) working days after 
implementation.  The Study Chair and the UA study team will be responsible for updating any 
participating sites. 
11.5 
Deviations 
A protocol deviation (noncompliance, unanticipated problem) may be either on the part of the 
participant, the investigator, or the study site staff. No changes from current IRB-approved 
research protocol are allowed except where a change may be necessary to eliminate an apparent 
immediate hazard to a human subject. Deviations may be identified by any study staff or 
monitoring/oversight entity. As a result of deviations, as applicable, corrective actions are to be 
developed by the site and implemented promptly.  
Deviations will be documented in the CTMS and reported to oversight entities, as applicable. 
11.6 
Maintenance of Subject Specimens 
Specimens collected as part of this study will be maintained for future use to learn about 
preventing or treating cancer. Subjects will be asked to consent to the future use during the 
informed consent process, and asked to positively indicate their consent to future use in writing 
within the informed consent document. Samples will be maintained in a secure location within the 
UACC. 
11.7 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to the PI, study participants, 
investigator, Lilly, the FDA Investigational New Drug (IND and other regulatory authorities as 
applicable. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 

 
 
 
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promptly inform study participants, the Institutional Review Board (IRB), and will provide the 
reason(s) for the termination or suspension. Study participants will be contacted, as applicable, 
and be informed of changes to study visit schedule. 
 Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of the study meeting futility and/or stopping rules 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB, and/or Food and Drug Administration (FDA). 
11.8 
Handling and Documentation of Clinical Supplies 
The UA Principal Investigator and each participating site will maintain complete records showing 
the receipt, dispensation, return, or other disposition of the study drug. The date, quantity and 
batch or code number of the drug, and the identification of patients to whom study drug has been 
dispensed by patient number and initials will be included. The sponsor-investigator will maintain 
written records of any disposition of the study drug. 
The Principal Investigator shall not make the study drug available to any individuals other than to 
qualified study patients. Furthermore, the Principal Investigator will not allow the study drug to be 
used in any manner other than that specified in this protocol. 
11.9 
Case Report Forms (CRFs) 
The Principal Investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis. All study data will be entered into OnCore® via standardized 
CRFs in accordance with the CTMS study calendar, using single data entry with a secure 
access account. The Clinical Research Coordinator (CRC) will complete the CRFs as soon as 
possible upon completion of the study visit; the Investigator will review and approve the 
completed CRFs.  
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records maintained by UA 
personnel.  All source documentation should be kept in separate research folders for each 
patient. 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate.  
All source documentation and CTMS data will be available for review/monitoring by the UA 
DSMC and regulatory agencies. 
The Principal Investigator will be responsible for ensuring the accurate capture of study data.  At 
study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked.  Any changes to the data entered into the CRFs after that time can only 

 
 
 
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be made by joint written agreement among the Study Chair, the Trial Statistician, and the 
Protocol Project Manager. 
11.10 Record Keeping and Record Retention 
The Principal Investigator is required to maintain adequate records of the disposition of the 
drug, including dates, quantity, and use by subjects, as well as written records of the disposition 
of the drug when the study ends.   
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data (e.g., signed and dated 
consent forms and medical records, such as progress notes of the physician, the individual's 
hospital chart(s), and the nurses' notes. The case history for each individual shall document that 
informed consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, CHR correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified. 
11.11 Coordinating Center Documentation of Distribution [multi center studies] 
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution 
of study documents as well as their receipt (when possible). The HDFCCC recommends that 
the Study Chair maintain a correspondence file and log for each segment of distribution (e.g., 
FDA, drug manufacturer, participating sites, etc.). 
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt. 
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received. 
At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its 
updates and safety information are distributed. 
12 Protection of Human Subjects 
12.1 
Protection from Unnecessary Harm  
Each clinical site is responsible for protecting all subjects involved in human experimentation. 
This is accomplished through the IRB mechanism and the process of informed consent. The 
IRB reviews all proposed studies involving human experimentation and ensures that the 
subject’s rights and welfare are protected and that the potential benefits and/or the importance 
of the knowledge to be gained outweigh the risks to the individual. The IRB also reviews the 
informed consent document associated with each study in order to ensure that the consent 

 
 
 
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document accurately and clearly communicates the nature of the research to be done and its 
associated risks and benefits.  
12.2 
Protection of Privacy 
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the PHI Authorization form (to authorize use and disclosure of PHI in compliance with 
HIPAA) form and informed consent documents. The original signed document will become part 
of the patient’s medical records, and each patient will receive a copy of the signed document. 
The use and disclosure of protected health information will be limited to the individuals 
described in the informed consent document. 
In the event that a subject revokes authorization to collect, use, and/or disclose PHI, the 
investigator, by regulation, retains the ability to use all information collected prior to the revocation 
of subject authorization. For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (i.e., that the subject 
is alive) at the end of their scheduled study period. 
Only authorized individuals will have access to the identifiable study data. All records identifying 
subjects must be kept confidential per local and Federal policy. Minimum necessary standards 
must be followed. All subjects are assigned a study ID number. The study data to be used for 
purposes of analysis and reporting will be coded. Specimens will also be coded using the study 
ID number. Subject identities will not be used in any results that are published. 
Study subjects and study data will be entered into the CTMS. The system is password protected 
and meets HIPAA requirements. 
 
 
 

 
 
 
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Appendices 
Appendix 1 
Performance Status Criteria 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity 
Fully active, able to carry on all 
pre-disease performance 
without restriction 
100 
Normal, no complaints, no evidence 
of disease 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease 
1 
Symptoms, but ambulatory 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry out 
work of a light or sedentary 
nature (e.g., light housework, 
office work) 
80 
Normal activity with effort; some 
signs or symptoms of disease 
70 
Cares for self, unable to carry on 
normal activity or to do active work 
2 
In bed < 50% of the time 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities 
Up and about more than 50% of 
waking hours 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs 
50 
Requires considerable assistance 
and frequent medical care 
3 
In bed > 50% of the time 
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking hours 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization 
indicated 
Death not imminent 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
20 
Very sick, hospitalization indicated 
Death not imminent 
10 
Moribund, fatal processes 
progressing rapidly 
5 
Dead 
0 
Dead 
 
 
 
 
 

 
 
 
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Appendix 2 
Permitted medications to be used with caution 
Table 1. List of medications to be used with caution during treatment with 
alpelisib 
Category 
Drug Name 
CYP2A6 substrates 
Disulfiram, fadrozole, halothane, losigamone, methoxyflurane, 
nicotine, valproic acid 
Sensitive CYP2C8 substrates2 
Paclitaxel, repaglinide 
Sensitive CYP2C9 substrates2 
Phenytoin 
Sensitive CYP2C19 substrates2 
S-mephenytoin, R/S-lansoprazole, clobazam, omeprazole, tilidine  
ModerateCYP3A Inhibitors  
Amprenavir, atazanavir, casopitant, cimetidine, ciprofloxacin, 
cyclosporine, darunavir, diltiazem, dronedarone, erythromycin, 
fluconazole, fosamprenavir, grapefruit juice (citrus paradisi fruit 
juice), imatinib, Schisandra sphenanthera2, tofisopam, verapamil 
Moderate CYP3A Inducers  
Bosentan, efavirenz, etravirine, genistein, modafinil, nafcillin, 
ritonavir, talviraline, thioridazine, tipranavir 
Gastric protection agents 
BYL719 is characterized by a pH-dependent solubility. Medicinal 
products that alter the pH of the upper gastro-intestinal tract may 
alter the solubility of alpelisib and hence its bioavailability. These 
agents include, but are not limited to, proton-pump inhibitors (e.g., 
omeprazole), H2-antagonists (e.g., ranitidine) and antacids. 
BYL719 should preferably be dosed in a staggered manner, i.e., at 
least 1 hour before or 10 hours after dosing with a gastric 
protection agent. Note that some proton pump inhibitors may 
possibly inhibit BCRP (see below). 
BCRP inhibitors 
BYL719 was identified as a substrate for the human BCRP. Co-
administration of alpelisib with BCRP inhibitors may possibly 
increase systemic exposure and/or alter tissue uptake of oral 
BYL719.The treatment with BCRP inhibitors should be kept as 
short as possible or, if possible, fully avoided. 
Drugs with a possible risk for 
Torsades de Pointes / QT 
prolongation4 
Alfuzosin, amantadine, atazanavir, chloral hydrate, clozapine, 
dolasetron, eribulin, escitalopram, famotidine, felbamate, 
fingolimod, foscarnet, fosphenytoin, gatifloxacin, gemifloxacin, 
granisertron, iloperidone, indapamide, isradipine, lapatinib, 
levofloxacin, lithium, moexipril, nicardipine, nilotinib, octreotide, 
ofloxacin, ondansetron, oxytocin, paliperidone, pasireotide, 
ranolazine, risperidone, roxithromycin, sertindole, sunitinib, 
tamoxifen, tizanidine, venlafaxine, voriconazole, ziprasidone 
Hematopoietic growth factors 
Hematopoietic growth factors (e.g. erythropoietins, G-colony 
stimulating factor (CSF) and GM-CSF) are not to be administered 
prophylactically. Use of these drugs should be reserved to patients 
with severe neutropenia and anemia as per the labeling of these 
agents or as dictated by local practice (see also the guidelines 
established by the American Society of Clinical Oncology (ASCO)). 
Corticosteroids 
Chronic dosing of high levels of corticosteroids such as 

 
 
 
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Category 
Drug Name 
dexamethasone and prednisone are known to induce CYP3A 
enzymes, thereby increasing the risk of reducing letrozole drug 
exposure to sub-therapeutic levels. Since corticosteroids may 
prolong or aggravate hyperglycemia (steroid-induced diabetes), 
which is a common adverse event for PI3K inhibitors such as 
alpelisib, they should be additionally used with caution and closely 
monitored. 
Anticoagulation 
Anticoagulants other than warfarin/coumarin derivates (Appendix 
2, Table 8) or antiaggregation agents may be administered under 
the discretion of the investigator. However, caution is advised 
when alpelisib is co-administered with anti-platelet pro-drugs such 
as clopidogrel, ticlopidine and prasugrel, which requirBYL719 has 
the potential to inhibit some of these enzymes and may therefore 
decrease the metabolic activation and clinical efficacy of these pro-
drugs. Patients using anti-platetet pro-drugs should be carefully 
monitored. 
1Any drug mentioned in the above list should be contraindicated if they are excluded based on any other 
exclusion criteria, or as specified in Section Concomitant Medications of this guideline document or listed 
in 
Appendix 
2, 
Table 
8. 
2Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher 
when 
co-administered 
with 
a 
potent 
inhibitor. 
3NTI = narrow therapeutic index drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., 
Torsades de Pointes). 
4 Please also refer to http://crediblemeds.org/ for a comprehensive list of agents that prolong the QT interval. 
 
 
 
 

 
 
 
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Appendix 3 
 Prohibited medications 
List of prohibited medications during BYL719 treatment 
Category 
Drug Name 
Strong CYP3A Inhibitors  
Boceprevir, clarithromycin, cobicistat, conivaptan, elvitegravir, indinavir, 
itraconazole, ketoconazole, lopinavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, 
troleandomycin, voriconazole 
Strong CYP3A Inducers  
Avasimibe2,3, carbamazepine, mitotane, phenobarbital, phenytoin, 
rifabutin, rifampin (rifampicin)3, St. John's wort (hypericum perforatum)3 
CYP3A substrates with NTI1 
Alfentanil, 
astemizole, 
cisapride, 
cyclosporine, 
diergotamine 
(dihydroergotamine), 
ergotamine, 
fentanyl, 
pimozide, 
quinidine, 
sirolimus, tacrolimus, terfenadine 
Sensitive CYP3A Substrates4 
Alpha-dihydroergocryptine, 
aplaviroc, 
aprepitant, 
atorvastatin, 
brecanavir, brotizolam, budesonide, buspirone, capravirine, casopitant, 
conivaptan, darifenacin, darunavir, dasatinib, dronedarone, ebastine, 
eletriptan, eplerenone, everolimus, felodipine, fluticasone, indinavir, 
levomethadyl, lopinavir, lovastatin, lumefantrine, lurasidone, maraviroc, 
midazolam, neratinib, nisoldipine, perospirone, quetiapine, ridaforolimus, 
saquinavir, sildenafil, simvastatin, ticagrelor, tipranavir, tolvaptan, 
triazolam, vardenafil, vicriviroc 
Other 
investigational 
and 
antineoplastic therapies 
Other investigational therapies should not be used while the patient is on 
the study. Anticancer therapy [chemotherapy, biologic or radiation 
therapy, and surgery (unless specified in protocol)] other than the study 
treatments must not be given to patients while the patient is on the study 
medication. If such agents are required for a patient then the patient must 
be discontinued from the study. 
Herbal medications 
Herbal preparations/medications are prohibited throughout the study, 
as a potential drug-drug-interaction is always possible. These herbal 
medications include, but are not limited to: St. John’s wort, Kava, 
ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, and ginseng. Patients should stop using these 
herbal medications 7 days prior to first dose of study drug. 
Warfarin and coumarin 
derivatives 
Therapeutic doses of warfarin sodium (Coumadin®) or any other 
coumarin-derivative anticoagulants are prohibited in this study. Warfarin 
has a narrow therapeutic range and BYL719 is a possible inhibitor of 
CYP2C8 and 2C9, the major metabolizing enzyme of warfarin. 
Therapeutic anticoagulation may be accomplished using low-molecular 
weight heparin. 
Drugs with a known risk for 
Torsades de Pointes / QT 
prolongation5 
Amiodarone, amitriptyline (2C19), arsenic trioxide, astemizole, cepridil, 
chloroquine, chlorpromazine, cisapride, citalopram, clarithromycin, 
clomipramine (2C19), disopyramide, dofetilide, domperidone, 
dronedarone (CYP3A4), droperidol, erythromycin, flecainide, 
halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, 
methadone, moxifloxacin, pentamidine, pimozide, probucol, 
procainamide, quetiapine (3A4), quinidine, ritonavir (3A4), sotalol, 
sparfloxacin, tacrolimus (3A4), telithromycin (3A4), terfenadine, 
thioridazine, trazodone (3A4), vandetanib, vardenafil (3A4) 

 
 
 
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Category 
Drug Name 
1NTI = narrow therapeutic index drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., 
Torsades de Pointes) 
 2Herbal product 
3P-gp inducer 
4Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher 
when 
5 Please also refer to http://crediblemeds.org/ for a comprehensive list of agents that prolong the QT 
interval.  
 
 
 
 
 
 
 
 
 
 

 
 
 
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Appendix 4 
 Study Medication Instructions and Diary 
 
BYL719 Medication Instructions 
 
Please complete the diary each day even if you miss your dose.  If you do not take your 
medication on the day it is scheduled, please write in the reason.  Also write in any side effects 
that you experience.  Please also note if you lose any pills.  It is very important that you maintain 
this diary and bring it with you when you see your study doctor or nurse. Also bring all tablets 
and bottles with you.  
 
Please remember:  Do not take the dose on the day of clinic visits.  Take the tablets with 
you to the clinic.  They will be taken after the blood draw. 
 
The BYL719 tablets are provided in 200 mg tablets and 50 mg tablets.  The study dose is 350 
mg/day, but if you experience side effects, you may be given a reduced dose.  Depending 
on your dose, you will take a different number of tablets.  This table below provides details on 
how many tablets of each you will take depending on the dose. 
 
Dose 
Number of 200 mg tablets to 
take 
Number of 50 mg tablets to take 
350 mg/day 
One 200mg tablet 
Three 50 mg tablets 
300 mg/day 
One 200mg tablet 
Two 50 mg tablets 
250 mg/day 
One 200mg tablet 
One 50 mg tablet 
 
Instructions for taking the medication: 
• 
The daily dose of BYL719 should be taken at approximately the same time each day, 
preferably in the morning, except on the days you will visit the clinic for a blood draw.   
 
• 
The dose should be taken within 1 hour after a meal, and with a glass of water. 
 
• 
The tablets must be swallowed whole; do not chew, crush, or break them. 
 
• 
If vomiting occurs, do not take another dose that day.   
o Take the medication the following day, as usual. 
o Indicate the vomiting on the study diary. 
 
• 
If you forget to take study treatment during the daytime, it should be taken in the evening 
at the latest within 1 hour after a meal, but not later than 6 pm.  
o If not taken by this time, the dose should be withheld that day.  
o Document the missed dose in the study diary 
 
• 
Missed doses should not be made up the next day.  
 
• 
IMPORTANT: Do not take a double dose to compensate for missed doses 
 
• 
If you lose pills, make note on the diary. 

 
 
 
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• 
A pill count will be performed when medication is returned. 
 
• 
There are medications you need to avoid while you are on the study medication.  These 
are listed in the consent form.  Before you begin any new medications, talk to the study 
doctor.    
 
If you have any questions or concerns, contact the study team. 
 
 
Study Doctor:   
 
Research Nurse:   
 
Study Coordinator:   
 

 
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Initials 
Year of Birth 
Participant ID 
Protocol # 
 
BYL719 Trial  
Patient Diary 
 
 
 
1802258478 
Day 
Date 
Dose time 
Number of 200 mg 
Tablets Taken  
(If missed, mark 0) 
Number of 50 mg 
Tablets Taken 
(If missed, mark 0) 
Comments/Side Effects/Vomiting/Reason Missed  
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
 
Other comments, including number of tablets lost, if any: 
 
You will be asked to sign this document (both pages, if necessary) once complete to confirm that you or a caregiver completed the diary. 
 
Subject or Caregiver Signature: ___________________ Date: __________________ 

 
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Initials 
Year of Birth 
Participant ID 
Protocol # 
 
BYL719 Trial  
Patient Diary 
 
 
 
1802258478 
Day 
Date 
Dose time 
Number of 200 mg 
Tablets Taken  
(If missed, mark 0) 
Number of 50 mg 
Tablets Taken 
(If missed, mark 0) 
Comments/Side Effects/Vomiting/Reason Missed  
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 
 
Other comments, including number of tablets lost, if any: 
 
You will be asked to sign this document (both pages, if necessary) once complete to confirm that you or a caregiver completed the diary. 
 
Subject or Caregiver Signature: ___________________ Date: __________________ 
 
 

 
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Appendix 5  Tumor Biomarkers 
Tumor tissues obtained before treatment with BYL719 will be assessed for canonical PIK3CA 
mutations by SNaPshot PCR(60) and amplifications by FISH.(53) PTEN loss will be assessed 
by FISH.(53)  In addition, we will assess PIK3CA mutations using a comprehensive full length 
sequencing approach covering 202 cancer associated genes to ultradeep depth developed as 
part of the SU2C PI3K in women project.(53) We will assess HPV viral load and levels of HPV 
E6 and E7 transcripts in paired, pre- and post-treatment tissues by RT-qPCR. We will assess 
HPV viral load by qPCR and levels of HPV E6 and E7 transcripts by RT-qPCR in paired, pre- 
and post-treatment tissues. We will also assess paired tumor cell lysates for expression of total 
and phosphorylated signaling proteins using reverse phase protein array (RPPA), a high-
through-put quantitative proteomics platform to detect changes in signaling events.