INST UNM 1601: Compassionate Use of BYL 719 Alpelisib
Conditions: Lymphangioma
Sponsor: New Mexico Cancer Research Alliance

Protocol Date: 01/19/2017 
Page 1 of 29 
Phase II form 
Revised 12/10/2010 
 
 
 
New Mexico Cancer Care Alliance 
INST UNM 1601: Compassionate Use of BYL 719 Alpelisib 
TABLE OF CONTENTS: 
1.0     RATIONALE 
2.0     OBJECTIVES 
3.0     BACKGROUND 
4.0     PATIENT ELIGIBILITY 
5.0     TREATMENT PLAN 
6.0     PRETREATMENT EVALUATION  
7.0     EVALUATION DURING STUDY 
8.0     CRITERIA FOR RESPONSE AND TOXICITY 
9.0     CRITERIA FOR DISCONTINUING THERAPY 
10.0   STATISTICAL CONSIDERATIONS 
11.0   DATA AND PROTOCOL MANAGEMENT 
12.0   ANALYSIS OF DATA 
13.0   REPORTING REQUIREMENTS 
14.0   REFERENCES 
     Appendix I -  CONCOMITANT MEDICATIONS 
       
 
Ian Rabinowitz, MD  
 
 
 
 
 
 
Principal Investigator  
 
 
 
                        Date  01/19/2017 
 
 
 
 
 

Protocol Date: 01/19/2017 
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Phase II form 
Revised 12/10/2010 
1.0  RATIONALE 
This is a compassionate use protocol of BYL719 (alpelisib) treatment for a single patient with 
locally advanced lymphangioma positive PI3K alpha H1047R mutation. 
 
2.0  
OBJECTIVES 
2.1 
To provide off-label use of alpelisib to this patient with locally advanced lymphangioma.  
2.2 
To record outcomes of this patient while he is on alpelisib. 
  
3.0 
BACKGROUND 
3.1  
Drug Chemistry: 
Alpelisib is provided as 50-mg and 200-mg film coated tablets as individual patient supply, 
packaged in bottles.  Alpelisib will be administered at a starting dose of 350mg orally once daily 
on a continuous dosing schedule and can be adjusted for toxicity.  
Alpelisib is currently prepared as film-coated tablets, which are intended for oral 
administration. The tablets in early phases are supplied at dosage strengths 10 mg, 50 mg, and 
200 mg. 50 mg, 150 mg, and 200 mg are planned to be used as commercial strengths.  
Different formulations of the drug product have been used in early trials. The tablets that were 
developed initially contained the following excipients: Microcrystalline cellulose / cellulose 
microcrystalline, Lactose monohydrate, Croscarmellose sodium, Hypromellose / 
hydroxypropylmethylcellulose, Poloxamer, Colloidal silicon dioxide / colloidal anhydrous silica, 
and Magnesium stearate. The tablet film coat contains the following excipients: Hypromellose 
/ Hydroxypropylmethylcellulose, Titanium dioxide, Macrogol / Polyethylene glycol (PEG), Talc, 
Iron oxide yellow, Iron oxide red, and Iron oxide black.  
An optimized tablet was developed to replace the initial tablet formulation. In addition to the 
active substance, the tablets contain the following excipients: Microcrystalline cellulose / 
cellulose microcrystalline, Mannitol, Sodium starch glycolate (Type A) / Sodium starch 
glycolate, Hypromellose / hydroxypropylmethylcellulose, and Magnesium stearate. The tablet 
film coat contains the following excipients: Hypromellose / Hydroxypropylmethylcellulose, 
Titanium dioxide, Macrogol / Polyethylene glycol (PEG), Talc, Iron oxide red, and Iron oxide 
black.  
Alpelisib is (2S)-1-N-{4-Methyl-5- [2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl]-1,3-
thiazol-2-yl} pyrrolidine-1,2-dicarboxamide. Its molecular formula is C19H22F3N5O2S . Its 
relative molecular mass is 441.47. 
 Its structural formula is: 
 

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Phase II form 
Revised 12/10/2010 
 
Alpelisib exists as white to practically white powder.  
Alpelisib, being a base drug substance, shows pH dependent solubility, is soluble in low (acidic) 
pHs, and remains insoluble in high (alkaline) pHs. The following table shows its solubility in 
various media.  
Table 3-1 Solubility of alpelisib at 25 degree Celsius  
 
Solvent  
 
Solubility (mg/mL)  
 
Buffer pH 1.0  
 
>5  
 
Buffer pH 3.0  
 
0.08  
Buffer pH 5.0  
0.03  
Buffer pH 6.8  
0.02  
SGF1, pH 2.0  
0.30  
FaSSIF2, pH 6.5  
0.05  
FeSSIF3, pH 5.0  
0.32  
1 Simulated gastric fluid 2 Fasted state simulated intestinal fluid 3 Fed state 
simulated intestinal fluid  
 

Protocol Date: 01/19/2017 
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Phase II form 
Revised 12/10/2010 
3.2 Reported adverse Events  
Summary and incidence of adverse events is mentioned here and detailed management 
algorithms will be mentioned later in the protocol.  
1) Hyperglycemia  
Hyperglycemia is an on-target effect of alpelisib, and it has been observed both in preclinical 
and clinical studies.  In studies of alpelisib, at the maximum tolerated dose (MTD) of 400 mg, 
the frequency of hyperglycemia (all grades) ranged between 51.4 and 66.2%; being the 
frequency of grade 3/4 events from 21.4 to 40.0%. When alpelisib is administered at 300 mg 
QD as a single agent in study CBYL719X2101, the frequency of grade 3/4 hyperglycemia is 
12.5%.  
2) Rash 
Skin toxicity, mainly in the form of maculopapular rash or generalized rash, has been observed 
in clinical trials with alpelisib. In studies of alpelisib, at the MTD of 400 mg, the frequency of 
rash (all grades) ranged between 43.1-60%; and the frequency of grade 3/4 events from 0-
21.4%. When alpelisib is administered at 300 mg daily (QD) as a single agent in study 
CBYL719X2101, the frequency of grade 3/4 rash is 0%. 
3) Gastrointestinal (GI) toxicity  
In preclinical toxicology studies, animals treated at the MTD of alpelisib experienced 
gastrointestinal (GI) toxicity, mainly consisting of vomiting and diarrhea. Clinical experience 
shows that nausea, vomiting and diarrhea are common AEs when alpelisib is administered 
either as a single agent or in combination; however grade 3/4 events are infrequent. In BYL719 
studies (including combination studies with other agents) at the MTD of 400 mg the frequency 
of nausea, vomiting, diarrhea ranged between 40-83.1%; and the frequency of grade 3/4 
events from 0-13.8%. When alpelisib is administered at 300 mg QD as a single agent in study 
CBYL719X2101, the frequency of grade 3/4 nausea, vomiting, diarrhea is 0%. 
 4) Cardiovascular toxicity  
Preclinical studies indicate a minimal risk of an electrophysiological effect of alpelisib . In the 
single agent arm of the study CBYL719X2101, when BYL719 was administered above 270 mg 
QD, three cases of QT prolongation were observed. Two of them when alpelisib at 300 mg QD 
(n=6), and one case was observed at 400 mg QD (n=65). None of these events were grade 3/4 
nor had a clinically-significant associated signs and/or symptoms. Alpelisib did not cause any 
clinically significant arrhythmia.  
In the single agent arm of the study CBYL719X2101, at the MTD (i.e. 400 mg QD cohort, n=65) 
one patient (1.5%) experienced drug-related hypertension. Single measurements of increased 
blood pressure were observed at various dose levels, which were all transient without clinical 
significance. No other clinically significant hypertension was reported at lower dose, further 
selected for clinical development (i.e. 300 mg QD or 350 mg QD).  

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Phase II form 
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In the single agent arm of the study CBYL719X2101, at the MTD (i.e. 400 mg QD cohort, n=65) 
one episode of ST segment depression [0.7%] was reported. This event was not grade 3/4 and 
had not clinically significant associated signs and/or symptoms, such as cardiac arrhythmias or 
cardiac ischemia events. No clinically evident arrhythmias have been reported with alpelisib as 
a single-agent.  
5) Hematological toxicity  
In animal toxicology studies, BYL719 showed effects on the erythropoietic (decrease in 
hemoglobin, red blood cells, and reticulocytes) and lymphopoietic (decrease in lymphocytes) 
systems. In the study CBYL719X2101, at 400 mg QD of alpelisib (n=65) given as a single agent, 
there were 18 events (27.7%) of hematopoietic cytopenias, of which 3 (4.6%) were grade 3/4. 
One event (1.5%) of grade 3/4 febrile neutropenia was observed. Current protocols mandate 
for an adequate bone marrow function at study entry. In addition, in order to ensure patients’ 
safety, hematological assessments are conducted at regular intervals, at least once per 
treatment cycle, in all alpelisib clinical studies.  
 6) Pneumonitis, interstitial lung disease  
Based on the most recent review of both the clinical and pharmacovigilance databases, 
Novartis concludes that as of 20 May 2015, there were nine serious cases of pneumonitis 
reported with alpelisib (regardless of relationship to drug) including three with fatal outcome. 
Of the nine serious cases, one case was reported with BYL719 single agent and eight with 
alpelisib in combination with agents including cetuximab, fulvestrant, MEK162, AMG479, 
LGX818, LJM716 and LEE011. On 12th December 2014, Novartis issued an Investigator 
Notification for a patient from the CLJM716X2103 trial (alpelisib in combination with the anti-
HER3 monoclonal antibody LJM716) with a serious, unexpected, possibly related adverse event 
of fatal pneumonitis.  
3.3 Mechanism of action  
The phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates diverse cellular functions, 
including cell proliferation, survival translational regulation of protein synthesis, glucose 
metabolism, cell migration, and angiogenesis (Katso 2001) PI3K signaling also serves a central 
role in the pathogenesis of numerous forms of neoplasia. At the structural level, the enzyme 
PI3K is composed of a 110-kDa catalytic subunit and an 85-kDa adaptor subunit. PI3K signaling 
is modulated by multiple regulators, including growth factors (such as EGF, IGF-1, and FGF), 
hormones (such as estrogen and thyroid hormone), integrins, intracellular calcium levels, and 
RAS signaling. PI3K signaling is negatively regulated at the level of PIP3 clearance by 
phospholipid phosphatases, such as the phosphatase and tensin homologue (PTEN) protein 
and the inositol 5-phosphatase-2 (SHIP2) protein.  
Constitutive activation of PI3K signaling is known to be a critical step in mediating the 
transforming potential of oncogenes and tumor suppressors which contribute to the onset and 
growth of many solid tumors as well as tumors of the hematopoietic system (Liu 2009). 
Resistance to a variety of therapeutic interventions, including chemotherapy, hormonal 

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therapy and anti-HER2 therapies, can also be linked to constitutive activation of the PI3K 
pathway (McCubrey 2006). Moreover, preliminary data suggest that activation of the PI3K 
pathway might be a predictor of poor prognostic outcome in many cancers.  
The dysregulation of the PI3K signaling pathway is implicated in many human cancers (Samuels 
2004, Hennessy 2005, Markman 2010) includes the inactivation of the PTEN tumor suppressor 
gene (Sansal and Sellers 2004), amplification/overexpression or activating mutations of some 
receptor tyrosine kinases (e.g.: erbB3, erbB2, EGFR), and amplification of genomic regions 
containing AKT or PIK3CA genes (Cheng 1992, Cheng 1996, Shayesteh 1999, Markman 2010).  
PI3K alpha signaling in malignant cells  
Somatic PIK3CA missense mutations have received a great deal of attention since the discovery 
that these missense mutations occur at high frequency in many human cancer types. 
Sequencing of the entire gene revealed that PIK3CA, is somatically mutated in 32% of CRCs 
(Samuels 2004), 27% of glioblastomas (Samuels 2004, Hartmann 2005), 25% of gastric cancers 
(Samuels 2004a Samuels 2004b, Li 2005), 36% of hepatocellular carcinomas (Lee 2005), 18 to 
40% of breast cancers (Bachman 2004, Levine 2005, Wu 2005), 4-12% of ovarian cancers 
(Levine 2005, Wu 2005), and 4% of lung cancers (Samuels 2004). 
From these mutation frequencies, PIK3CA, the gene encoding p110α is one of the most 
commonly mutated genes identified in human cancers, suggesting that p110α is the main PI3K 
isoform which drives tumor growth. In particular, high frequencies of “hot spot” mutations 
have been observed in colorectal, gastric, brain, breast and lung cancers (Samuels 2004, Liu 
2006, Isakoff 2005, Ikenoue 2005). These mutations are clustered in hot spots within the helical 
(exon 9) and kinase (exon 20) domains of p110α. Among these hot spot mutations, the three 
most common tumor-derived alleles of p110α are E542K, E545K and H1047R, which represents 
about 80% of the mutations observed, suggesting that they confer a selective advantage to the 
cell carrying the mutation.  
In addition to the hot-spot mutations, numerous rare cancer specific mutations are widely 
distributed over the entire coding sequence of p110α (Bader 2005, Samuels 2004). Fifteen of 
these have been studied, and all except one show a gain of function. Recently, it has been 
found that the expression of the kinase domain mutant H1047R of p110α in mouse lungs 
induced adenocarcinomas in vivo (Engelman 2008).  
Together these observations suggest that the catalytic subunit p110α of the PI3K pathway 
could be a critical therapeutic target for the treatment of patients with advanced PIK3CA- 
driven malignancies who often have limited therapeutic options beyond the standard of care.  
Hence, the α-selective-PI3K inhibitor alpelisib may potentially address an unmet medical need 
in such patients.  
Alpelisib (NVP-BYL719) is an oral class I α-specific phosphatidylinositol-3-kinase (PI3K) inhibitor 
belonging to the 2-aminothiazole class of compounds. Alpelisib is best described as PI3Kα 
inhibitor in that it inhibits p110α (and p110α mutations) but less strongly the β, δ, and γ 

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Phase II form 
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isoforms. It is inactive against the majority of other kinases. Alpelisib has been studied 
extensively in non-clinical models and is currently being evaluated in clinical trials.  
3.4 Distribution 
Alpelisib had a low clearance (CL), a moderate volume of distribution at steady state (Vss) and 
a good absolute oral bioavailability in all preclinical species tested (Wistar rats, Beagle dogs, 
mice). The compound is moderately bound to plasma proteins and its binding is independent 
of the concentration. Alpelisib showed a rapid distribution to almost all rat tissues, except the 
brain (radiolabeled 14C-BYL719 study). Alpelisib 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 (CYP)3A4 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 alpelisib 
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.  
Alpelisib is a substrate of breast cancer resistance protein (BCRP) and multidrug resistance 
(MDR)-1 (low affinity). It also showed very weak inhibition of MDR-1. No inhibition could be 
observed on BCRP- or MRP2-mediated transport. Uptake of alpelisib in human hepatocytes 
was found to be concentration-independent and was not influenced by inhibitors of the major 
transporter families OCT, OAT, OATP and NTCP. Assessment of the hepatobiliary disposition 
mechanisms of alpelisib in sandwich-cultured rat and human hepatocytes showed that it is 
actively transported into bile pockets. Alpelisib is not considered a human pregnane X receptor 
(PXR) or aryl hydrocarbon receptor (AhR) activator. Reversible weak inhibition of CYP2C8, 
CYP2C9 and CYP2C19 was observed. The compound is also a strong time-dependent inhibitor 
of CYP3A4. Alpelisib may possibly inhibit acetaminophen sulfation but is not expected to inhibit 
acetaminophen glucuronidation.  
Results from 4-week Good Laboratory Practice (GLP)-toxicology studies in dogs 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 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.  
The overall biotransformation of alpelisib in hepatocytes was low in all species tested (i.e. low 
in the rat, lower in dog and lowest in human hepatocytes). The main biotransformation 
pathway that was observed consistently across species was hydrolysis of proline amide moiety 

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Phase II form 
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(this is the only metabolite that was detected in human and dog hepatocyte incubations). No 
covalent drug protein adduct formation was noted in human microsomes or hepatocytes.  
3.5 Metabolism 
Preliminary pharmacokinetic data of study [CBYL719X2101] showed that alpelisib is well 
absorbed after oral administration. Median time to reach the peak plasma concentration 
(Tmax) at the MTD dose (400 mg once daily) was 2 hours. Tmax did not correlate with dose and 
the median values at different doses spanned a wide range (range 1 to 7 hours), both after 
single and repeated dose. Plasma concentrations of alpelisib generally declined in a 
monoexponential manner, suggesting rapid distribution towards the tissue (relative to 
absorption).  
Median terminal elimination half-life (T1/2) after a 400 mg oral dose was 7 to 8 hours and 
generally appeared to be independent of dose and time. Steady-state alpelisib plasma levels 
can be expected to be reached at 2 to 3 days following onset of therapy in most patients. At 
the MTD dose, median Cmax and drug exposure within a dosing interval (AUC0-24h) after one 
month of daily dosing was ~3810 ng/mL and ~46600 ng·h/mL, respectively. The median 
accumulation ratio (Racc) of alpelisib across all dose levels was calculated to be about 1.3 
which is in agreement with the short half-life of alpelisib. An apparent higher drug 
accumulation than expected based on the drug half-life was observed in some patients, with 
no clear relationship with dose. Also, an approximate dose proportional increase in both Cmax 
and AUC was found, indicating no relevant deviation from linear pharmacokinetics. Dosing at 
400 mg once daily produced a low mean oral plasma clearance (CLss/F) of 9.6 L/h. CLss/F 
appeared to be independent of dose. Moreover, the estimate of oral plasma clearance 
obtained from AUCinf after a single 400 mg dose was comparable to the values obtained at 
steady-state (11.5 L/h), suggesting that clearance is not expected to change with dose or time. 
The oral clearance was about 10 to 15% of liver blood flow, and therefore a relatively minor 
contribution of hepatic first pass metabolism to the overall clearance of the drug is expected.  
 
3.6 Excretion  
Results from the rat ADME study showed that [14C]BYL719- derived radioactivity was mainly 
excreted into feces with ~75-85% of the dose recovered by day 7, regardless of dose route 
(DMPK R0900368). Renal excretion was minor at 11-15% of the dose in urine in intact animals. 
In bile duct-cannulated rats, ~40% of BYL719 related radioactivity was recovered in bile, with 
an additional 25% being excreted in feces indicating potential intestinal secretion in rats 
Distribution data in rats following i.v. dosing indicate that radioactivity was present in the 
intestinal mucosa, which supports this conclusion. In total, about 20% of the dose was excreted 
unchanged in rat as BYL719 following i.v. and p.o. dosing. Unchanged BYL719 was found at 
8.66% and 10.9% of dose in bile and feces after i.v. dosing to bile cannulated rats. Renal 
excretion of parent BYL719 was a minor component and accounted for less than 2% of the 
dose. Recovery of radiolabeled material was nearly complete for both dose routes with values 
of 92-100% indicating BYL719 related substance(s) is not retained in the body.  

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Phase II form 
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The potential active hepatobiliary disposition of apelisib was studied in sandwich-cultured rat 
(DMPK R1200423) and human hepatocytes (DMPK R1300212), which exhibit the formation of 
canalicular networks as well as polarized excretory function. Apelisib was found to be actively 
transported into the bile pockets of both the sandwich cultured rat and human hepatocytes.  
3.7 Drug Interactions  
In vitro studies demonstrate that alpelisib was found to be a time dependent inhibitor of 
CYP3A4 (Ki 5.6 μM, Kinact 0.011 min-1). Alpelisib may therefore increase exposure to drugs 
metabolized by CYP3A4. Reversible inhibition of CYP2C8 (Ki 32 μM = 14 μg/mL), CYP2C9 (Ki 22 
μM = ~10 μg/mL) and CYP2C19 (IC50 75 μM) was also observed. Alpelisib may inhibit metabolic 
clearance of co-medications metabolized by CYP3A4, CYP2C8, CYP2C9 and CYP2C19, if 
sufficiently high concentrations are achieved in vivo (Cmax ~3 μg/mL see 1.2.1.3). Clinically 
significant pregnane X receptor-mediated induction of CYP3A4 or aromatic hydrocarbon 
receptor-mediated induction of CYP1A2 by alpelisib is not expected.  
Alpelisib is also a substrate of Breast Cancer Resistance protein (BCRP) and has low affinity for 
Pglycoprotein (P-gp/MDR1). Alpelisib does not inhibit BCRP or Multi-drug resistance protein-2 
(MRP2), but showed very weak inhibition of P-gp (IC50 = 97 μM). As the maximal inhibition of 
P-gp was only about 32% with respect to positive control, the overall interaction potential is 
expected to be low.  
Treating Physicians, at their discretion, may administer concomitant medications known to be 
metabolized by CYP3A4/5, CYP2C8, CYP2C9 and CYP2C19. Patients receiving such medications 
must be carefully monitored for potential toxicity due to any individual concomitant 
medications. Particularly, caution is advised when alpelisib is co- administered with drugs that 
are sensitive substrates for CYP3A4, CYP2C8, CYP2C9 or CYP2C19 and which have a narrow 
therapeutic index  
3.8 How supplied  
Alpelisib will be supplied as 50-mg and 200-mg film coated tablets, packaged in bottles, and 
will be given orally with a flat daily dose based. The tablets are packaged in HDPE bottles with a 
plastic child resistant closure.  
The storage conditions for alpelisib will be described on the medication label. Indication labels 
will provide no information about the patient.  
Treatment with Alpelisib  
Packaging and labeling: 
Treatment 
Packaging 
Labeling  
Dosing Frequency 
Alpelisib 
Tablets in bottle 
50 MG and 200 MG 
Labeled as BYL719 
Once Daily Dosing 

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Phase II form 
Revised 12/10/2010 
 
 
4.0  
PATIENT ELIGIBILITY 
4.1 
Inclusion criteria 
Patient eligible for inclusion in this Treatment Plan have to meet all of the following criteria:  
1) Patient has signed the Informed Consent (ICF) prior to any eligibility evaluations being 
performed and is able to comply with protocol requirements   
2) Patient is an adult and ≥ 18 years old at the tim e of inform ed consent   
3) Patient has locally advanced or metastatic cancer resistant or refractory to available 
standard of care treatment options and has no other available comparable or 
satisfactory alternative treatment options   
4) PIK3CA mutation, or other molecular alteration known to activate PI3K, in tumor 
tissue as determined by a standard Laboratory 
5) Patient is not eligible for participation in any ongoing clinical trials with alpelisib, or 
has recently completed a clinical trial with alpelisib that has been terminated, and 
after considering other options (e.g. trial extensions, amendments, etc.), the treating 
physician has determined that treatment is necessary and there are no other feasible 
alternatives for the patient   
6) Patient is not being transferred from an ongoing clinical trial for which they are still 
eligible   
7) Patient has adequate bone marrow and organ function as defined by the following 
laboratory values:  
a. 
Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L   
b. 
Platelets ≥ 100 x 109/L (For patients with hematologic malignancies 
involving  the bone m arrow , platelet count > 75 x 109/L may be 
acceptable)   
c. 
Hemoglobin ≥ 9.0 g/dL   
d. 
INR ≤ 1.5   
e. 
Potassium, magnesium and calcium (corrected for albumin), within 
normal limits for the institution, or ≤ Grade 1 severity according to NCI-

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Phase II form 
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CTCAE version 4.03 if judged clinically not significant by the investigator   
f. 
Serum creatinine ≤ 1.5 x ULN and/or creatinine clearance > 50% LLN 
(Lower Limit of Normal)   
g. 
Total serum bilirubin < ULN (or ≤ 1.5 x ULN if liver metastases are present; 
or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in 
patients with well documented Gilbert’s Syndrome, (defined as presence 
of several episodes of unconjugated hyperbilirubinemia with normal CBC 
results including normal reticulocyte count and peripheral blood smear, 
normal liver function test results, and absence of other contributing 
disease processes at the time of diagnosis) 
h. 
Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) ≤ 
2.5 ULN (or < 5.0 x ULN if liver metastases are present)  
8) Patient is deemed by the Treating Physician to have the initiative and means to be 
compliant with the treatment plan (treatment and follow-up requested by the 
Treating Physician)  
4.2 Exclusion criteria  
Patients eligible for this Treatment Plan must not meet any of the following criteria:  
1) Patient has history of hypersensitivity to any drugs or metabolites of similar chemical 
classes as alpelisib   
2) Patient has not recovered to grade 1 or better (except alopecia) from related side 
effects of any prior antineoplastic therapy   
3) Patient has had major surgery within 4 weks prior to starting treatment with alpelisib or 
has not recovered from major side effects   
4) Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to 
starting treatment with alpelisib, or has not fully recovered from side effects of such 
treatment   
5) Patient with clinically manifest diabetes mellitus, or documented steroid induced 
diabetes mellitus   
6) Patient is being treated at start of treatment with alpelisib with any of the following 
drugs:  
Drugs known to be strong inhibitors or inducers of isoenzyme CYP3A4 including 

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Phase II form 
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herbal medications, or drugs with a known risk to induce Torsades de Pointes 
(See Appendix 1, Table 2 for a full list of prohibited medications). 
Note: The patient must have discontinued strong inducers for at least one week 
and must have discontinued strong inhibitors before the treatment with 
alpelisib is initiated. Switching to a different medication prior to starting 
treatment with alpelisib is allowed.   
7) Patient is currently receiving warfarin or other coumarin derived anti-coagulant for 
treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight 
heparin (LMWH), or fondaparinux is allowed.   
8) Patients who have other concurrent severe and/or uncontrolled medical conditions that 
would, in the Treating Physician’s judgment, contraindicate patient participation in the 
individual patient program (eg. active or uncontrolled severe infection, chronic active 
hepatitis, immuno-compromised, acute or chronic pancreatitis, uncontrolled high blood 
pressure, interstitial lung disease, etc.)   
9) Patient has a known history of HIV infection (testing not mandatory) infection   
10) Patient has any of the following cardiac abnormalities:   
a. Symptomatic congestive heart failure 
i. History of documented congestive heart failure (New York Heart 
Association functional classification III-IV), documented cardiomyopathy 
ii. Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple 
Gated acquisition (MUGA) scan or echocardiogram (ECHO) 
b. Myocardial infarction ≤ 6 months prior to enrolment  
c. Unstable angina pectoris   
Acute coronary angioplasty, or stenting), < 3 months prior to screening coronary 
syndromes (including myocardial infarction, unstable angina, coronary artery 
bypass graft (CABG). 
d. Serious uncontrolled cardiac arrhythmia    
History or current evidence of clinically significant cardiac arrhythmias, atrial 
fibrillation and/or conduction abnormality, e.g. congenital long QT syndrome, 
high-grade/complete AV-blockage: per guidelines. 

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e. Symptomatic pericarditis   
f. QTcF > 480 msec on the screening ECG (using the QTcF formula) currently 
receiving treatment with medication that has a known risk to prolong the QT 
interval or inducing Torsades de Pointes, and the treatment cannot be 
discontinued or switched to a different medication prior to starting treatment 
with alpelisib.    
11) Patient has impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of alpelisib (e.g., ulcerative diseases, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)   
12) Patient has other prior or concurrent malignancy (except for the following: adequately 
treated basal cell or squamous cell skin cancer, or other adequately treated in situ 
cancer, early gastric or GI cancer resected completely by endoscopy procedures or any 
other cancer from which the patient has been disease free for ≥ 3 years)   
13) Patient has a history of non-compliance to medical regimen or inability to grant consent 
14) Patient who does not apply highly effective contraception during the treatment with 
alpelisib and through the duration as defined below after the final dose of alpelisib: 
a. Sexually active males should use a condom during intercourse while taking drug 
and for 4 weeks* after the final dose of alpelisib 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 female physiologically capable 
of becoming pregnant, must use highly effective contraception during the IPP 
and through at least 4 weeks* after the final dose of alpelisib 
c. 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), total hysterectomy or tubal ligation at least six 
weeks before starting treatment with alpelisib. 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 
patients participating to this IPP, the vasectomized male partner should 
be the sole partner for that patient] 

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iv. Use a combination of the following (both a+b): 
a. Placement of an intrauterine device (IUD) or intrauterine system 
(IUS) 
b. Barrier methods of contraception: Condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/vaginal suppository. 
Note: Hormonal contraception methods (e.g. oral, injected, and implanted) are 
not allowed as alpelisibBYL719 may decrease the effectiveness of hormonal 
contraceptives. 
* Please consult your local product labels should any concomitant medications 
be used, as this period may be longer for other potentially genotoxic 
compounds. 
A female is 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 before the treatment start. For females 
with therapy-induced amenorrhea, oophorectomy or serial measurements of 
Follicle-Stimulating Hormone (FSH) and/or estradiol are needed to ensure 
postmenopausal status. 
NOTE: Ovarian radiation or treatment with a luteinizing hormone-releasing 
hormone (LHRH) agonist (goserelin acetate or leuprolide acetate) is not 
permitted for induction of ovarian suppression. 
 
 
5.0       TREATMENT PLAN 
Informed consent must be obtained before conducting any treatment-specific procedures.  
Alpelisib is provided as 50-mg and 200-mg film coated tablets as individual patient supply, 
packaged in bottles. Alpelisib will be dosed on a flat scale of mg/day and not be adjusted to 
body weight or body surface area.  
As a single agent, alpelisib will be administered at a starting dose of 350 mg orally once daily on 
a continuous dosing schedule and can be adjusted for toxicity per the recommendations in this 
protocol.  No pretreatment will be given prior to the medication.  
We plan on treating this individual patient for a tentative period of 12 weeks at which time 
treating physician will reevaluate the patient’s clinical and radiological response and further 
duration of treatment will be contingent on that assessment.  
The following general guidelines must be followed for alpelisib administration:  
1) Patients should be instructed to take the dose of alpelisib once daily in the morning, at 
approximately the same time each day   
2) Alpelisib must be taken within 1 hour after a light breakfast (e.g., consisting juice, toast 
and jam). A light breakfast is defined as approximately 500 calories, with approximately 

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75% from carbohydrates and approximately 25% from protein and/or fat.   
3) Alpelisib should be taken with a glass of water. Patients should swallow the tablets as a 
whole and not chew them, however for patients with swallowing dysfunction without G 
tube, BYL719 film-coated tablets can be administered as drinkable suspension by 
crushing the tablets and suspending them in water. The drinkable suspension prepared 
from the film-coated crushed tablets is not permitted for administration into feeding 
tubes.  
4) To limit the potential impact of H2 antagonists, alpelisib should be administered at least 
one hour before or 10 hours after H2 antagonists (or proton pump inhibitor, antacid, 
etc.) administration   
5) If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose   
6) If the patient forgets to take her dose before 18:00 (6:00 PM), then the dose should be 
withheld that day and alpelisib should be restarted the following day   
7) Patients must avoid concomitant intake of strong CYP3A inhibitors and inducers.  
 
6.0       PRETREATMENT EVALUATION 
6.1 
A complete history and physical examination to include performance status, weight, 
vital signs and concurrent non-malignant disease and therapy will be done before 
starting treatment.  Prior surgery, chemotherapy, and radiotherapy details will be 
noted. 
6.2 
Laboratory studies should include a CBC with differential cell count, platelet count, 
electrolytes, liver function tests, fasting plasma glucose, and coagulation parameters.  
6.3 
A pregnancy test in women of childbearing potential. 
6.4        ECG, ECHO cardiogram. 
 
7.0       EVALUATION DURING STUDY 
1) 
Physical examination, performance status and toxicity recording will be done every 4 
weeks.  
2) 
During the study, patients will be followed every 4 weeks with a (+7 days) CBC, 
differential and platelet counts, electrolytes, liver function tests 
3) 
Measurable and evaluable disease will be evaluated by appropriate studies at least 
every 12 weeks to evaluate response.  
4) 
All female patients of childbearing potential will use barrier contraception during 
treatment. 
5) 
Monitoring will continue for at least 8 weeks after the end of drug treatment, or until 

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any adverse events are resolved (whichever is longest). 
 
8.0 
CRITERIA FOR RESPONSE AND TOXICITY 
1) 
Toxicity will be evaluated at each course of therapy. The following dose modifications 
will be used for toxicity: 
Starting Dose Level 0   
350 MG 
Dose Level -1                  
300 MG 
Dose Level -2                 
250 MG 
 
2) 
All toxicities encountered during the study will be evaluated according to the grading 
system (0-4) NCI CTCAE version 3 and recorded prior to each course of therapy.  
Duration of side effects and ancillary treatment will be recorded.  The management of 
individual toxicities and grading will be as below 
 
 

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Management of Pneumonitis 
This patient receiving treatment with alpelisib will be routinely asked about and observed for 
the occurrence of adverse events which could include new or changed pulmonary symptoms 
(consistent with lung abnormalities). Patients who are suspected to have developed 
pneumonitis should suspend study treatment (alpelisib with or without any other agent in 
combination) immediately and undergo appropriate imaging (high resolution CT scans) and 
broncho-alveolar lavage and biopsy should be considered if clinically appropriate. Infectious 
causes of interstitial lung disease should be ruled out. Management of pneumonitis which 
generally includes treatment with high dose corticosteroids; antibiotic therapy should be 
administered concurrently if infectious causes are suspected. Consultation with a 
pulmonologist is highly recommended for any pneumonitis case during the study treatment. 
Alpelisib and any other drug (if suspected to be etiologically related to the AE of pneumonitis) 
should be permanently discontinued in all patients with confirmed pneumonitis. In case of 
documented pneumonitis, the guidelines in this table should be followed.  

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3) 
Any adverse event will be evaluated and treated by the investigator as deemed 
appropriate in light of the medical situation.  All pertinent observations and treatments 
will be recorded, both on an outpatient and inpatient basis (should hospital admission 
be required).  Should death occur on study, every effort will be made to obtain autopsy 
data with careful examination of suspected target organs such as the bone marrow and 
lungs, as well as examination of the tumor for possible chemotherapy induced changes. 
 
9.0       CRITERIA FOR DISCONTINUING THERAPY 
1) 
Increasing disease during therapy 
2) 
The development of unacceptable toxicity as mentioned above 
3) 
Change in the medical status of the patient such that the investigator believes that 
patient safety will be compromised. 
4) 
Non-compliance by the patient with protocol requirements. 
5) 
Patient refusal. 
 
10.0 
STATISTICAL CONSIDERATIONS 
1) 
This is a compassionate use protocol. No statistics will be used. Only descriptive data 
will be collected as described above. 
 
 

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11.0     DATA AND PROTOCOL MANAGEMENT 
1) 
Protocol Compliance: The attending physician and oncology research nurse must see 
each patient prior to each course of treatment.  All required interim and pre treatment 
data should be available prior to each treatment course for the physician to make a 
designation as to tumor response and toxicity grade. 
2) 
At the conclusion of the study, appropriate follow-up care will be provided for this 
patient. 
 
12.0     ANALYSIS OF DATA 
None will be performed. However, case reports may be drafted from the data observed 
in this compassionate protocol 
 
13.0     REPORTING REQUIREMENTS 
An adverse event is defined as any untoward medical occurrence in a patient 
administered alpelisib that does not necessarily have a causal relationship with the 
treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of alpelisib, 
whether or not related to it. 
Medical conditions/diseases present before starting treatment with alpelisib are only 
considered adverse events if they worsen after starting treatment with alpelisib. The 
occurrence of adverse events should be sought by non-directive questioning of the 
patient at each visit. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory 
test, or other assessments. 
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more 
frequently, if necessary) of any changes in severity, the suspected relationship to 
alpelisib, the interventions required to treat it, and the outcome. 
Adverse event reporting includes but is not limited to the following: 
1) 
Any serious and/or unexpected and severe (grade 4 non-hematologic toxicity) toxicity 
will be reported immediately to the study sponsor (Novartis) who, in turn, must notify 
the Chairman of the IRB (CFR 312.32). 
2) 
Serious adverse events include toxicities which cause death, are life-threatening, result 
in inpatient hospitalization or prolongation of an existing hospitalization, cause a 
persistent or significant disability/incapacity, or a congenital anomaly/birth defect.   To 
ensure patient safety, every SAE, regardless of causality assessment, occurring after the 
patient has provided informed consent and until 30 days after the patient has stopped 
participation to the IPP (defined as time of last dose of alpelisib taken or last visit 
whichever is later) 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 

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Novartis if the Treating Physician or other involved health care professional suspects a 
causal relationship to the treatment with alpelisib. Recurrent episodes, complications, 
or progression of the initial SAE must be reported as follow-up to the original episode, 
regardless of when the event occurs. This report must be submitted within 24 hours of 
the Treating Physician or other involved health care professional receiving the follow-up 
information. An SAE that is considered completely unrelated to a previously reported 
one should be reported separately as a new event. 
3) 
Laboratory tests for hematology, chemistry will be performed to assess toxic effects of 
the study treatment.  All laboratory tests performed will be assessed by the investigator 
as to their clinical significance.  Any post-baseline laboratory value which is found to be 
clinically significant will be assessed by the investigator for a causal relationship to the 
study drug and the appropriate action taken. 
4) 
Removal of a patient from the study because of adverse experiences or changes in 
laboratory test values, whether by the investigator or by the patient's own volition, 
should be reported promptly to the study sponsor (Novartis). 
 
 
14.0 
REFERENCES 
Katso, R., et al. (2001). "Cellular function of phosphoinositide 3-kinases: implications for development, 
homeostasis, and cancer." Annu Rev Cell Dev Biol 17: 615-675. 
 
Liu, P., et al. (2009). "Targeting the phosphoinositide 3-kinase pathway in cancer." Nat Rev Drug Discov 
8(8): 627-644. 
 
McCubrey, J. A., et al. (2006). "Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant 
transformation and drug resistance." Adv Enzyme Regul 46: 249-279. 
 
Samuels, Y., et al. (2004). "High frequency of mutations of the PIK3CA gene in human cancers." Science 
304(5670): 554. 
 
Hennessy, B. T., et al. (2005). "Exploiting the PI3K/AKT pathway for cancer drug discovery." Nat Rev 
Drug Discov 4(12): 988-1004. 
 
Markman, B., et al. (2010). "Status of PI3K inhibition and biomarker development in cancer 
therapeutics." Ann Oncol 21(4): 683-691. 
 
Sansal, I. and W. R. Sellers (2004). "The biology and clinical relevance of the PTEN tumor suppressor 
pathway." J Clin Oncol 22(14): 2954-2963. 
 
Cheng, J. Q., et al. (1992). "AKT2, a putative oncogene encoding a member of a subfamily of protein-
serine/threonine kinases, is amplified in human ovarian carcinomas." Proc Natl Acad Sci U S A 89(19): 
9267-9271. 
 

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Cheng, J. Q., et al. (1996). "Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 
expression and tumorigenicity by antisense RNA." Proc Natl Acad Sci U S A 93(8): 3636-3641. 
 
Shayesteh, L., et al. (1999). "PIK3CA is implicated as an oncogene in ovarian cancer." Nat Genet 21(1): 
99-102. 
 
Hartmann, C., et al. (2005). "PIK3CA mutations in glioblastoma multiforme." Acta Neuropathol 109(6): 
639-642. 
 
Li, V. S., et al. (2005). "Mutations of PIK3CA in gastric adenocarcinoma." BMC Cancer 5: 29. 
 
Lee, J. W., et al. (2005). "PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular 
carcinomas." Oncogene 24(8): 1477-1480. 
 
Bachman, K. E., et al. (2004). "The PIK3CA gene is mutated with high frequency in human breast 
cancers." Cancer Biol Ther 3(8): 772-775. 
 
Levine, D. A., et al. (2005). "Frequent mutation of the PIK3CA gene in ovarian and breast cancers." Clin 
Cancer Res 11(8): 2875-2878. 
 
Wu, G., et al. (2005). "Somatic mutation and gain of copy number of PIK3CA in human breast cancer." 
Breast Cancer Research 7(5): R609-R616. 
 
Isakoff, S. J., et al. (2005). "Breast cancer-associated PIK3CA mutations are oncogenic in mammary 
epithelial cells." Cancer Res 65(23): 10992-11000. 
 
Ikenoue, T., et al. (2005). "Functional analysis of PIK3CA gene mutations in human colorectal cancer." 
Cancer Res 65(11): 4562-4567. 
 
Bader, A. G., et al. (2005). "Oncogenic PI3K deregulates transcription and translation." Nat Rev Cancer 
5(12): 921-929. 
 
Engelman, J. A., et al. (2008). "Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and 
PIK3CA H1047R murine lung cancers." Nat Med 14(12): 1351-1356. 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 1:  Concomitant Medications 
 
Table 1:  List of medications to be used with caution during treatment with apelisib 
 
 
 
 

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Table 2:  List of prohibited medications during apelisib treatment 

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