EPIK-P2: A Phase II Double-blind Study With an Upfront, 16-week Randomized, Placebo-controlled Period, to Assess the Efficacy, Safety and Pharmacokinetics of Alpelisib (BYL719) in Pediatric and Adult Patients With PIK3CA-related Overgrowth Spectrum (PROS)
Phase: PHASE2
Conditions: PIK3CA-related Overgrowth Spectrum (PROS)
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
CBYL719F12201 / NCT04589650
Clinical Trial Protocol  
EPIK-P2: A Phase II double-blind study with an upfront, 16-
week randomized, placebo-controlled period, to assess the 
efficacy, safety and pharmacokinetics of alpelisib (BYL719) 
in pediatric and adult patients with PIK3CA-related 
overgrowth spectrum (PROS) 
Clinical Trial Protocol Number: CBYL719F12201 
Version number: V05 (amended protocol) (Clean)  
Compound: BYL719 
Brief Title: Study assessing the efficacy, safety and pharmacokinetics of alpelisib 
(BYL719) in pediatric and adult patients with PIK3CA-related overgrowth spectrum 
(PROS) 
Study Phase: II 
Study Acronym: EPIK-P2 
Sponsor Name: Novartis Pharma AG or its affiliates outside of the EEA (where 
applicable) 
Sponsor address in the EEA: Novartis Pharma AG, Lichtstrasse 35, 4056 Basel, 
Switzerland 
Regulatory Agency Identifier Number(s): EU CT Number: 2023-508530-34-00, 
IND: 143387 
Content final date: 21-Oct-2024 
Property of Novartis Pharma AG 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020 

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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 7 
List of abbreviations ............................................................................................................ 9 
Glossary of terms ............................................................................................................... 13 
Global Protocol Amendment 05 (21-Oct-2024) ................................................................ 16 
Global Protocol Amendment 04 (05-Oct-2023) ................................................................ 20 
Global Protocol Amendment 03 (11-Apr-2023) ............................................................... 22 
Global Protocol Amendment 02 (28-Sep-2022) ................................................................ 24 
Global Protocol Amendment 01 (14-Jan-2022) ................................................................ 36 
Protocol summary .............................................................................................................. 51 
1 
Introduction ....................................................................................................................... 58 
1.1 
Background ............................................................................................................ 58 
1.2 
Purpose .................................................................................................................. 64 
2 
Objectives, endpoints and estimands ................................................................................. 64 
2.1 
Primary estimands ................................................................................................. 68 
2.2 
Secondary estimands ............................................................................................. 69 
3 
Study design ...................................................................................................................... 69 
4 
Rationale ............................................................................................................................ 75 
4.1 
Rationale for study design ..................................................................................... 75 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 77 
4.3 
Rationale for choice of control drugs (comparator/placebo) ................................. 79 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 80 
4.5 
Risks and benefits .................................................................................................. 80 
4.6 
Public health emergency mitigation procedures .................................................... 81 
4.7 
Rationale for planned off-site procedures (for Netherlands only) ......................... 81 
5 
Study Population ............................................................................................................... 81 
5.1 
Inclusion criteria .................................................................................................... 82 
5.2 
Exclusion criteria ................................................................................................... 84 
6 
Treatment ........................................................................................................................... 87 
6.1 
Study treatment ...................................................................................................... 87 
6.1.1 
Investigational and control drugs .......................................................... 87 
6.1.2 
Additional study treatments .................................................................. 90 
6.1.3 
Treatment arms/group ........................................................................... 90 
6.1.4 
Guidelines for continuation of treatment .............................................. 91 

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6.1.5 
Treatment duration ................................................................................ 91 
6.2 
Other treatment(s) .................................................................................................. 93 
6.2.1 
Concomitant therapy ............................................................................. 93 
6.2.2 
Prohibited medication ........................................................................... 95 
6.3 
Participant numbering, treatment assignment, randomization .............................. 96 
6.3.1 
Participant numbering ........................................................................... 96 
6.3.2 
Treatment assignment, randomization .................................................. 96 
6.4 
Treatment blinding ................................................................................................. 97 
6.5 
Dose escalation and dose modification .................................................................. 98 
6.5.1 
Dose modifications ................................................................................ 98 
6.5.2 
Follow-up for toxicities ....................................................................... 114 
6.6 
Additional treatment guidance ............................................................................. 119 
6.6.1 
Treatment compliance ......................................................................... 119 
6.6.2 
Emergency breaking of assigned treatment code ................................ 119 
6.7 
Preparation and dispensation ............................................................................... 120 
6.7.1 
Handling of study treatment and additional treatment ........................ 121 
6.7.2 
Instruction for prescribing and taking study treatment ....................... 122 
7 
Informed consent procedures .......................................................................................... 124 
8 
Visit schedule and assessments ....................................................................................... 125 
8.1 
Screening ............................................................................................................. 147 
8.1.1 
Eligibility screening ............................................................................ 148 
8.1.2 
Information to be collected on screening failures ............................... 149 
8.2 
Participant demographics/other baseline characteristics ..................................... 149 
8.3 
Efficacy ................................................................................................................ 150 
8.3.1 
Evaluation of response of PROS lesions ............................................. 151 
8.3.2 
Other assessments for PROS ............................................................... 155 
8.3.3 
Blinded Independent Review Committee (BIRC) assessment ............ 156 
8.3.4 
Appropriateness of efficacy assessments ............................................ 156 
8.4 
Safety ................................................................................................................... 157 
8.4.1 
Laboratory evaluations ........................................................................ 158 
8.4.2 
Electrocardiogram (ECG) ................................................................... 160 
8.4.3 
Pregnancy and assessments of fertility ............................................... 162 
8.4.4 
Other safety evaluations ...................................................................... 164 
8.4.5 
Appropriateness of safety measurements ............................................ 165 
8.5 
Additional assessments ........................................................................................ 165 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................. 165 

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8.5.2 
Pharmacokinetics ................................................................................ 170 
 
 173 
8.5.4 
Imaging ............................................................................................... 175 
8.5.5 
Lung function assessment ................................................................... 175 
9 
Study discontinuation and completion ............................................................................ 176 
9.1 
Discontinuation and completion .......................................................................... 176 
9.1.1 
Study treatment discontinuation and study discontinuation................ 176 
9.1.2 
Discontinuation from study ................................................................. 177 
9.1.3 
Withdrawal of informed consent ......................................................... 177 
9.1.4 
Lost to follow-up ................................................................................. 178 
9.1.5 
Early study termination by the sponsor ............................................... 178 
9.2 
Study completion and post-study treatment ........................................................ 178 
10 Safety monitoring, reporting and committees ................................................................. 179 
10.1 
Definition of adverse events and reporting requirements .................................... 179 
10.1.1 
Adverse events .................................................................................... 179 
10.1.2 
Serious adverse events ........................................................................ 181 
10.1.3 
SAE reporting...................................................................................... 182 
10.1.4 
Pregnancy reporting ............................................................................ 183 
10.1.5 
Reporting of study treatment errors including misuse/abuse .............. 184 
10.1.6 
Off-site procedures (for Netherlands only) ......................................... 184 
10.2 
Additional Safety Monitoring .............................................................................. 185 
10.2.1 
Liver safety monitoring ....................................................................... 185 
10.2.2 
Data Monitoring Committee ............................................................... 185 
10.2.3 
Steering Committee ............................................................................. 186 
11 Data Collection and Database management .................................................................... 186 
11.1 
Data collection ..................................................................................................... 186 
11.2 
Database management and quality control .......................................................... 187 
11.3 
Site monitoring .................................................................................................... 187 
12 Data analysis and statistical methods .............................................................................. 188 
12.1 
Analysis sets ........................................................................................................ 189 
12.2 
Participant demographics and other baseline characteristics ............................... 190 
12.3 
Treatments ........................................................................................................... 190 
12.4 
Analysis of the primary estimand(s) .................................................................... 190 
12.4.1 
Definition of primary estimand(s) ....................................................... 190 
12.4.2 
Statistical model, hypothesis, and method of analysis ........................ 191 
12.4.3 
Handling of remaining intercurrent events of primary estimand ........ 191 

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12.4.4 
Handling of missing values not related to intercurrent event ............. 191 
12.4.5 
Supplementary analysis ....................................................................... 192 
12.4.6 
Sensitivity analyses for primary endpoint/estimand ........................... 192 
12.5 
Analysis of secondary endpoints/estimands ........................................................ 192 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................. 192 
12.5.2 
Safety endpoints .................................................................................. 197 
12.5.3 
Pharmacokinetics ................................................................................ 199 
12.5.4 
Patient reported outcomes ................................................................... 200 
 
 200 
12.7 
Interim analyses ................................................................................................... 203 
 
 203 
 
 203 
 
 206 
13 Ethical considerations and administrative procedures .................................................... 207 
13.1 
Regulatory and ethical compliance ...................................................................... 207 
13.2 
Responsibilities of the Investigator and IRB/IEC ............................................... 208 
13.3 
Publication of study protocol and results............................................................. 208 
13.4 
Quality Control and Quality Assurance ............................................................... 209 
13.5 
Data protection ..................................................................................................... 209 
13.6 
Participant Engagement ....................................................................................... 209 
14 Protocol adherence .......................................................................................................... 210 
14.1 
Protocol amendments ........................................................................................... 210 
15 References ....................................................................................................................... 211 
16 Appendices ...................................................................................................................... 215 
16.1 
Appendix 1: PROS diagnostic criteria ................................................................. 215 
16.2 
Appendix 2: Karnofsky performance scale index ............................................... 216 
16.3 
Appendix 3: Lansky play performance scale ....................................................... 216 
16.4 
Appendix 4: Tanner assessment staging scale ..................................................... 217 
16.5 
Appendix 5: QT Heart rate Fridericia's Correction Formula ............................... 218 
16.6 
Appendix 6: List of concomitant medications ..................................................... 218 
16.6.1 
Permitted medication to be used with caution and/or action .............. 219 
16.6.2 
Prohibited Medication ......................................................................... 219 
 
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List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 66 
Table 6-1 
Investigational and control drug - Core period Week 1 - Day 1 to 
Week 16 ................................................................................................ 88 
Table 6-2 
Investigational drug - Core period Week 17 to Week 24 ...................... 89 
Table 6-3 
Investigational drug - Extension 1 and Extension 2 .............................. 89 
Table 6-4 
Investigational drug - Exploratory Group 3 .......................................... 89 
Table 6-5 
Investigational drug - Exploratory Group 4 .......................................... 90 
Table 6-6 
Investigational drug - Exploratory Group 5 .......................................... 90 
Table 6-7 
Group 3 starting dose and maximum age-related dose ......................... 91 
Table 6-8 
Dose escalation for alpelisib in Group 1 and Group 5 .......................... 99 
Table 6-9 
Dose escalation for alpelisib in Groups 2, 3 and 4 .............................. 100 
Table 6-10 
Dose reduction sequential steps for alpelisib in Group 1 .................... 101 
Table 6-11 
Dose reduction sequential steps for alpelisib in Group 2 and 4 .......... 101 
Table 6-12 
Dose reduction sequential steps for alpelisib in Group 5 .................... 101 
Table 6-13 
Dose reduction sequential steps for alpelisib in Group 3 .................... 102 
Table 6-14 
Criteria for interruption and re-initiation of alpelisib/placebo 
treatment due to QTcF prolongation ................................................... 102 
Table 6-15 
Criteria for interruption and re-initiation of alpelisib/placebo 
treatment due to skin toxicity .............................................................. 103 
Table 6-16 
Criteria for interruption and re-initiation of alpelisib/placebo 
treatment due to hyperglycemia .......................................................... 105 
Table 6-17 
Management of pneumonitis related to alpelisib/placebo with or 
without other agents in combination ................................................... 107 
Table 6-18 
Criteria for interruption and re-initiation of alpelisib treatment due 
to diarrhea ............................................................................................ 107 
Table 6-19 
NCI CTCAE version 4.03 grading of diarrhea for participants 
without Colostomy .............................................................................. 111 
Table 6-20 
Criteria for interruption and re-initiation of alpelisib treatment due 
to stomatitis ......................................................................................... 112 
Table 6-21 
Criteria for interruption and re-initiation of alpelisib treatment due 
to pancreatitis. ..................................................................................... 112 
Table 6-22 
Criteria for interruption and re-initiation of alpelisib treatment: 
Investigations (hematologic) ............................................................... 113 
Table 6-23 
Criteria for interruption and re-initiation of alpelisib treatment: 
Investigations (other) .......................................................................... 113 

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Figure 8-1 
Timing of study procedures ................................................................ 161 
Figure 12-1 
Graphical gatekeeping procedure to test procedure to test primary 
and key secondary endpoints in order to control overall type I 
error. .................................................................................................... 194 
Figure 12-2 
Example rejection sequences for the sequentially rejective 
graphical procedure ............................................................................. 195 
Figure 16-1 
Sexual maturity rating (Tanner stages) of secondary sexual 
characteristics ...................................................................................... 217 
 
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List of abbreviations 
ADA 
American Diabetes Association  
ADL 
Activity of Daily Living 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
AKT 
Protein Kinase B 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANA 
Antinuclear Antibodies 
ANC 
Absolute Neutrophil Count 
aPTT 
activated Partial Thromboplastin Time  
ARA 
Acid Reducing Agents  
ASMA 
Anti-Smooth Muscle Antibody 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical Classification System 
AUC 
Area Under the Curve 
b.i.d. 
twice a day 
BAL 
Broncho-Alveolar Lavage  
BCRP 
Breast Cancer Resistance Protein 
BIRC 
Blinded Independent Review Committee 
BMI 
Body Mass Index 
BPI 
Brief Pain Inventory  
BSA 
Body Surface Area  
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulation 
CI 
Confidence Interval 
CLOVES 
Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi and 
Skeletal/Scoliosis/Spinal abnormalities 
CO 
Country Organization 
COA 
Clinical Outcome Assessment 
COVID-19 
COronaVIrus Disease 2019 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTT 
Clinical Trial Team 
CV 
Coefficient of Variation 
CYP 
Cytochrome P450 
DBP 
Diastolic Blood Pressure 
DDE 
Direct Data Entry 
DILI 
Drug-Induced Liver Injury 
DLco 
Diffusing Capacity of the Lung for Carbon Monoxide 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 

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DTI 
Direct Thrombin Inhibitors  
DXA 
Dual-energy X-ray Absorptiometry 
EASD 
European Association for the Study of Diabetes 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report/Record Form 
EDC 
Electronic Data Capture 
EM 
Erythema Multiforme 
EMA 
European Medicines Agency  
EoS 
End of Study 
EOT 
End Of Treatment 
ePRO 
electronic Patient Reported Outcomes 
ERCP 
Endoscopic Retrograde Cholangiopancreatography 
ESMO 
European Society for Medical Oncology 
FAS 
Full Analysis Set 
FCT 
Film-Coated Tablets  
FDA 
Food and Drug Administration 
FEV 
Forced Expiratory Volume  
FFPE 
Formalin Fixed Paraffin Embedded  
FPG 
Fasting Plasma Glucose  
Fr 
French scale (used to measure the size of a catheter) 
FSH 
Follicle Stimulating Hormone 
FVC 
Full Vital Capacity 
FVCPP 
Percent Predicted Forced Vital Capacity 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GFR 
Glomerular Filtration Rate  
GGT 
Gamma-Glutamyl Transferase 
GI 
Gastrointestinal 
h 
Hour 
HbA1c 
Glycosylated hemoglobin 
HBsAg 
Hepatitis B virus surface Antigen 
HBV 
Hepatitis B Virus 
HDL 
High Density Lipoprotein 
HER 
Human Epidermal Growth Factor Receptor 
HR 
Hormone Receptor  
HRQoL 
Health-Related Quality of Life 
i.v. 
intravenous 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IDFU 
Investigational directions for use 
IEC 
Independent Ethics Committee 
IPTW 
Inverse Probability of Treatment Weighting 

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IgM 
Immunoglobulin M 
IMP 
Investigational Medicinal Product 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
KTS 
Klippel-Trenaunay Syndrome 
LCMS/MS 
Liquid Chromatography-tandem Mass Spectrometry  
LDH 
Lactate Dehydrogenase 
LDL 
Low Density Lipoprotein 
LFT 
Liver Function Test 
LLN 
Lower Limit of Normal 
LLOQ 
Lower Limit Of Quantification 
LPLV 
Last Participant Last Visit 
LVEF 
Left Ventricular Ejection Fraction  
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram(s) 
ml 
milliliter(s) 
MRI 
Magnetic Resonance Imaging 
mTOR 
mammalian Target Of Rapamycin 
NCI 
National Cancer Institute 
NGS 
Next-Generation Sequencing  
NTI 
Narrow Therapeutic Index 
OHP 
Off-site Health Provider 
OL 
Open-Label 
p.o. 
oral 
PAS 
Pharmacokinetic Analysis Set 
PBPK 
Physiologically Based Pharmacokinetic  
PDCO 
Pediatric Committee 
PIP 
Pediatric Investigation Plan 
PI3K 
Phosphatidylinositol-3-Kinase 
PIK3CA 
Phosphoinositide-3-Kinase Catalytic subunit Alpha 
PK 
Pharmacokinetic(s) 
PLT 
Platelets 
PRO 
Patient Reported Outcomes 
PROMIS 
Patient Reported Outcome Measurement Information System 
PROS 
PIK3CA-Related Overgrowth Spectrum  
PS 
Proteus Syndrome 
PSDS 
Post-Study Drug Supply 
PTA 
Post-Trial Access 
PTT 
Partial Thromboplastin Time 
QD 
Once a Day 
QMS 
Quality Management System 
QOD 
Every Other Day 

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QTcF 
QT interval corrected by Fridericia’s formula 
RDI 
Relative Dose Intensity 
REB 
Research Ethics Board 
RNA 
Ribonucleic Acid 
s.c. 
subcutaneous 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SC 
Steering Committee 
SD 
Standard Deviation 
SDS 
Standard Deviation Scores  
SJS 
Stevens-Johnson Syndrome 
SMT 
Safety Management Team  
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
t.i.d 
ter in die (3 times a day) 
T1/2 
Half Life  
tbd 
to be discussed 
TBIL 
Total Bilirubin 
TEN 
Toxic Epidermal Necrolysis 
TFQ 
Trial Feedback Questionnaire 
Tmax 
Time to maximum concentration 
TTF 
Time to Treatment Failure 
ULN 
Upper Limit of Normal 
US 
United States 
VES 
Visual Evaluation Scale 
WBC 
White Blood Cell(s) 
WHO 
World Health Organization 
WoC 
Withdrawal of Consent 
XR 
Extended Release 
yr 
year 
 

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Glossary of terms 
ARAs 
Acid Reducing Agents  
Assessment 
A procedure used to generate data required by the study. 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant.  
Clinical Outcome Assessment 
(COA) 
A measure that describes or reflects how a participant feels, functions, or 
survives. 
Clinical Trial Team 
Group of people responsible for the planning, execution and reporting of all 
clinical trial activities. Examples of team members include the Study Lead, 
Medical Monitor, Trial Statistician etc. 
Coded Data 
Personal Data which has been de-identified by the investigative center team 
by replacing personal identifiers with a code. 
Cohort 
A group of individuals who share a common exposure, experience or 
characteristic, or a group of individuals followed up or traced over time. 
Control drug 
A study intervention (active or placebo) used as a comparator to reduce 
assessment bias, preserve blinding of investigational drug, assess internal 
study validity, and/or evaluate comparative effects of the investigational drug. 
Discontinuation from study 
Point/time when the participant permanently stops receiving the study 
treatment and further protocol required assessments or follow-up, for any 
reason. 
Discontinuation from study 
treatment 
Point/time when the participant permanently stops receiving the study 
treatment for any reason (prior to the planned completion of study 
intervention administration, if any). Participant may agree to the other 
protocol required assessments including Safety follow-up. 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 100 
mg once a day, 75 mg twice a day). 
Electronic Data Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used to 
capture data transcribed from source data/documents used at the point of 
care. 
End of the clinical trial 
The end of the clinical trial is defined as the last visit of the last participant.  
Enrollment 
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the 
protocol). The action of enrolling one or more participants. 
eSource (DDE) 
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and case report forms (eCRFs) into one application, 
allowing for the real time collection of clinical trial information to Novartis and 
other oversight authorities, as appropriate. 
Estimand  
As defined in the ICH E9(R1) addendum, estimand is a precise description of 
the treatment effect reflecting the clinical question posed by the trial 
objective. It summarizes at a population-level what the outcomes would be in 
the same participants under different treatment conditions being compared. 
Attributes of an estimand include the population, variable (or endpoint) and 
treatment of interest, as well as the specification of how the remaining 
intercurrent events are addressed and a population-level summary for the 
variable. 
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation 
or the existence of the measurements associated with the clinical question of 
interest. 
Investigational drug 
The study drug whose properties are being tested in the study. 

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Medication number 
A unique identifier on the label of medication kits. 
Off-site 
Describes trial activities that are performed at remote location by an off-site 
healthcare professional, such as procedures performed at the participant's 
home. 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy). 
Participant 
A trial participant (patient). “Participant” terminology is used in the protocol 
whereas term “Subject” is used in data collection. 
Patient-Reported Outcome 
(PRO) 
A measurement based on a report that comes directly from the participant 
about the status of a participant's health condition without amendment or 
interpretation of the participant's report by a clinician or anyone else. 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis. 
Personal data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis/Sponsor for the purpose of the clinical trial. This data 
includes participant identifier information, study information and biological 
samples. 
Randomization 
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the 
assignments in order to reduce bias. 
Randomization number 
A unique identifier assigned to each randomized participant. 
Remote 
Describes any trial activities performed at a location that is not the 
investigative site where the Investigator will conduct the trial, but is for 
example a home or another appropriate location. 
Re-screening 
If a participant fails the initial screening and is considered as a Screen 
Failure, he/she can be invited once for a new Screening visit after medical 
judgment and as specified by the protocol. 
Screen Failure 
A participant who did not meet one or more criteria that were required for 
participation in the study. 
Source Data/Document 
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource. 
Start of the clinical trial 
The start of the clinical trial is defined as the signature of the informed 
consent by the first participant. 
Study drug discontinuation 
Point/time when subject permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature subject withdrawal. 
Study treatment 
Any drug administered to the study participants as part of the required study 
procedures; includes investigational drug (s), control(s). 
Tele-visit 
Procedures or communications conducted using technology such as 
telephone or video-conference, whereby the participant is not at the 
investigative site where the Investigator will conduct the trial. 
Subject number 
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc. 

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Treatment arm/group  
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts. 
Variable (or endpoint) 
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. The specification of the variable might 
include whether the participant experiences an intercurrent event. 
Withdrawal of study consent 
(WoC) / Opposition to use of 
data / biological samples 
Withdrawal of consent from the study occurs when the participant explicitly 
requests to stop use of their data and/or biological samples AND no longer 
wishes to receive study treatment AND does not agree to further protocol 
required assessments. This request should be in writing (depending on local 
regulations) and recorded in the source documentation. 
This request should be distinguished from a request to discontinue the study. 
Other study participant’s privacy rights are described in the corresponding 
informed consent form. 

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Made clerical updates throughout the amendment, such as revising patients to participants and 
updating table numbers.  
Review requirements by IRB/IEC and Health Authorities 
A copy of this amended protocol will be sent to the Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 

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Global Protocol Amendment 04 (05-Oct-2023) 
As of the release of this Global Protocol Amendment, 186 participants have been either 
randomized or enrolled in EPIK-P2 (81 in Group 1 [≥ 18 years of age]; 84 in Group 2 
[6-17 years of age]; 7 in Group 4 [2-5 years of age] and 14 in Group 5 [6-17 years]). Enrollment 
in Groups 1, 2, and 4 has been completed. 
This protocol amendment is being implemented to change the timing of the primary analyses 
which will occur after all ongoing participants from Groups 1 and 2 have completed at least 
48 weeks (instead of at least 24 weeks) of treatment or discontinued earlier. In line with the 
change in the timing of the primary analyses, the durability of the confirmed objective response 
will be assessed when all participants from Groups 1 and 2 have reached at least 48 months 
(instead of at least 42 months) of treatment or discontinued earlier to characterize the duration 
of response (DOR). 
Amendment rationale: 
In the context of the review of pooled blinded EPIK-P2 data (i.e., combined blinded data for 
participants randomized to alpelisib and placebo) in preparation for a regularly scheduled data 
monitoring committee (DMC) meeting which took place on 30-Jun-2023, Novartis identified 
that 66% (29/44) of adult participants randomized in Group 1 and 72% (41/57) of pediatric 
participants randomized in Group 2 who were eligible for alpelisib dose escalation for response 
optimization as per protocol (i.e., after Week 28) had at least one dose increase. Furthermore, 
42% (8/19) of adult participants randomized in Group 1 and 38% (9/24) of pediatric participants 
randomized in Group 2 who were eligible for a second dose escalation (i.e., after Week 40) had 
a second dose increase. 
Given the higher-than-expected rates of participants with dose escalation(s), modification to the 
timing of the primary analyses for Groups 1 and 2 to occur after all ongoing participants from 
these groups have completed at least 48 weeks, instead of at least 24 weeks, of treatment or 
discontinued earlier is warranted. This change will capture additional data from participants 
with dose escalation(s) and consequently allow for the more comprehensive assessment of the 
impact of dose escalation(s) on efficacy. 
This protocol amendment only impacts the timepoint of the data cut-off for the primary 
analyses; it does not result in changes to individual participant care (e.g., no changes will be 
made to participant visits, clinical assessments, blinded independent review committee [BIRC] 
assessments, etc.). Besides the timing of the primary analysis, there is no impact on any other 
component of the study design or the analyses. Additionally, no impact on the integrity of the 
trial is expected based on the modification to the timing of the primary analyses. 
List of modified Protocol Amendment 04 sections: 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. The 
following sections have been modified in the amended protocol: 

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Review requirements by IRB/IEC and Health Authorities 
A copy of this amended protocol will be sent to the Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 

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Global Protocol Amendment 03 (11-Apr-2023) 
As of the release of this Global Protocol Amendment, 39 sites have been initiated and 177 
participants have been either randomized or enrolled (81 in Group 1 [≥18 years of age]; 84 in 
Group 2 [6-17 years of age]; 7 in Group 4 [2-5 years of age] and 5 in Group 5 [6-17 years of 
age]). 
The main changes implemented in this amendment are: 
a. Inclusion of a new exclusion criterion # 23.  
b. A mandate for a physical examination on Day 1 of the trial, prior to the start of study 
treatment.  
Amendment rationale: 
Addition of a new exclusion criterion and physical examination on Day 1  
An ad hoc Safety Data Monitoring Committee (DMC) Meeting was held on 27-Jan-2023 to 
discuss on the death of a study participant that occurred 
.  
Subsequently on the same day, the DMC held a closed session to review unblinded data for the 
same study participant.  
The fatal case concerned a pediatric participant who was taken off treatment with an inhibitor 
of the PI3K/AKT/mTOR pathway prior to the start of study treatment and died on Study Day 4 
due to a massive embolism of leg/vena cava/heart/pulmonal and haemolytic streptococcus 
group A infection. These events were deemed unrelated to study treatment by the investigator.  
After reviewing the case, the DMC recommended inclusion of the following new exclusion 
criterion to help further strengthen the existing exclusion criterion #16 (Participant with other 
concurrent severe and/or uncontrolled medical conditions that would, in the Treating 
Physician’s judgment, contraindicate administration of alpelisib) and call for particular 
attention on evolving signs and symptoms in those patients who washed out of another inhibitor 
of the PI3K/AKT/mTOR pathway:  
Participants with clinically significant worsening of PROS-related laboratory anomalies, 
physical signs and symptoms (such as, but not limited to increase of D-dimers, worsening of 
underlying pain, newly occurring swelling or redness) indicating an uncontrolled condition 
during the screening phase, particularly if systemic treatment with any other inhibitor of the 
PI3K/AKT/mTOR pathway was stopped prior to the start of study treatment. This includes but 
is not limited to hypercoagulability state in participants not receiving prophylactic treatment. 
The DMC has also recommended to mandate a physical examination on Day 1 of the trial, prior 
to the start of study treatment.  
In addition, the following changes are implemented: 

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List of modified Protocol Amendment 03 sections: 
Review requirements by IRB/IEC and Health Authorities 
A copy of this amended protocol will be sent to the Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs) and Health Authorities.  
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 

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it is anticipated that most of the responses in EPIK-P2 will be associated with an onset within 
the first 24 weeks of treatment and subsequently sustained. Hence, the expected confirmed 
response rate of alpelisib is anticipated to be similar to the expected response rate at Week 24 
and the analysis of this primary objective will be performed around this timeframe (i.e., at the 
time all participants in Groups 1 and 2 reached at least 24 weeks of treatment or discontinued 
earlier). Of note, the specification of the primary hypothesis tests as well as the sample size for 
the primary analysis remain unchanged.  
Subsequently, a secondary endpoint has been added to assess the efficacy of alpelisib as 
measured by the proportion of participants with a response by BIRC at Week 24 in Groups 1 
and 2.  
Additionally, all the responses reported in Groups 1, 2, 4 and newly added Group 5 as of the 
Week 24 cut-off date (i.e., at the time all participants reached at least 24 weeks of treatment or 
discontinued earlier) will be followed for at least 36 months to characterize the duration of 
response and therefore an additional analysis will be performed. 
Addition of exploratory group (i.e., Group 5) 
In accordance with FDA’s accelerated approval of alpelisib for the treatment of adult and 
pediatric patients 2 years of age and older with severe manifestations of PROS who require 
systemic therapy, Novartis agreed to a Post Marketing Commitment (PMC) (4260-6) to assess 
a starting dose of alpelisib 125 mg (in addition to the alpelisib 50 mg starting dose) in pediatric 
patients 6 to 17 years of age to evaluate the pharmacokinetics, safety, and clinical outcomes for 
dose optimization in this patient population. As such, an exploratory group, Group 5, has been 
added to the study design.  
In EPIK-P1, 28 of 57 participants were 6 to 17 years of age; 12 participants were 6 to 11 years 
of age and 16 participants were 12 to 17 years of age. Per the Study [CBYL719F12002 (EPIK-
P1) CSR], the median duration of exposure was 13.6 months for the participants aged 6 to 11 
years and 19 months for those aged 12 to 17 years, with a median relative dose intensity (RDI) 
of 100% and 112.6%, respectively, providing a long period of observation for safety. No life-
threatening treatment related events or adverse events (AEs) leading to discontinuations or 
deaths were observed. There were no unique toxicities noted in these age groups. Additionally, 
one participant in the 6 to 11 years age group started alpelisib at 100 mg, two participants in the 
12 to 17 years age group started alpelisib at 150 mg, and one participant in the 12 to 17 years 
age group started alpelisib at 250 mg. Lastly, ten out of 28 (35.7%) pediatric participants had at 
least one dose increase of alpelisib during the study, without safety concerns, of which five 
participants were in 6 to 11 years age group and the other five in the 12 to 17 years age group.  
As such, the purpose of this Global Protocol Amendment 02 is to open an exploratory group 
(i.e., Group 5) which will include approximately 15 participants 6 to 17 years of age who will 
start treatment with alpelisib 125 mg film-coated tablets.  
Enrollment of Group 5 participants will start after the approval of this Global Protocol 
Amendment 02 and immediately after the enrollment of Group 2 participants has been 
completed in order to avoid competition of enrollment amongst these two groups. 
Data from the participants included in Group 5 will support the following objectives:  

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• Provide efficacy and safety information of a higher starting dose in participants 6 to 17 years 
of age. 
• Contribute to the totality of PROS information and further evaluate the pharmacokinetics, 
safety, and clinical outcomes for dose optimization in this age group. 
Addition of an imaging assessment at Week 72 for Groups 1,2,4, and 5  
Based on the modification of the primary objective and related endpoint, i.e., to demonstrate 
the efficacy of alpelisib as measured by the proportion of participants randomized to alpelisib 
film-coated tablets (in Groups 1 and 2) with a confirmed objective response by BIRC, an MRI 
at Week 72 (i.e., 24 weeks after the Week 48 efficacy assessment) will be performed to allow 
for a more precise assessment of the efficacy and more specifically document confirmation of 
response for participants who may have a late response to treatment. 
Clarification regarding whole-body MRI requirement 
Whole-body MRI is the primary and preferred method of response evaluation. However, 
undergoing this procedure requires multiple hours and is creates a heavy burden for participants, 
especially children. These concerns were raised by several study Investigators, including 
Steering Committee members. To decrease this burden the MRI schedule requirements have 
been adjusted as follows: it is mandatory that a whole-body MRI be performed at baseline; if at 
the subsequent timepoints whole-body MRI is not feasible, at least the lesions identified at 
baseline by the Investigator should be captured. In addition, focused MRI imaging may be 
required to adequately assess small anatomic areas with PROS lesions. 
Clarification regarding the mandatory unscheduled whole-body MRI prior to a surgery due 
to PROS 
In protocol Section 8.3.1 about “Evaluation of response for PROS lesions”: it has been clarified 
that the Investigator must perform a whole-body unscheduled MRI prior to any surgical 
procedure if a surgery due to PROS is deemed necessary. No additional unscheduled whole-
body MRI is required if an existing MRI was already performed within 4 weeks prior to the 
surgical procedure. This clarification is applicable to participants in all Groups and at any time 
point in the study in order to support the assessment of the PROS lesions. 
In addition, the following change is implemented: 
• Revision added to specify Walking Distance Test is not applicable for Groups 3 and 4 
participants (2-5 years of age). 
List of modified Protocol Amendment 02 sections: 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. The 
following sections have been changed in the amended protocol: 
Section 1.1: Abbreviation of “Food and Drug Administration” has been specified (FDA). 
Section updated to specify that data from EPIK-P1 were submitted to the US FDA and resulted 
in the FDA granting an accelerated approval on 05-Apr-2022 for Vijoice® (alpelisib) tablets for 
the treatment of adult and pediatric patients 2 years of age and older with severe manifestations 

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• Primary estimants #1: “Randomized” has been specified. 
• Primary estimands #3: Replaced Week 24 with confirmation of response.  
• Primary estimands #4: Removed Week 24 and specified that confirmation of response 
requires a subsequent imaging assessment performed at least 4 weeks after the onset of the 
response.  
• Primary estimands #5: Updated as “proportion of participants (children/adolescents aged 6 
to 17 years and adults) achieving confirmed response by BIRC”. Removed response at 
Week 24.  
Section 3: Specified that three additional groups with a total of approximately 33 participants 
will be enrolled for exploratory purposes and added a description of Groups 3, 4 and 5. Updated 
the entire section to include Group 5, including Figure 3-1 (study design). 
Section 4.1: Added a statement to specify there is no approved pharmacological treatment for 
PROS outside the US.  
Response rate was also updated in this section with the removal of “achieving response at Week 
24” and updated to the following language:  
Response rate (based on pre-defined volumetric reduction of target lesions) has been selected 
as a primary endpoint in pivotal studies to demonstrate treatment efficacy and has been used as 
the basis for regulatory approval of agents in different indications in a number of therapeutic 
areas such as oncology and neurology. The primary endpoint of this study is the proportion of 
participants randomized to alpelisib with a confirmed objective response. 
Section 4.2: The entire section was updated to include Group 5. Group 5 rationale for 
dose/regimen and duration of treatment was provided for the alpelisib starting dose of 125 mg 
FCT once daily (taken with food) for pediatric participants from age 6 to 17 years based on the 
data available from the EPIK-P1 study results.  
Description of Group 5 dose escalation for long-term extension periods to optimize the dose for 
all participants for long-term efficacy and safety was added to the section.  
Section 4.5: It was specified that PROS is a serious condition with no approved 
pharmacological treatment targeting the underlying cause of the disease outside the US. 
Section 4.6: This section had a minor update based on the most recent Clinical Trial Protocol 
template V05. The first sentence now states, during a public health emergency as declared by 
local or regional authorities i.e., pandemic, epidemic or natural disaster, mitigation procedures 
may be required to ensure participant safety and trial integrity and are listed in relevant sections 
of the study protocol. 
Section 5: Study enrollment figures were updated with the addition of Group 5. The section 
now states; 189 participants in total, 78 adults and 111 children and adolescents. 
A description of Group 5 was added to the section; Specified that, following the implementation 
of Global Protocol Amendment 02 and once enrollment of Group 2 is completed, exploratory 
Group 5 will be opened to enroll approximately 15 additional pediatric participants with PROS, 
treated with alpelisib FCT at a higher starting dose: Group 5: 6 to 17 years old. 

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Section 5.1: Inclusion criteria #2 was updated to add Group 5 and mention Group 3; Inclusion 
Criteria #5; Inclusion criteria #9 were updated to add Group 5.  
Section 5.2: Exclusion criteria #8 and #9 were updated with the addition of Group 5.  
A sentence within the exclusion criteria #18 was changed to ensure if local regulations are more 
stringent than the contraception methods listed to prevent pregnancy, local regulations apply 
and will be described in the ICF. 
Section 6.1: Within the section, core period Week 0 was corrected to Core period Week 1. 
Section 6.1.1: Three sections were updated to include Group 5 and to specify that, Group 5 will 
start after implementation of Global Protocol Amendment 02 and enrollment in Group 2 is 
completed. The participants in Group 5 will receive alpelisib FCT 125 mg once daily in an 
open-label setting. 
A new table (Table 6-6) labeled “Investigational drug- Exploratory Group 5” was also added to 
the section to provide details on age range, investigational drug, dosage form, route, strength 
and supply type. The subsequent numbering of tables was revised accordingly.  
The footnote “c” in Table 6-4 has been updated concerning granules under development for 
Group 3, that “additional data from Groups 4 and 5 as available” will be used in addition to the 
data of Group 1 and 2 into the primary analysis to determine Group 3 dose strengths.  
In addition, the Table 6-5 has been updated to specify the other possible dose strengths 125 and 
200 mg. 
Section 6.1.3: Group 5 was added and specified for those participants they will receive 125 mg 
alpelisib FCTs once daily in an open-label setting. Once a participant has reached at least 
Week 25, dose escalation will be allowed. 
Section 6.1.5: The section was updated to include Group 5. It was specified in Section 6.1.5.1 
that participants of Group 1, Group 2 and Group 5 with BIRC- confirmed disease progression 
by Week 24 and later, who do not have safety/tolerability issues, may remain on study therapy 
at the discretion of the Investigator; they will also have the option to undergo dose escalation 
after 28 weeks for Groups 1 and 2 and after 24 weeks for Group 5 of study treatment. 
Section 6.2.1: The following language was added based on Clinical Trial Protocol template 
V5.0: 
Each concomitant drug must be individually assessed against all exclusion criteria and 
prohibited medication. If in doubt, the Investigator should contact the Novartis medical monitor 
before randomizing a participant or allowing a new medication to be started. If the participant 
is already enrolled, contact Novartis to determine if the participant should continue participation 
in the study. 
Section 6.3.1: Within the section, “Center Number (Center No.)” was replaced with “Site 
Number (site No.)”. 
Section 6.3.2: The entire section was updated to include Group 5.  
Section 6.4: The section was updated to include Group 5. 
Section 6.5.1 (dose escalation): The section was updated in 4 locations to include Group 5. 

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• Dose escalation is allowed for Group 5 once the participant has reached at least Week 25. 
• In Group 5, dose escalations are possible from Week 25 onwards as follows: from 125 mg 
to 200 mg, from 200 mg to 250 mg once daily p.o.  
• Table 6-7 was updated to include dose escalation for alpelisib in Group 5.  
• For those participants from Group 5, who receive the lower dose because of 
safety/tolerability concerns, re-escalation of the dose is possible starting from Week 25 in 
certain conditions as defined in the dose modification guidance below. The Investigator 
should consult Novartis to make a decision to re-escalate the dose. 
Clarification also added for Group 4 that, dose escalations are possible from Week 25 onward.  
Section 6.5.1 (dose reduction): The dose reduction sequential steps for alpelisib in Group 5 were 
added in Table 6-11. The dose reduction sequential steps for alpelisib in Groups 2 and 4 have 
been grouped in Table 6-10.  
Section 6.7 Table 6-23 (preparation and dispensation): Updated to include Group 5. 
Section 8: Group 5 was added to the following visit names in Table 8-2 (assessment schedule):  
• Addition of Group 5 concerning the exception regarding IRT randomization 
• Whole-body MRI, Digital photography of PROS related lesions with corresponding 
imaging timepoints for Group 5 added  
• Overall clinical response assessment with corresponding imaging timepoints for Group 5 
added  
• Spirometry  
• Table 8-11 added for Blood sample for alpelisib PK sampling in Group 5 
• Footnote 5 was updated with the following text to include Group 5. If archival block or 
slides is not available, a fresh biopsy is required for participants in Groups 1, 2 and 5, if it 
is not clinically contraindicated. 
In Table 8-2 the footnote 9 has been modified to specify Bone development assessments are 
required per scheduled protocol timepoints. In addition, the footnote 13 has been added to 
specify that Walking distance test will not be performed in Groups 3 and 4. 
For assessments, whole-body MRI, digital photography of PROS related lesions as well as 
overall clinical response assessment for Groups 1, 2 and 4, the Week 72 timepoint has been 
added. 
Performance Status assessment has been updated as “Karnofsky (in patients > 16 years old / 
Lansky ≤ 16 years old)” consistently with Inclusion Criteria#6.  
Section 8.1: A sentence has been added to specify that technical aspects on imaging are provided 
in the Vendor Site Manual. 
The following 2 sentences were also updated to include Group 5.  
It is strongly recommended to provide a tissue sample and/or slides in which the initial PIK3CA 
determination was made by the local laboratory, when an archival tissue sample is not available, 
a fresh biopsy is required for participants in Groups 1, 2 and 5, if it is not clinically 
contraindicated, and tissue to be sent to the central laboratory. 

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Investigator should be captured. Additionally, focused MRI imaging may be required to 
adequately assess small anatomic areas with PROS lesions.”  
It was specified in this sub-section that, technical aspects on imaging are provided in the Vendor 
Site Manual. 
For Groups 1 and 2, the Week 72 and 96 imaging assessment timepoints were added concerning 
the MRI of the whole-body to be performed (i.e., MRI will be performed at screening, at Week 
16, 24, 40, 48, 72, 96 and then at other time points of response assessment). 
Similarly for Groups 4, the Week 72 and 96 imaging assessment timepoints were added 
concerning the MRI of the whole-body to be performed (i.e., MRI will be performed at 
screening, at Week 24, 48, 72, 96 and then at other time points of response assessment). 
Group 5 specifications were added and indicate MRI will be performed at screening, at Week 
16, 24, 48, 72, 96 and then at other time points of response assessment. At the End of treatment, 
an MRI will also be performed for all participants if not performed within last 8 weeks during 
Year 1 (until visit Week 48 included), and within last 3 months during Year 2 - Year 5. 
Lastly, language was added in this sub-section to indicate, in the event of a surgery due to PROS 
lesions, an MRI must be performed, prior to the procedure. No additional MRI is required if an 
existing MRI was already performed within 4 weeks of the surgical procedure. 
Section 8.3.1 and Table 8-3 (Imaging assessment collection plan): table was updated to add the 
new mandated MRI assessment at Week 72 and to specify the originally existing assessment 
timepoint planned at Week 96 for Groups 1, 2 and 4. The imaging assessments collection plan 
has been added for Group 5. 
Section 8.3.2 and Table 8-2: Revision added for Walking Distance Test to specify it will not be 
performed in Groups 3 and 4.  
Section 8.3.4: Section was revised to remove “at week 24” for the proportion of participants 
with confirmed response. As a result, the revised text is “The primary/key secondary objectives 
are to demonstrate the efficacy of alpelisib as measured by the proportion of participants with 
confirmed objective response (primary) and response at Week 16 (key secondary) by BIRC for 
Group 2 (6 - 17 yr-old) and for Group 1 (≥ 18 yr-old)”. 
Section 8.4.1: Added the following sentence based on the Clinical Trial Protocol template 
version 5.0: “Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples”. 
Section 8.5.2: Group 5 was added to the section as well as the new related Table 8-11 for 
pharmacokinetic blood collection log. A revision has also been added into the footnote of 
Table 8-9 to clarify, concerning participants who had dose escalation after Week 28 that, PK 
sample is expected on the next scheduled visit after each dose escalation. 
Sentence was added to specify for standard pharmacokinetic abbreviations and definitions, to 
refer to the list of abbreviations. 
Section 8.5.3: Group 5 was added in the following text related to tissue sampling: 

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“A tissue sample (fresh or archival) is to be sent to Novartis designated central Laboratory. If 
archival tissue is not available, collection of a fresh tissue biopsy is required for participants in 
Groups 1, 2 and 5, if it is not clinically contraindicated.” 
Section 8.5.5: Section updated to specify that spirometry will be applicable for participants in 
Group 5. 
Section 9.1.3: Revisions added to bring clarifications on the procedures for Withdrawal of 
consent/opposition to use of data and/or biological samples, in alignment with Novartis Protocol 
template v5.0 language 
Section 10.1.5: Updated in alignment with Novartis Protocol template v5.0 language to align to 
current safety guidance. 
Section 11.3: Site monitoring information updated in alignment with Novartis Protocol template 
v5.0 language. 
Section 12: Specified that an additional CSR will be developed once all participants in Groups 
1, 2, 4 and 5 have reached at least 42 months (i.e., 36 months after the Week 24 timepoint) of 
treatment or discontinued earlier to characterize the durability of response. Revision also added 
to indicate any additional data for participants continuing to receive study treatment past the 
data cutoff date in Groups 1, 2, 4 and 5 as well as new data collected from participants in Group 
3, as allowed by the protocol, will be reported at completion of the study in a final CSR.  
• Section 12.1 
• Group 5 added to the analysis sets. 
• Section 12.4, Section 12.4.1, Section 12.4.2 
• Modified the primary endpoint/estimand to confirmed objective response. 
• Section 12.4.3 
• Updated the intercurrent events of the primary estimand with regards to confirmation 
of response. 
• Section 12.4.4 
• Updated the handling of missing values not related to intercurrent events with regards 
to confirmation of response. 
• Section 12.5.1.1 
• Clarified the description of the key secondary efficacy variable due to the 
modification of the primary efficacy variable. 
• Section 12.5.3 
• Revision added for T1/2 in the Table 12-1 to remove “Use qualifier for other half-
lives”. 
• Section 12.6  
• Added details on the statistical analysis for the exploratory Group 5. 
• Section 12.7  
• Introduced an additional CSR once all participants in Groups 1, 2, 4 and 5 have 
reached at least 42 months (i.e., 36 months after the Week 24 timepoint) of treatment 
or discontinued earlier to characterize the durability of response. It was also specified 

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that additional reports may also be developed prior to the final clinical study report in 
order to respond to Health Authority requests or to support Health Authority 
submissions. 
• Section 12.8.1  
• Revisions added in this section considering data from Study [CBYL719F12002 
(EPIK-P1)], in which most participants with a response experienced early reduction 
in target lesion volume which was subsequently sustained, and that it is anticipated 
that most of the responses in EPIK-P2 will be associated with an onset within the first 
24 weeks of treatment and subsequently sustained. 
• Modified the sample size calculation with regards to confirmed objective response for 
the primary endpoint, and added details about sample size/operating characteristics 
for Group 5. Table 12-3: ‘95% Confidence interval for the difference in confirmed 
response rates (Group 5 vs Group 2)’and Table 12-4: ‘Operating characteristics for 
Group 5’ have been newly added in Section 12.8.1. 
• Section 12.8.2 
• Header of the Table 12-6 updated with regards to confirmation of response for the 
primary endpoint. 
Section 13.1: Language on Regulatory and ethical compliance has been updated in alignment 
with Novartis Protocol template v5.0. 
Section 13.3: Language into this section about Publication of study protocol and results has 
been revised in alignment on Novartis Protocol template v5.0. 
Section 13.5: New section entitled “Data Protection” was added in alignment with Novartis 
Protocol template v5.0. 
Section 15: Added two references “Hernán MA and Robins JM (2020)” and “Vijoice® 
(alpelisib) United States Prescribing Information (2022)”. Two references also moved to the 
appropriate place in alphabetic order: “(2007) Patient-reported outcomes to support medical 
product labeling claims: FDA perspective” and “The EuroQol Group (1990) EuroQol--a new 
facility for the measurement of health-related quality of life. Health Policy;16(3):199-208”. 
In addition, the following editorial changes are implemented within the protocol 
sections: 

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Review requirements by IRB/IEC and Health Authorities 
A copy of this amended protocol will be sent to the Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs) and Health Authorities.  
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 

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The hypothesis to be tested was therefore determined based on a case series of patients with 
PROS published in Venot et al (2018), where: response was derived from changes in the volume 
of a single target lesion, as assessed by the investigator. It is expected that selecting up to 3 
target lesions to assess the radiological response may result in different findings. It is also well 
known from the oncology setting that lack of concordance in response status may be observed 
between local assessments and independent, blinded central assessments. 
The futility threshold was based on results of a study of sirolimus in patients with complicated 
vascular anomalies Adams et al (2016). A 35% response rate was considered as an appropriate 
surrogate estimation of sirolimus efficacy in PROS and was selected as the futility threshold. 
Of note, none of the patients in Adams et al (2016) had a diagnosis of PROS and the response 
criteria were based on changes in the size of a single lesion and not on volumetric changes in 
up to 3 lesions (as in EPIK-P2).  
Since the release of the original EPIK-P2 protocol, additional data for alpelisib in the treatment 
of PROS became available from EPIK-1. This new information is relevant and must be 
considered in determining efficacy assumptions. It further triggered the revision of the futility 
threshold to be based on the Parker et al (2019) publication. 
The results from EPIK-P1 in 57 patients ≥ 2 years of age with severe or life-threatening 
complications of PROS recently became available (Jul-2021). The efficacy results in EPIK-P1 
are based on the same assessment approach as that considered in EPIK-P2 (i.e., up to 3 clinically 
relevant lesions selected as target and response status at Week 24 assessed based on ICRR) and 
allowed to obtain more accurate information regarding a clinically significant response rate at 
Week 24. 
In EPIK-P1 (Canaud et al 2021), 37.5% (95% CI: 21.1 to 56.3) of patients (12/32) included in 
the complete case analysis had a radiological response at Week 24 based on independent central 
radiological review (ICRR). Most of the 57 patients included in the study reported clinical 
benefit (e.g., signs and symptoms improvement, no rescue surgery). Based on the primary 
efficacy endpoint, none of the patients had radiologically confirmed progression of disease.  
EPIK-P1 results demonstrate a meaningful, compelling, and sustained clinical benefit for PROS 
patients treated with alpelisib. This triggered a review of the efficacy assumptions used for the 
EPIK-P2 study design as data from EPIK-P1 support the notion that a lower response rate at 
Week 24 (than expected based on data from Venot et al 2018 publication) is associated with 
clinically meaningful benefit. 
Furthermore, the futility threshold has been revised from 35% to 15% based on published results 
with sirolimus treatment in a PROS population exclusively (Parker et al 2019), allowing a more 
accurate estimation of the treatment effect with sirolimus using similar response rate criteria as 
in EPIK-P2. Among the 22 participants with evaluable volume for affected tissue at the end of 
26 weeks of treatment, none (0% of participants, 95% CI: 0 to 15.4%) achieved ≥ 20% 
reduction (derived from supplementary material Table S2 in Parker et al 2019). The upper limit 
of the confidence interval of 15.4% is now considered as a more suitable threshold to define the 
insufficient level of activity for the EPIK-P2 sample size calculation. 
As a result of the revised primary hypothesis test, approximately 52 participants are now 
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4. To modify the imaging assessment (MRI and photography) frequency in Groups 1 and 
2, add a new imaging frequency for Group 4 and clarify the timing of the mandatory 
unscheduled MRI following a suspected disease progression. 
Rationale: 
Following the initial implementation of this Global Protocol original version 00, several study 
Investigators, including Steering Committee members, raised concerns about the need for 
repeated whole-body MRI after 48 weeks of treatment. This is supported by the heavy burden 
for patients, especially children, to undergo such procedure and the absence of strong 
justification for this high MRI assessments frequency once the treatment is efficacious and 
given the known evolution of the underlying disease. The MRI schedule that was proposed in 
Global Protocol original version 00 is seen as a serious risk for patients’ retention in this study 
after 48 weeks of treatment. Therefore, it has been decided to decrease the MRI assessments 
frequency to closer follow the current medical practice in PROS patients (once yearly in absence 
of sign or symptoms suggestive of a negative evolution). Thus, for Groups 1 and 2: MRI of the 
whole-body will be performed at screening, Weeks 16, 24, 40, and 48 as well as every 48 weeks 
thereafter until Week 264 (End of Treatment). Thus, this amendment decreases the frequency 
of MRI after Week 48 for patients from Groups 1 and 2 from every 24 weeks to every 48 weeks. 
Given that the primary and main secondary analyses are based on data collected up to Week 48, 
the frequency of MRI could be decreased following these milestones. 
For the newly introduced Group 4: MRI of the whole-body will be performed at screening, 
Weeks 24 and 48 as well as every 48 weeks thereafter until Week 264 (End of Treatment). 
Given that all participants from Group 4 will receive alpelisib and that none will receive 
placebo, there is no need to perform imaging assessments at Week 16 or at Week 40. Week 16 
assessments are used to assess efficacy in Groups 1 and 2 only, as part of the key secondary 
objective (comparison of the response rate between the placebo and the alpelisib arms), whereas 
Week 40 will assess the effect of alpelisib on participants originally randomized to the placebo 
arm and who have then been treated with alpelisib for 24 weeks. Thus, only the main analysis 
milestone, at Weeks milestones: Week 24 and 48, followed by a yearly assessment thereafter, 
are applicable for participants of Group 4. 
In protocol Section 6.1.5.1 about “Treatment beyond disease progression”: it has been clarified 
that if disease progression is suspected for any patient, the Investigator must perform an 

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unscheduled MRI as soon as feasible and within the coming 3 months maximum. This is 
applicable to participants of all groups at any time point in the study in order to support 
assessment of duration of response. 
In addition, the following changes are implemented: 

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List of modified Protocol Amendment 01 sections: 

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In addition, the following editorial changes are implemented within the protocol 
sections: 
Review requirements by IRB/IEC and Health Authorities 
A copy of this amended protocol will be sent to the Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs) and Health Authorities.  
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 

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Protocol summary 
Protocol number 
CBYL719F12201 
Full Title 
EPIK-P2: A Phase II double-blind study with an upfront, 16-week randomized, placebo-
controlled period to assess the efficacy, safety and pharmacokinetics of alpelisib 
(BYL719) in pediatric and adult patients with PIK3CA-related overgrowth spectrum 
(PROS) 
Brief title 
Study assessing the efficacy, safety and pharmacokinetics of alpelisib (BYL719) in 
pediatric and adult patients with PIK3CA-related overgrowth spectrum (PROS)  
Sponsor and 
Clinical Phase 
Novartis Pharma AG 
Phase II  
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
This study will be the first prospective study of alpelisib in participants with PROS. Local 
overgrowth or hemihypertrophy, mostly progressive, is the most frequently observed 
manifestation of the disease, often causing functional and/or mobility impairment and 
reduction in health related quality of life. The first experience with alpelisib in overgrowth 
related to mutation in PIK3CA gene provides the direct evidence of clinical improvement 
in participants supporting PIK3CA inhibition as a promising therapeutic strategy in 
participants with PROS. PROS is a serious condition with no approved pharmacological 
treatment targeting the underlying cause of the disease. Current therapy includes 
debulking surgery, amputation, and/or endovascular occlusive procedures and mainly 
addresses symptoms and complications of the disease. There is a high unmet medical 
need for an effective systemic treatment. 
The purpose of this study is to assess the efficacy, safety/tolerability and evaluate 
pharmacokinetics (PK) of alpelisib in participants of different ages with confirmed 
diagnosis of PROS. As the disease continues throughout the participant life and may be 
diagnosed at different time points (Keppler‑Noreuil et al 2014), the study will enroll adult 
participants (Group 1; treated with film-coated tablets (FCT)), 6 to 17 years old pediatric 
participants (Group 2; treated with FCT), two exploratory groups of pediatric participants 
less than 6 years old (Group 3, 0-5 years old treated with granules and Group 4, 2-5 
years old treated with FCT) and an exploratory group of 6 to 17 years old pediatric 
participants (Group 5, treated with FCT [at a higher starting dose than Group 2]).  
Group 3 will be enrolled after the completion of the primary analysis when the efficacy, 
safety and PK data will be available from the participants in Groups 1 and 2 in addition 
to the data from Groups 4 and 5 as available, in order to select the recommended dose 
for participants in Group 3. Recruitment of participants in Group 3 will start only after 
implementation of Global Protocol Amendment 05. Group 4 will be enrolled before 
Group 3 and immediately after implementation of Global Protocol Amendment 01. 
Group 5 will be open to enrollment after implementation of Global Protocol Amendment 
02 and immediately after enrollment of Group 2 has been completed. 
Primary 
Objective(s)  
The primary objective of this study is to demonstrate the efficacy of alpelisib as 
measured by the proportion of participants randomized to alpelisib with a confirmed 
objective response by BIRC in at least one of the following groups: 
• 
Group 1 (≥ 18 yr-old) 
• 
Group 2 (6 - 17 yr-old) 
The primary scientific question of interest is, for children/adolescents aged 6 to17 years 
(in Group 2) and adults (Group 1: ≥ 18 years) with PROS, to assess the benefit of 
alpelisib with regards to the proportion of confirmed responders by BIRC, considering 
participants that discontinue treatment prior to confirmation of response and participants 
that receive surgery as rescue therapy for any PROS lesions prior to confirmation of 
response as non-responders. 
Secondary 
Objectives 
Key secondary objective: 
• 
To demonstrate the efficacy of alpelisib vs placebo based on the comparison of the 
proportion of participants with response at Week 16 in Group 1 or Group 2 

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Other secondary objectives:  
• 
To assess the efficacy of alpelisib as measured by the proportion of participants 
with a response at Week 24 (by BIRC) in Groups 1 and 2  
• 
To assess the safety and tolerability of alpelisib as compared to placebo in Groups 
1 and 2 up to week 16 
• 
To assess the overall safety and tolerability of alpelisib in participants with PROS 
over time 
• 
To assess changes in patient-reported pain intensity and overall severity of 
symptoms at week 16 on treatment with alpelisib as compared to placebo in 
pediatric and adult populations 
• 
To assess changes in target and non-target lesions over time and appearance of 
new lesions on treatment from baseline over time 
• 
To assess the PK of alpelisib in adult and pediatric patients with PROS 
• 
To assess changes in patient-reported pain, health-related quality of life and overall 
impression of symptoms in pediatric and adult populations over time 
• 
To assess the duration of response in participants who receive alpelisib 
• 
To assess the time to treatment failure in participants who are on treatment with 
alpelisib 
• 
To assess the rate of overall clinical response as assessed by Investigator at the 
scheduled protocol visits for disease evaluation (e.g., week 16, 24, 40, 48, 72, 96 
and thereafter every 48 weeks) 
• 
To assess the proportion of participants with a response at the scheduled protocol 
visits for disease evaluation during the extension periods 
• 
To assess changes in symptoms and complications/comorbidities up to week 16 on 
treatment with alpelisib as compared to placebo  
• 
To assess changes in symptoms and complications/comorbidities associated with 
PROS over time  
• 
To assess the frequency of healthcare visits/hospitalizations due to PROS, rescue 
surgeries for PROS (incl. avoidance/delay in planned disease-related surgery) over 
time·  
Study design 
This is a Phase II multi-center study with an upfront 16-week, randomized, double-blind, 
placebo-controlled period, and extension periods, to assess the efficacy, safety and PK 
of alpelisib in pediatric and adult participants with PROS. 
Study period 1 - Core Period: Double-blind treatment, with an upfront 16-week 
placebo-controlled period (From Randomization to the end of Week 24) – Groups 
1 and 2 
At study start, participants in Group 1 and Group 2 will be enrolled and randomized in a 
2:1 ratio (104 participants in the active arms and 52 participants in the placebo arms) to 
alpelisib or matching placebo. The upfront placebo-controlled period will continue for the 
first 16 weeks. At the conclusion of week 16, those participants who were randomized to 
receive placebo will be switched to active treatment with alpelisib in a blinded fashion at 
the dose level received at the end of the placebo period. Those participants who were 
randomized to receive alpelisib, will continue their treatment at the same dose level.  
During the initial 16 weeks of the Core period, study treatment will be given in a blinded 
fashion, starting from week 17 of the Core period in open label fashion. The randomized 
treatment assignment to the treatment arms will remain blinded to participants, 
Investigators and the study team until the time of the primary analysis, when the last 
participant reaches week 48 from randomization or discontinues earlier. 
Study period 1 – Exploratory; Group 4, open label treatment with the alpelisib FCT 
formulation  
After the implementation of Global Protocol Amendment 01, approximately 6 
participants 2 to 5 years of age will be enrolled in exploratory Group 4. These 
participants will receive alpelisib FCT in an open label setting.  

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Study period 2 - Extension 1: treatment with alpelisib (week 25 up to the end of 
week 48) – Groups 1 and 2 
Participants (Group 1 and Group 2) will continue their treatment during this study period. 
For Groups 1 and 2, dose escalation is NOT allowed during first 4 weeks of Extension 1 
period (weeks 25-28). 
Once a participant (Groups 1 and 2) has completed initial 24 weeks of study treatment 
and reached Week 29, dose escalation will be allowed (Refer to Section 6.5.1): 
• 
Group 1: Alpelisib (125mg, or 200mg, or 250 mg QD) 
• 
Group 2: Alpelisib (50mg, or 125mg, or 200mg, or 250 mg QD) 
Study period 2 – Exploratory: Group 4, open label treatment with the alpelisib FCT 
formulation  
For Group 4 dose escalation is allowed once participant has reached the age of 6 years 
old, has completed the initial 24 weeks of study treatment, and has reached week 25: 
• 
Group 4: Alpelisib (50 mg, or 125 mg, or 200 mg, or 250 mg QD) 
Study period 3 - Extension 2: long-term treatment with alpelisib (Week 49 up to 5 
years) – Groups 1 and 2 
Groups 1 and 2 participants who continue the study until Week 48 and have clinical 
benefit from the study treatment, will enter a long-term extension period. 
Dose escalation and treatment beyond progression are allowed in both Group 1 and 
Group 2. 
Study period 3 – Exploratory: Group 4, open label treatment with the alpelisib FCT 
formulation 
Group 4 participants who continue the study until Week 48 and have clinical benefit 
from the study treatment, will enter a long-term extension period. Dose escalation is 
allowed once a participant has reached the age of 6 years old, has completed the initial 
24 weeks of study treatment, and has reached Week 25. 
Exploratory study part: Group 3, open label treatment with the alpelisib granules 
formulation  
Group 3 will be an exploratory group of participants who are  0 to 5 years old and will 
receive the alpelisib granules formulation with an age-dependent starting dose and 
maximum dose levels ranging from 20 mg every other day to 50 mg once daily. Group 3 
will be open to enrollment only after implementation of Global Protocol Amendment 05. 
Dose escalation is allowed once a participant has reached the age of 6 years, has 
completed the initial 24 weeks of study treatment, and has reached Week 25. 
Group 5 open-label treatment with the alpelisib FCT formulation: 
Participants of Group 5 will be enrolled after implementation of Global Protocol 
Amendment 02 and immediately after enrollment of Group 2 has been completed and will 
receive a starting dose of 125 mg alpelisib FCT formulation once daily in an open-label 
setting. 
Dose escalation is allowed for those who did not derive sufficient clinical benefit at the 
Investigator’s discretion and once participant has reached at least Week 25. 
Study population 
It is planned to enroll approximately 192 participants in total, 78 adults and 114 children 
and adolescents. A total of approximately 156 male or female participants (of age ≥ 6 
years) with PROS will be randomized in a 2:1 ratio in Groups 1 and 2 (approximately 78 
participants per age group). Additional exploratory groups (Group 3, Group 4 and Group 
5) will include approximately a total of 36 participants (approximately  15 in Group 3, 6 
in Group 4 and 15 in Group 5). 
Key Inclusion 
criteria 
• 
Signed informed consent and assent (when applicable) from the patient, parent, 
legal authorized representative or guardian prior to any study related screening 
procedures are performed. 
• 
Patients with diagnosis of PROS with symptomatic and /or progressive overgrowth 
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• 
Participants with clinically significant worsening of PROS-related laboratory 
anomalies, physical signs and symptoms (such as, but not limited to increase of D-
dimers, worsening of underlying pain, newly occurring swelling or redness) 
indicating an uncontrolled condition during the screening phase, particularly if 
systemic treatment with any other inhibitor of the PI3K/AKT/mTOR pathway was 
stopped prior to the start of study treatment. This includes but is not limited to 
hypercoagulability state in participants not receiving prophylactic treatment. 
For the full exclusion criteria, please refer to Section 5.2. 
Study treatment 
Study treatment in Group 1 and Group 2  
Alpelisib/matching placebo FCT will be administered immediately after food at the 
assigned starting doses based on the age groups: 
• 
125 mg alpelisib/matching placebo once daily p.o. in Group 1 
• 
50 mg alpelisib/matching placebo once daily p.o. in Group 2. 
After Week 16 those participants who were randomized to receive placebo will be 
switched to active treatment with alpelisib in a blinded fashion at the dose level received 
at the end of the placebo period. Those participants who were randomized to receive 
alpelisib will continue their treatment at the same dose level. 
Participants (Group 1 and Group 2) will continue their treatment at the randomized dose 
unless the dose is reduced for safety reason. When the dose was reduced because of 
toxicity, the participant remains on reduced dose at least until end of Week 28, when 
escalation becomes allowed. 
Study treatment in Group 4 
The participants in Group 4 will receive 50 mg alpelisib (FCT) once daily, administered 
immediately after food, in an open-label setting. 
Study treatment in Group 5 
The participants in Group 5 will receive 125 mg alpelisib (FCT) once daily, administered 
immediately after food, in an open-label setting. 
Study treatment in Group 3 
The participants in Group 3 will receive alpelisib (granules) administered with food in an 
open-label setting. Group 3 dosing will be age-based with starting dose and maximum 
dose levels ranging from 20 mg every other day to 50 mg once daily. 
Treatment of 
interest 
Randomized treatment with daily alpelisib, regardless of dose changes, in absence of 
rescue surgery for PROS lesions. Further details are provided in Section 6.  
Efficacy 
assessments 
Refer to Section 8 for more details. 
• 
For Groups 1 and 2: MRI of the whole-body will be performed at screening, Weeks 
16, 24, 40, 48, 72, 96 as well as every 48 weeks thereafter, until Week 264 (End of 
Treatment). 
For Group 4: MRI of the whole-body will be performed at screening, Weeks 24, 48, 
72, 96 as well as every 48 weeks thereafter until Week 264 (End of Treatment). 
For Group 3: MRI of the whole-body will be performed at screening, Weeks 24, 48, 
72, 96 as well as every 48 weeks thereafter until Week 264 (End of Treatment). 
For Group 5: MRI of the whole-body will be performed at screening, Weeks 16, 24, 
48, 72, 96 as well as every 48 weeks thereafter until Week 264 (End of Treatment). 
• 
For Groups 1 and 2: Digital photography (images of the whole-body; images of the 
body parts changed due to PROS when applicable; Images of PROS-related 
skin/superficial visual lesions) will be performed at screening, at Week 16, 24, 40, 
48, 72 and 96 as well as every 48 weeks thereafter until Week 264 (End of 
Treatment). 
For Group 4: Digital photography will be performed at screening, at Weeks 24, 48, 
72 and 96, as well as every 48 weeks thereafter until Week 264 (End of Treatment). 
For Group 5: Digital photography will be performed at screening, at Weeks 16, 24, 
48, 72 and 96, as well as every 48 weeks thereafter until Week 264 (End of 
Treatment). 

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1 
Introduction 
1.1 
Background 
The PI3K/AKT/mTOR pathway in PIK3CA-related overgrowth spectrum (PROS): 
Tissue proliferation is a tightly regulated process in the organism from embryonic development 
to adult life. One of the main regulators of cell proliferation is the PI3K/AKT/mTOR signaling 
pathway, which is a well-known target of multiple therapeutic strategies. The hyper-activation 
of the PI3K/AKT/mTOR pathway results in significant dysregulation of cellular functions, 
which in turn leads to a competitive growth advantage. Somatic mutations and gains or losses 
in these genes are linked to many different solid and hematological tumors 
(De Santis et al 2017). In addition to the well-characterized role of PIK3CA in cancer, post 
zygotic somatic mutations in PIK3CA have also been identified in a spectrum of overgrowth 
disorders comprising a wide group of clinically recognizable mutation-driven malformations 
referred to as PIK3CA-related overgrowth spectrum (PROS) (De Santis et al 2017). 
PIK3CA-Related Overgrowth Spectrum (PROS) designates a heterogeneous group of rare, 
asymmetric overgrowth disorders caused by post zygotic variants in the gene PIK3CA 
(Keppler-Noreuil et al 2014). 
PIK3CA 
encodes 
the 
p110α 
catalytic 
subunit 
of 
phosphatidylinositol 3-kinase (PI3K), which transduces activation of tyrosine kinase growth 
factor and hormone receptors into activation of Protein Kinase B (AKT) and Mammalian Target 
of Rapamycin (mTOR) signaling to promote tissue growth. In PROS, activation of this pathway 
is associated with overgrowth which may include adipose tissue, muscle, skin, bone, blood or 
lymph vessels, or neural tissue (Kurek et al 2012, Lindhurst et al 2012). 
The prevalence of PROS is difficult to estimate because of its rarity, its recent characterization 
(i.e., in 2014 by the National Institutes of Health), variation in ascertainment, the broad 
phenotypic spectrum, and the occurrence of atypical or mild phenotypes leading to misdiagnosis 
(Keppler-Noreuil et al 2014, Mirzaa et al 2013). The incidence rate was estimated by medical 
experts to be approximately 1 in 70,000; essentially based on the number of patients they see. 
PROS is characterized by congenital or early childhood-onset overgrowth, sporadic occurrence, 
and mosaic distribution. Segmental overgrowth is often congenital at onset, but it is usually 
noted by 1 year of age with progressive overgrowth of tissues persisting in some cases into 
adulthood. Though some genotype–phenotype correlation in PROS has been suggested 
(Mirzaa et al 2016, Keppler-Noreuil et al 2014), the main determinant of phenotype is the 
timing and location of the pathogenic mutation. Consequently, PROS is characterized by a high 
degree of interindividual phenotypic heterogeneity. The overgrowth features vary greatly for 
reasons which are unknown: some lesions exhibit excess growth which is limited to childhood, 
while other individuals have progressive soft tissue overgrowth during adult life. Complications 
of PROS depend on the anatomical site and extent of overgrowth, but may include functional 
impairment (e.g., of walking or swallowing), pain, cardiac function impairment, pulmonary 
hypertension, seizures, impaired neurological development, recurrent superficial infections, 
thromboembolism, and/or hemorrhage, amongst other manifestations all of which may be 
debilitating, and cause early mortality. Current treatment relies on surgery primarily with 
debulking objectives - amputation, and/or endovascular occlusive procedures. Regrowth 

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following surgery frequently occurs and often requires repeated surgery. There is large unmet 
need for targeted, new therapeutic approaches and effective treatments to combat PROS. 
Disorders that lead to inappropriate activation of the PI3K/AKT/mTOR pathway have been 
shown to result in tissue overgrowth in association with vascular anomalies. Inhibitors targeting 
different components of the PI3K/AKT/mTOR signaling pathway are/were under clinical 
investigation (Keppler-Noreuil et al 2016, Suzuki et al 2017, Venot et al 2018). However only 
a very limited number of clinical studies were conducted with medical treatment in the PROS 
population. 
Development of PI3K/AKT/mTOR inhibitors in PROS indication: 
Investigation of efficacy and safety of mTOR inhibitor sirolimus (rapamycin) was first 
conducted in vascular anomalies, a spectrum of the rare diseases classified into vascular tumors 
and malformations. A prospective study enrolled children and young adults (n=61). They 
received up to 12 courses of 28 days, sirolimus was administered orally at a starting dose of 
0.8mg/m² twice daily, then the levels were maintained between 10 and 15 ng/ml. In terms of 
efficacy, at the end of course 6 no complete response was seen, a total of 47 participants had a 
partial response, 3 participants had stable disease, and 7 participants had progressive disease 
(57 participants were evaluable for efficacy). Grade 3 and higher toxicities attributable to 
sirolimus included blood/bone marrow toxicity in 27% of participants, gastrointestinal toxicity 
in 3%, and metabolic/laboratory toxicity in 3%; 2 participants were taken off of study medicine 
secondary to persistent adverse effects; no toxicity-related deaths occurred. It was concluded 
that sirolimus demonstrated activity in participants with complicated vascular anomalies, and 
further investigations are needed to evaluate specific disease phenotypes (Adams et al 2016). 
Another sirolimus study was conducted in patients with PROS. Thirty-nine participants with 
PROS and progressive overgrowth (22 children ˂ 16 years old, 17 adults ≥16 years old) were 
included in an open-label study (with a 26 weeks run-in period) of efficacy and safety of low-
dose sirolimus. The dose of sirolimus was titrated to achieve a target plasma concentration of 
2-6 ng/ml (based on renal transplants dosing algorithms). Evaluations for efficacy were done at 
Weeks 0 (before the run-in phase), Week 26 (after the run-in phase and before treatment), and 
at Week 52 (after 26 weeks of treatment) with use of dual energy X-ray absorptiometry (DXA) 
scans (quantification for primary outcome) and MRI without contrast. Sirolimus led to a change 
in mean percentage total tissue volume of –7.2% (SD 16.0, p = 0.04) at affected sites affected 
by PROS, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (completed the study: n=30, 
evaluable: n = 23). The adverse-effect profile was interpreted as significant: twenty-eight of 39 
(72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 
in severity and 7/39 (18%) participants were withdrawn consequently; in the opinion of the 
Investigators, treatment of PROS with sirolimus mandates individualized risk-benefit 
evaluations (Parker et al 2019). 
The results of sirolimus studies in participants with vascular anomalies and PROS support the 
hypothesis that the agents targeting PI3K/AKT/mTOR pathway may be good candidates to be 
further explored (Adams et al 2016, Parker et al 2019). 
The pan-AKT inhibitor, miransertib (ARQ 092), is known to decrease pAKT and pPRAS40 in 
PROS and PS (Proteus Syndrome) participant-derived cells (primarily fibroblasts) in a dose-
dependent manner (Lindhurst et al 2015, Ranieri et al 2018). Miransertib was investigated in 

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phase 1/2 non-randomized open-label study in participants with PROS and PS. Preliminary 
results from dose escalation and signal finding Part A of the study are available. Children 
(n=13), young adults (n=2) and adults (n=2) were enrolled in Part A of the study, 5 of 17 
previously received Sirolimus. They received miransertib at the recommended dose of 15 
mg/m² with subsequent dose increase to 25 mg/m². Median time on treatment in the study was 
54 weeks (7 to 91 weeks). Miransertib demonstrated preliminary evidence of clinical activity 
(n=17): radiologic (MRI) response to treatment as assessed by Investigators has been reported 
for 10 participants (stable disease over one year – 9, reduction in lesions by 15 % - 1), response 
by clinical assessments has included reduction in lesion sizes in 2 participants, decrease in nevi 
pigmentation and lip angioma in 1 participant, decrease in pain in 11 participants, improved 
walking in 2 participants, epilepsy control in 1 participant, normalized hemoglobin (with no 
more blood transfusions) in 1 participant, started eating by mouth in 1 participant. 
All participants experienced at least one adverse event; 5 (29%) of participants had at least one 
drug-related adverse event, all Grade 1 or 2. Two Grade 3 adverse events (pyrexia, cellulitis) 
were interpreted as non-related to miransertib. Two participants discontinued the study because 
of adverse events (1 Grade 5 non drug-related suspected dehydration, 1 Grade 1 drug-related 
thrombocytopenia). Summary of safety findings (n=17) include the following adverse events 
interpreted as related to the drug and assessed as being Grade 1 or 2 of severity: diarrhea, 
stomatitis, vomiting, anemia, lymphocytopenia, neutropenia, thrombocytopenia, white blood 
cells (WBC) decrease, hypercholesterolemia, hyperinsulinemia. Each of these adverse events 
were reported in 1 (6%) of 17 participants. The most common reported adverse events of any 
Grade of severity (≥3 participants) regardless their relation to study drug included pyrexia 
(82%), vomiting (53%), cough (41%), abdominal pain (29%), diarrhea (29%), constipation 
(24%), pharyngitis (18%), rhinitis (18%), upper respiratory infection (18%), neutropenia (18%), 
gastroenteritis (18%), pain in extremity (18%), headache (18%), maculopapular rash (18%). 
Based on preliminary results of Part A of the study, miransertib has been considered to be 
a potential drug to provide a molecularly targeted treatment for participants with rare 
PI3K/AKT driven overgrowth diseases with a manageable safety profile; Part B of the study is 
ongoing (Leoni et al 2019).  
Identification of gain-of-function mutations in PI3K has raised the possibility to treat PROS 
with drugs that inhibit PIK3CA. Taselisib is a selective inhibitor of class I PI3Ks with direct 
inhibitory activity of the p110α isoform. An open-label, single-arm, Phase IB/IIA study was 
started in participants with PROS. Occurrence of dose limiting toxicities was a primary 
outcome. 
The 
study 
was 
stopped 
early 
for 
safety 
reasons 
(clinicaltrials.gov/ct2/show/record/NCT03290092?view=record).  
Overview of alpelisib: 
Alpelisib (BYL719) is an oral α-specific class I phosphatidylinositol-3-kinase (PI3K) inhibitor 
belonging to the 2-aminothiazole class of compounds. In biochemical assays, alpelisib potently 
inhibits the p110α subunit of PI3K (IC50 = 4.6 nM) ≥ 50-fold compared to the other class I 
PI3K isoforms (e.g., p110β IC50 = 1156 nM, p110δ IC50 = 290 nM, p110γ IC50 = 250 nM), 
and is inactive against most other kinases (Fritsch et al 2014). 

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Non-clinical experience with alpelisib: 
Alpelisib has demonstrated antitumor activity in a variety of cancer cell lines, particular those 
harboring PIK3CA mutations and in xenograft models with mutated or amplified PIK3CA 
(Keegan et al 2018). 
Clinical studies also demonstrated the antitumor activity of alpelisib, especially in tumors with 
PIK3CA alterations, with a favorable safety profile (Juric et al 2018, Hoste et al 2019). 
Based on the efficacy shown in participants carrying tumors with PIK3CA mutations, it was 
hypothesized that alpelisib could be an effective treatment for PROS due to the similarities 
related to the presence of somatic mutation in the same gene, causing cell proliferation. To 
demonstrate the efficacy of alpelisib in preventing and improving organ dysfunction in PROS, 
Venot and co-Investigators developed a postnatal mouse model of PROS/CLOVES (Congenital 
Lipomatous 
Overgrowth, 
Vascular 
malformations, 
Epidermal 
nevi 
and 
Skeletal/Scoliosis/Spinal abnormalities) that partially recapitulates the human disease. The 
transgenic mouse strain, R26StopFLP110 after breeding with Cre recombinase mice expressed 
a dominant active PI3KCA transgene. R26StopFLP110 mice were crossed with CAGG-
CreER mice to generate PIK3CACAGG-CreER animals that ubiquitously express PIK3CA. As a 
next step, the effect of alpelisib on PIK3CACAGG-CreER mice was studied. First, alpelisib was 
administered orally each day starting on the day of Cre induction. Whereas all placebo-
treated PIK3CACAGG-CreER mice died within 15 days, all alpelisib-treated PIK3CACAGG-
CreER mice were alive after 40 days and had an overtly normal appearance. Histological 
examination at 40 days showed that the alpelisib treated mice had preserved tissues and normal 
vessels. PIK3CACAGG-CreER mice treated with alpelisib had a strong reduction of proliferation, 
but senescence and apoptosis did not change. Western blot and immunofluorescence analyses 
confirmed that PI3KCA pathway activation was effectively inhibited. However, interruption of 
treatment 40 days after Cre recombination led to the rapid death of all PIK3CACAGG-CreER mice 
(median survival 9.8 days after withdrawal of the drug). During the next part of experiment, 
either placebo or alpelisib were administered to PIK3CACAGG-CreER mice seven days 
after Cre induction, when tissue abnormalities were already detected by MRI. Alpelisib 
treatment improved the survival of the PIK3CACAGG-CreER mice. MRI performed 12 days after 
the start of treatment (19 days after Cre induction) showed improvements in scoliosis, muscle 
hypertrophy, and vessel malformations; histological analysis of alpelisib-treated mice revealed 
only minor tissue changes compared to wild-type mice. Alpelisib administration strongly 
reduced cell proliferation in all affected organs, and western blot and immunofluorescence 
analyses confirmed PIK3CA pathway inhibition (Venot et al 2018). In comparison with 
rapamycin (Sirolimus), alpelisib notably blocked phosphorylation of AKT on both Thr308 and 
Ser473 in the PIK3CACAGG-CreER mouse model. These pre-clinical results confirmed that 
alpelisib could be a good therapeutic option even for participants for whom rapamycin is not an 
effective option (Venot et al 2018).  
Clinical experience with alpelisib in PROS: 
Alpelisib was administered to participants with PROS under a compassionate use program. 

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therapy fulvestrant, to treat postmenopausal women and men with hormone receptor (HR)-
positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, 
advanced or metastatic breast cancer (as detected by an FDA-approved test) following 
progression on or after an endocrine-based regimen. 
Please refer to the latest version of [Alpelisib (BYL719) Investigator's Brochure] for additional 
information pertaining to alpelisib. 
The results described in preclinical studies including a mouse model have shown that alpelisib 
inhibits the PI3K/AKT/mTOR signaling pathway and rescues the PROS phenotype in the 
mouse model efficaciously. The first reported case series demonstrated that alpelisib is 
clinically effective and well tolerated by both pediatric and adult participants with PROS. The 
drug improved the disease symptoms in all 19 participants treated in a single center over a 
variable period of time (beyond 18 months for some participants) (Venot et al 2018). Alpelisib 
demonstrated therapeutic activity in participants with PROS regardless of the type of PIK3CA 
mutation and was effective in treatment naive participants and those who previously received 
mTOR inhibitor Sirolimus.  
In Aug-2021, results from EPIK-P1 [CBYL719F12002] study, a retrospective non-
interventional study of 57 patients with PIK3CA Related Overgrowth Spectrum (PROS) were 
available and later presented at the European Society for Medical Oncology (ESMO) congress 
2021 (Canaud et al 2021). This study’s results provide evidence of meaningful clinical benefit 
of alpelisib for the treatment of patients aged 2 years and older with PROS. Compelling 
response at Week 24 showed that 37.5% (12/32, 95% CI: 21.1 to 56.3%) of patients (30.4% 
(7/23, 95% CI: 13.2 to 52.9%) in pediatric and 55.6% (5/9, 95% CI: 21.2 to 86.3%) in adult 
patients) achieved at least 20% reduction in the sum of target lesion volumes, without disease 
progression from the index date (complete case analysis). In addition, 74.2% (23/31) of patients 
with imaging assessments at the index date and at Week 24 had any reduction in sum of target 
lesion volume indicating that alpelisib can control the overgrowth of PROS lesions. Patients 
had clinically meaningful benefit as demonstrated by the early improvement in PROS related 
signs and symptoms in the full population, irrespective of whether the patient was considered a 
responder, non-responder, or had missing assessment. No patient required rescue surgery by 
Week 24 due to disease progression. The safety profile of alpelisib observed in EPIK-P1 was 
consistent with the mechanism of action of alpelisib and compares favorably with prior 
experience in clinical studies and post marketing exposure in the oncology setting. Diarrhea 
(reported in 15.8% of all patients), hyperglycemia (12.3%) and aphthous ulcer (10.5%) were 
the most common AEs. All events were of grade 1/2 in severity and were effectively managed 
with appropriate treatment. No AEs led to treatment discontinuation and no deaths were 
reported during the study. No new safety concerns have emerged with the administration of 
alpelisib to patients with PROS. Notably, the low frequency and generally mild severity of AEs 
suggest good tolerability and an acceptable and manageable safety profile in pediatric and adult 
patients. 
The EPIK-P1 data supports the first direct evidence of clinical improvement in PROS 
participants reported by Venot et al (2018) and confirms that PIK3CA inhibition is a promising 
therapeutic strategy in participants with PROS. 

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Of note, data from EPIK-P1 were submitted to the US FDA and resulted in the FDA granting 
approval on 05-Apr-2022 for Vijoice® (alpelisib) tablets for the treatment of adult and pediatric 
patients 2 years of age and older with severe manifestations of PROS who require systemic 
therapy. This indication is approved under accelerated approval based on response rate and 
duration of response. Continued approval for this indication may be contingent upon 
verification and description of clinical benefit in a confirmatory trial(s). 
1.2 
Purpose 
This study will be the first prospective study of alpelisib in participants with PROS. It will 
assess the efficacy, safety and PK of alpelisib in participants of different ages with confirmed 
diagnosis of PROS. As the disease continues throughout the participant life and may be 
diagnosed at different time points (Keppler-Noreuil et al 2014), the study will enroll adult 
participants (Group 1), 6 to 17 year old pediatric participants (Group 2), two exploratory groups 
of less than 6 year old pediatric participants (Group 3: 0-5 years old and Group 4: 2-5 years old) 
and an exploratory group of 6 to 17 years old pediatric participants (Group 5).  
This study is randomized and includes an upfront 16-week placebo-controlled period for Group 
1 and Group 2 treated with the alpelisib FCT formulation. Groups 3, 4 and 5 will be exploratory 
in nature and will be based on a small number of participants; in Groups 3, 4 and 5, participants 
will not be randomized and instead will be treated with the alpelisib granules formulation 
(Group 3) and FCT formulation (Groups 4 and 5) in an open-label fashion. Group 4 will be 
open to enrollment immediately after the implementation of Global Protocol Amendment 01. 
Group 5 will be open to enrollment after implementation of Global Protocol Amendment 02 
and immediately after enrollment of Group 2 has been completed. Group 3 will be open to 
enrollment after the primary analysis of participants in Group 1 and Group 2 will be available 
in addition to the data from Groups 4 and 5 as available and only after implementation of Global 
Protocol Amendment 05. 
Local overgrowth or hemihypertrophy, mostly progressive, is the most frequently observed 
manifestation of the disease, often causing functional and/or mobility impairment and reduction 
in health related quality of life (HR-QoL). The principal PROS overgrowth lesions will be 
measured in an objective way, the changes in the volume of the lesions will be considered as 
the main efficacy measure in the study. Whole-body MRI has been selected as the primary 
method of disease evaluation. This is in line with the clinical endpoints which have been used 
in clinical studies in PROS and similar syndromes for efficacy assessment [recently completed 
or ongoing studies with sirolimus, miransertib, taselisib etc. (Parker et al 2019, 
Adams et al 2016, NCT03290092, NCT03094832)]. 
Functional impairment and HR-QoL will also be assessed as secondary endpoints. 
2 
Objectives, endpoints and estimands 
Objectives and related selected endpoints are described in Table 2-1 below. More details 
are described in Section 8 and Section 12. 

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Primary, secondary and some exploratory objectives will be applicable for participants in 
Groups 1 and 2; 
 
. 

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Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• To demonstrate the efficacy of alpelisib 
as measured by the proportion of 
participants randomized to alpelisib 
with a confirmed objective response 
(by BIRC) in at least one of the 
following groups: 
• 
Group 1 (≥ 18 yr-old) 
• 
Group 2 (6 - 17 yr-old) 
• Response (yes/no) defined by achieving at least 20% 
reduction from baseline in the sum of target lesion volumes 
(1 to 3 lesions, assessed by MRI by a blinded independent 
review committee (BIRC)), provided that none of the 
individual target lesions has ≥ 20% increase from baseline 
and in absence of progression of non-target lesions and 
without new lesions. Confirmation of response requires a 
subsequent imaging assessment performed at least 4 
weeks after the onset of the response. See Section 2.1 for 
Primary Estimands and Section 8.3 for response definition.  
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
Key secondary objective 
• To demonstrate the efficacy of alpelisib 
vs placebo based on the comparison of 
the proportion of participants with 
response at Week 16 in Group 1 or 
Group 2 
Endpoint for key secondary objective 
• Response at Week 16 (by BIRC): See Section 2.2 for 
secondary Estimands and Section 8.3 for response 
definition. 
Other secondary objectives 
Endpoints for other secondary objectives 
• To assess the efficacy of alpelisib as 
measured by the proportion of 
participants with a response at Week 
24 (by BIRC) in Groups 1 and 2 
• Response at Week 24 (by BIRC). See Section 8.3 for 
response definition. 
• To assess safety and tolerability of 
alpelisib as compared to placebo in 
Groups 1 and 2 up to Week 16 
• Incidence, type, and severity of treatment-emergent adverse 
events per CTCAE v4.03 criteria and other safety data 
including changes in laboratory values, vital signs, 
assessments of cardiac and lung functions. 
• To assess the overall safety and 
tolerability of alpelisib in participants 
with PROS over time 
• Incidence, type and severity of treatment-emergent adverse 
events per CTCAE v4.03 criteria and other safety data 
including changes in laboratory values, vital signs, 
assessments of cardiac and lung functions, growth, 
bone/dental development and sexual maturation (for 
applicable age). 
• To assess changes in patient-reported 
pain intensity and overall severity of 
symptoms at Week 16 on treatment 
with alpelisib as compared to placebo 
in pediatric and adult populations 
• Change from baseline to Week 16 in Brief Pain Inventory 
(BPI) Worst Pain Intensity Item of the PRO (Patient 
Reported Outcomes) diary and Patient Global Impression of 
Symptom Severity in pediatric (12 to17 yr old) and adult 
populations (≥ 18 yr-old). See Section 8.5.1 for more details 
on Clinical Outcome Assessments. 
• To assess changes in target and non-
target lesions over time and 
appearance of new lesions on 
treatment from baseline over time 
• Change from baseline (as assessed by BIRC) in the: 
• 
Sum of target lesion volume 
• 
Sum of MRI-measurable non-target lesion volume 
• 
Sum of all MRI-measurable (target and non-target) 
lesion volume 
• Change in other non-target lesions (by BIRC) 
• Appearance of new lesions (by BIRC). 
• To assess the PK of alpelisib in adult 
and pediatric patients with PROS 
• PK parameters (e.g., Cmax, Ctrough) in Groups 1 and 2. 

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Objective(s) 
Endpoint(s) 
• To assess changes in patient-reported 
pain, health-related quality of life and 
overall impression of symptoms in 
pediatric and adult populations over 
time 
• Change in scores from BPI items, or Wong-Baker Faces 
Scale (age appropriate), PROMIS-profile (Patient Reported 
Outcome Measurement Information System) and Patient 
Global Impression of Symptom Severity. 
• To assess the duration of response in 
participants who receive alpelisib 
• Duration of response (see Section 12.5.1.2) in participants 
who receive alpelisib and who satisfy the response criteria 
(by BIRC). 
• To assess the time to treatment failure 
in participants who are on treatment 
with alpelisib 
• Time to treatment failure (see Section 12.5.1.2) in 
participants who are on treatment with alpelisib. 
• To assess the rate of overall clinical 
response as assessed by Investigator 
at the scheduled protocol visits for 
disease evaluation (e.g., Week 16, 24, 
40, 48, 72, 96 and thereafter every 48 
weeks) 
• Overall clinical response as assessed by Investigator (see 
Section 8.3 for definition). 
• To assess the proportion of 
participants with a response at the 
scheduled protocol visits for disease 
evaluation during the extension periods 
(See Section 3 for extension periods 
definition). 
• Response (yes/no) at scheduled protocol visit. (See 
Section 8.3 for response definition). 
• To assess changes in symptoms and 
complications/comorbidities up to 
Week 16 on treatment with alpelisib as 
compared to placebo.  
• Change in PROS-related symptoms and 
complications/comorbidities up to Week 16 among 
participants with symptoms and complications/comorbidities 
present at baseline. 
• To assess changes in symptoms and 
complications/comorbidities associated 
with PROS over time 
• Change in PROS-related symptoms and 
complications/comorbidities among participants with 
symptoms and complications/comorbidities present at 
baseline. 
• To assess the frequency of healthcare 
visits/hospitalizations due to PROS, 
rescue surgeries for PROS (incl. 
avoidance/delay in planned disease-
related surgery) over time 
• Number/percentage of participants with healthcare 
visits/hospitalized due to PROS; number of hospitalizations. 
• Number/percentage of participants with surgeries required 
to manage PROS; number of surgeries. 

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2.1 
Primary estimands 
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct which could impact the interpretation of the trial results 
(e.g., premature discontinuation of treatment).  
The primary scientific question of interest is, for children/adolescents aged 6 to 17 years (in 
Group 2) and adults (Group 1: ≥ 18 years) with PROS, to assess the benefit of alpelisib with 
regards to the proportion of confirmed responders (see Section 8.3 for definition) by BIRC, 
considering participants that discontinue treatment prior to confirmation of response and 
participants that receive surgery as rescue therapy for any PROS lesions prior to confirmation 
of response as non-responders. 
The primary estimands are characterized by the following 5 attributes: 
1. Treatment: The randomized treatment with daily alpelisib, regardless of dose changes, in 
absence of rescue surgery for PROS lesions (see Section 6.2).  
2. Population: Children/adolescents aged 6 to 17 years and adults aged ≥ 18 years with 
PROS (as per the inclusion/exclusion criteria) 

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3. Intercurrent events 
• participants discontinuing treatment prior to confirmation of response: Classified as a 
non-responder 
• participants receiving surgery as rescue therapy for any PROS lesions (target or other) 
prior to confirmation of response: Classified as a non-responder 
4. Variable: response (yes/no) defined by achieving ≥ 20% reduction from baseline in the sum 
of target lesion volumes (1 to 3 lesions, assessed by MRI by BIRC), provided that none of 
the individual target lesions has ≥ 20% increase from baseline and in absence of progression 
of non-target lesions and without new lesions. Confirmation of response requires a 
subsequent imaging assessment performed at least 4 weeks after the onset of the response. 
5. Summary Measure: Proportion of participants (children/adolescents aged 6-17 years and 
adults) achieving confirmed objective response (by BIRC). 
2.2 
Secondary estimands 
The key secondary scientific question of interest is, for children/adolescents aged 6 to 17 years 
(in Group 2) and adults (Group 1: ≥ 18 years) with PROS to assess the benefit of alpelisib as 
compared to placebo with regards to the proportion of responders (see Section 8.3 for 
definition) at Week 16, considering participants that discontinue treatment prior to Week 16 
and participants that receive surgery as rescue therapy for any PROS lesions as non-responders. 
The key secondary estimands are characterized by the following 5 attributes: 
1. Treatment: the randomized treatment (daily alpelisib or placebo), regardless of dose 
changes, in absence of rescue surgery for PROS lesions (as defined in Section 6.2). 
2. Population: Children/adolescents aged 6 to 17 years and adults aged ≥ 18 years with 
PROS (as per the inclusion/exclusion criteria) 
3. Intercurrent events 
• participants discontinuing treatment prior to Week 16: Classified as a non-responder 
• participants receiving surgery as rescue therapy for any PROS lesions (target or other) 
prior to Week 16: Classified as a non-responder 
4. Variable: response (yes/no) defined by achieving ≥ 20% reduction from baseline in the 
sum of target lesion volumes (1 to 3 lesions, by BIRC) at Week 16, provided that none of 
the individual target lesions has ≥ 20% increase from baseline at Week 16 and in absence 
of progression of non-target lesions and without new lesions 
5. Summary Measure: Difference in proportion of participants (children/adolescents aged 6-
17 years and adults) achieving response at Week 16. 
3 
Study design 
The study is a Phase II multi-center study with an upfront 16-week, randomized, double-blind, 
placebo-controlled period, and extension periods, to assess the efficacy, safety and PK of 
alpelisib in pediatric and adult participants with PROS. 
A total of approximately 156 participants (of age ≥ 6 years) will be randomized in the study 
from Groups 1 and 2. Three additional groups with a total of approximately 36 participants will 
be enrolled for exploratory purposes:  

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• Group 3 (0 to 5 years old) of approximately  15 participants will receive the alpelisib 
granules formulation in an open-label setting with age-based dosing. For additional 
details, including the recommended dosing for Group 3, see Section 6.1.3 and Table 6-7.  
• Group 4 (2 to 5 years old) of approximately 6 participants will receive a starting dose of 
50 mg alpelisib FCT formulation once daily in an open-label setting. 
• Group 5 (6 to 17 years old) of approximately 15 participants will receive a starting dose of 
125 mg alpelisib FCT formulation once daily in an open-label setting. 
Figure 3-1 
Study design 
 
1 Study level milestones once all participants have completed the specified time point or discontinued earlier. 
2 All participants from Groups 1 and 2 have completed 48 weeks of treatment or discontinued earlier and the alpelisib 
dose is defined based on data from the primary analysis from Groups 1 and 2 in addition to the data from Groups 
4 and 5 as available and only after implementation of Global Protocol Amendment 05. 
3 Decision on dose escalation will be taken by the Investigator based on local assessment of PROS lesions 
response, overall clinical response, and safety/tolerability concerns which may preclude from treatment continuation 
at higher dose level. For Groups 1 and 2, dose escalation is allowed starting at Week 29. For Group 3 and 4, dose 
escalation is allowed once participant has reached the age of 6 years old and has reached at least Week 25. For 
Group 5, dose escalation is allowed starting from Week 25. Refer to Section 6.5 for details on alpelisib dose 
escalation and dose modification. 
4 Enrollment in Group 5 will start after implementation of Global Protocol Amendment 02 and enrollment into Group 
2 has been completed. 
Core, Extension 1 and Extension 2 periods will be applied to the participants ≥6 years old 
(Group 1 – adults, Group 2 – participants 6 to 17 years old). 
Group 3 will include participants who are 0 to 5 years old and will be an exploratory group. 
Group 4 will include the participants who are 2 to 5 years old and will be an exploratory group. 
Group 5 will include participants who are 6 to 17 years old and will be an exploratory group.  
Group 1 and Group 2 will be enrolled in parallel.  

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Group 3 will be open to enrollment after the primary analysis of participants in Groups 1 and 
Group 2 will be available in addition to the data from Groups 4 and 5 as available and only after 
implementation of Global Protocol Amendment 05.  
Group 4 will be open to enrollment immediately after the implementation of Global Protocol 
Amendment 01.  
Group 5 will be open to enrollment after implementation of Global Protocol Amendment 02 
and immediately after enrollment of Group 2 has been completed. 
Study period 1 - Core Period:  
Double-blind treatment, with an upfront 16-week placebo-controlled period (From 
Randomization to the end of Week 24) – Groups 1 and 2 
At study start, the participants of Group 1 and Group 2 will be enrolled. Screening starts upon 
signature of the Informed Consent Form by the study participant. The screening assessments 
will be performed during a maximum of 42 days screening period (Day -42 to Day -1) to 
confirm participant's eligibility (Refer to Section 8.1 for more details on Screening). Eligible 
participants aged ≥6 years old will be randomized in a 2:1 ratio to alpelisib or matching placebo; 
the starting dose will be 125 mg once daily p.o. in Group 1, and 50 mg once daily p.o. in Group 
2. The upfront placebo-controlled period will continue for the first 16 weeks. At the conclusion 
of Week 16, those participants who were randomized to receive placebo will be switched to 
active treatment with alpelisib and will receive 125 mg once daily p.o (Group 1) and 50 mg 
once daily p.o (Group 2) in a blinded fashion. Those participants who were randomized to 
receive alpelisib, will continue their treatment at the same dose level. No information regarding 
the treatment received during the first 16 weeks will be shared at the time of the switch to ensure 
maintaining the blinding until the primary analysis is conducted.  
Dose escalation is NOT allowed during Core period. 
Dose reductions because of safety/tolerability issues will be allowed in both groups at any time 
(as described in Section 6.5.1). Participants who at Week 16 are taking a dose lower than the 
initial one at randomization due to safety-tolerability issues should continue on the same 
(reduced) dose until the end of Core period and for at least 4 weeks of Extension 1 (by the end 
of Week 28).  
Participants having a BIRC-confirmed progression at any time of Core Period may remain in 
the study at the discretion of the Investigator if the participant may derive clinical benefit from 
treatment continuation and has no safety/tolerability concerns. The participants will continue 
receiving active treatment with alpelisib. Alternatively, the participant with a BIRC-confirmed 
progression may be withdrawn from the study at the discretion of the Investigator. If 
progression, suspected by the Investigator at any time of Core period, is not confirmed by BIRC, 
the participant should remain on study treatment if not clinically contraindicated until BIRC 
confirms the progression at next radiological assessment. For more details, refer to 
Section 6.1.5.1.  
The primary analysis will be performed after all participants (Group 1 and 2) have completed 
48 weeks of study treatment or have discontinued earlier. The randomized treatment assignment 

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Participants having a BIRC- confirmed progression after completion of the Core Period may at 
the discretion of the Investigator remain in the study and undergo dose escalation (as described 
in Section 6.1.5.1) or, alternatively, may be withdrawn from the study at any time point. 
Study period 3 - Extension 2: long-term treatment with alpelisib (Week 49 up to 5 years) 
– Groups 1 and 2 
Groups 1 and 2 participants who continue the study treatment until Week 48 and continue 
deriving clinical benefit, will enter a long-term extension period. Dose escalation for response 
optimization as described above and treatment beyond progression are allowed in both Group 
1 and Group 2. Additional safety and efficacy data will be collected during the extension period. 
This period will last up to 5 years from randomization.  
Exploratory study part:  
Group 3, open-label treatment with the alpelisib granules formulation 
Group 3 participants will receive alpelisib granules in an open-label setting as follows: 
• 0-<1 month of age: 20 mg alpelisib granules every other day; 
• 1 month-<6 months of age: 20 mg alpelisib granules once daily; 
• 6 months-<24 months of age: 40 mg alpelisib granules once daily;  
• 2 years- < 6 years of age: 50 mg alpelisib granules once daily;   
Dose adjustments as participants age to account for metabolic enzyme maturation are allowed 
(see Table 6-4). 
Dose escalation is allowed for those participants who did not derive sufficient clinical benefit 
at the Investigator’s discretion, once a participant has reached the age of 6 years old and has 
reached at least Week 25.  
Decisions on dose escalation will be taken by the Investigator based on their local assessment 
of PROS lesions response, overall clinical response, and safety/tolerability concerns which may 
preclude from treatment continuation at a higher dose level. Further dose escalation is allowed 
at a minimum of 12-week intervals until the end of the study, according to the dose modification 
guidance. Refer to Section 6.5 for details on alpelisib dose escalation and dose modification. 
Dose reductions because of safety/tolerability issues will be allowed at any time (as described 
in Section 6.5.1). The participant who received a dose lower than the initial one at enrollment 
due to safety-tolerability issues, may be considered for dose re-escalation if the Investigator 
assess the clinical benefit/ safety risk of a dose re-escalation is favorable. Re-escalation may be 
permitted after reaching Week 25 according to the dose modification guidance. Refer to  
Section 6.5 for details on alpelisib dose escalation and dose modification.  
Participants having a BIRC- confirmed progression may at the discretion of the Investigator 
remain in the study and undergo dose escalation (as described in Section 6.1.5.1) or, 
alternatively, may be withdrawn from the study at any time point. 
Treatment beyond progression is allowed in Group 3. Exploratory efficacy, safety and PK data 
will be collected during the whole study period. This period will last up to 5 years from 
treatment start.  

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• Group 4, open-label treatment with the alpelisib FCT formulation:  
Participants of Group 4 will be enrolled immediately after implementation of Global Protocol 
Amendment 01 and will receive 50 mg alpelisib FCT formulation once daily in an open-label 
setting. 
Dose escalation is allowed for those who did not derive sufficient clinical benefit at the 
Investigator’s discretion, once participant has reached the age of 6 years old and has reached at 
least Week 25.  
Decision on dose escalation will be taken by the Investigator based on their local assessment of 
PROS lesions response, overall clinical response, and safety/tolerability concerns which may 
preclude from treatment continuation at a higher dose level. Further dose escalation is allowed 
at a minimum of 12-week intervals until the end of the study, according to the dose modification 
guidance. Refer to Section 6.5 for details on alpelisib dose escalation and dose modification. 
Dose reductions because of safety/tolerability issues will be allowed at any time (as described 
in Section 6.5.1). The participant who received a dose lower than the initial one at enrollment 
due to safety-tolerability issues, may be considered for dose re-escalation if the Investigator 
assess the clinical benefit/ safety risk of a dose re-escalation is favorable. Re-escalation may be 
permitted after reaching Week 25 according to the dose modification guidance. Refer to  
Section 6.5 for details on alpelisib dose escalation and dose modification.  
Participants having a BIRC- confirmed progression may at the discretion of the Investigator 
remain in the study and undergo dose escalation (as described in Section 6.1.5.1) or, 
alternatively, may be withdrawn from the study at any time point. 
Treatment beyond progression is allowed in Group 4. Exploratory efficacy, safety and PK data 
will be collected during the whole study period. This period will last up to 5 years from 
treatment start.  
• Group 5, open-label treatment with the alpelisib FCT formulation: 
Participants of Group 5 will be enrolled immediately after implementation of Global Protocol 
Amendment 02 and enrollment of Group 2 has been completed and will receive a starting dose 
of 125 mg alpelisib FCT formulation once daily in an open-label setting. 
Dose escalation is allowed for those who did not derive sufficient clinical benefit at the 
Investigator’s discretion and once participant has reached at least Week 25. 
A decision on dose escalation will be taken by the Investigator based on their local assessment 
of PROS lesions response, overall clinical response, and safety/tolerability concerns which may 
preclude from treatment continuation at a higher dose level. Further dose escalation is allowed 
at a minimum of 12-week intervals until the end of the study, according to the dose modification 
guidance or details on alpelisib dose escalation and dose modification. 
Dose reductions because of safety/tolerability issues will be allowed at any time (as described 
in Section 6.5.1). The participant who received a dose lower than the initial one at enrollment 
due to safety-tolerability issues, may be considered for dose re-escalation if the Investigator 
assesses that the clinical benefit/ safety risk of a dose re-escalation is favorable. Re-escalation 
may be permitted after reaching Week 25 according to the dose modification guidance. Refer 
to Section 6.5 for details on alpelisib dose escalation and dose modification.  

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Participants having a BIRC-confirmed progression may, at the discretion of the Investigator, 
remain in the study and undergo dose escalation (as described in Section 6.1.5.1) or, 
alternatively, may be withdrawn from the study at any time point. 
Treatment beyond progression is allowed in Group 5. Exploratory efficacy, safety and PK data 
will be collected during the whole study period. Trial participation will last up to 5 years from 
treatment start. 
• Discontinuation of study treatment and End of Study (EoS) for all Groups: 
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
permanently and the End of Treatment assessments are performed (End of Study Treatment 
visit/ Week 264). For the participants who discontinue treatment for reasons other than death, 
lost to follow-up, or withdrawal of consent, safety follow-up assessments must continue after 
study treatment discontinuation (30 days post-treatment safety follow-up visit).  
End of Study (EoS) will occur when all participants have completed 5 years of treatment, unless 
the participant discontinues earlier. The end of the study for a given participant is defined as 
when the participant permanently discontinues study treatment and all the end of study 
procedures are completed (Refer to Section 9.2 for more details). 
4 
Rationale 
4.1 
Rationale for study design 
This study is designed to demonstrate the efficacy and assess safety and tolerability of oral daily 
alpelisib in participants with PROS. Both pediatric and adult participants will be enrolled, as 
the disease may be diagnosed at different time points during a patient's life 
(Keppler-Noreuil et al 2014). 
There is no approved pharmacological treatment for PROS outside the US. In the US, data from 
EPIK-P1 were submitted to the FDA and resulted in the FDA granting approval on 05-Apr-
2022 for Vijoice (alpelisib) tablets for the treatment of adult and pediatric patients 2 years of 
age and older with severe manifestations of PROS who require systemic therapy. This 
indication is approved under accelerated approval based on response rate and duration of 
response. Continued approval for this indication may be contingent upon verification and 
description of clinical benefit in a confirmatory trial(s) (Vijoice® US Prescribing Information, 
2022). 
Venot et al 2018 described a postnatal mouse model of PROS/CLOVES and demonstrated the 
efficacy of alpelisib in preventing and improving organ dysfunction related to the disease. 
Preclinical results were promising and confirm the hypothesis of activity of alpelisib in PROS-
related overgrowth. The promising and encouraging results were observed in the participants 
with diagnosis of PROS treated with alpelisib through a compassionate use program: previously 
intractable vascular lesions became smaller, congestive heart failure was improved, 
hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated 
with any substantial side effects (for the details, efficacy and safety results please refer to 
Section 1.1). 

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A very limited number of clinical studies have been conducted with medical treatments in 
PROS; encouraging results were observed with alpelisib (Venot et al 2018) which 
demonstrated in some cases efficacy as early as at 3 months and showed further improvement 
in participants with follow up beyond 6 months. Due to the paucity of data with medical therapy 
in PROS, there is no consensus on the treatment of choice at any stage of the disease in children 
and adults. Hence, there is no suitable active comparator that could be used in a randomized, 
controlled study design. 
Based on published data from a few studies (Lindhurst et al 2012, Parker et al 2019, 
Venot et al 2018) volume measurement as a method of response evaluation will be 
implemented for the purpose of this study. Compared to photographs and linear measurements, 
MRI allows to assess volumetric changes in PROS-related domains. In the study, MRI 
assessment will be used to evaluate the primary endpoint, both MRI and other methods 
(including digital photography, measurements with caliper/ruler) will be used to evaluate the 
disease burden and secondary endpoints. Assessment of response of PROS lesions will be done 
by a BIRC, to ensure consistency in review. 
Local overgrowth or hemi hypertrophy, mostly progressive, is the most frequently observed 
manifestation of the disease, often causing functional and/or mobility impairment and reduction 
in HR-QoL. Since the overgrowth is measurable in an objective way, the changes in the volume 
of the lesions will be considered the main efficacy measure in the study. This is in line with the 
clinical endpoints which have been used in clinical studies in participants with PROS and 
similar syndromes for efficacy assessments [Recently completed or ongoing studies with 
Sirolimus, miransertib and taselisib (Parker et al 2019, Adams et al 2016, NCT03290092, 
NCT03094832)]. Functional impairment and HR-QoL will also be assessed as secondary 
objectives. 
Response rate (based on pre-defined volumetric reduction of target lesions) has been selected 
as a primary endpoint in pivotal studies to demonstrate treatment efficacy and has been used as 
the basis for regulatory approval of agents in different indications in a number of therapeutic 
areas such as oncology and neurology. The primary endpoint of this study is the proportion of 
participants randomized to alpelisib with a confirmed objective response. The 20% threshold is 
widely used in oncology and other indications for assessment of changes of tumor/other lesion 
size, based on intra-/inter- observer agreement (Solomon J. et al. 2004, Caron et al 2014). It is 
also expected that volumetric decrease in ≥20% of lesion(s) will be associated with clinical 
benefit such as improvement in pain, use of upper/low limbs, HRQoL, etc. (Venot et al 2018). 
The clinical relevance of the volumetric reduction of the lesions and the hypothesis to be tested 
in the current study are based on data published for other compounds (two studies with 
Sirolimus). In Adams et al 2016 study, 35% (95% CI: 20 to 51%) of participants with 
complicated vascular anomalies had ≥20% reduction in size (max diameter) of the target 
lesion(s) at 24 weeks of treatment with Sirolimus. In the Parker et al 2019 study of 39 
participants with PROS and progressive overgrowth, a significant reduction of 7.2% (SD 16.0) 
was observed in the volume change of affected tissues at the end of 26-week sirolimus treatment 
by dual energy X-ray absorptiometry (DXA) technique. 

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4.2 
Rationale for dose/regimen and duration of treatment 
Alpelisib was initially administered under compassionate use programs to 19 participants with 
severe/life threatening clinical manifestations of PROS and all participants showed substantial 
clinical improvement on alpelisib with acceptable tolerability. Film-coated tablets (FCT) 
containing 50 mg alpelisib once daily (taken without food) were used in all the pediatric 
participants regardless of age and body weight (15 out of 19 participants in total, there were 4 
participants of 4-5 years old, 5 participants 6-12 years old, 6 participants of 13-16 years old), 
while 250 mg alpelisib FCT once daily (taken without food) were used in the 4 adult 
participants. No formal justification for the dose was provided in the Venot et al 2018 
publication and no PK data of alpelisib in PROS participants are available.  
Alpelisib is classified as a Biopharmaceutics Classification System Class II compound, with 
high permeability and low solubility, according to the criteria in the FDA Guidance for Industry 
(Waiver of in vivo Bioavailability and Bioequivalence Studies, FDA 2017). Bioavailability in 
vivo under fasted conditions is limited by solubility. The increase in gastrointestinal solubility 
by bile, secreted in response to food intake, is considered to be the driver of the food effects 
that have been observed in earlier studies at high doses. Under fasted conditions, the fraction 
absorbed decreases at higher doses due to limited solubility (e.g., approximately 70% absorbed 
after a 300 mg dose and 50-60% absorbed after a 400 mg single dose in healthy volunteers). 
Under fed conditions, the absorption is nearly complete (>99%) irrespective of the dose. In 
addition, the PK of alpelisib under fed condition showed moderate inter-subject variability 
(Geo-mean CV% ~20-40%), while in fasted conditions, the inter-subject variability was higher 
(Geo-mean CV% ~40-70%). Thus, it is favorable to administer alpelisib with food to reduce 
the inter-subject variability, to use a lower dose to reach similar exposure as a high dose in a 
fasted state, as well as for the convenience for administration in children. 
Novartis Study CBYL719F12101 demonstrated bioequivalence between 50 mg alpelisib 
granules and 50 mg alpelisib FCT in adults, both administered in the fed state. Geometric mean 
ratio (granules:FCT) point estimates and corresponding 90% CIs of the PK exposure parameters 
AUCinf, AUClast, and Cmax were 0.984 (90% CI: 0.952, 1.02), 0.980 (90% CI: 0.946, 1.02), 
and 0.947 (90% CI: 0.891, 1.01), respectively. The 50 mg alpelisib granule and FCT dosages 
are interchangeable when administered with food.  
The proposed Phase II study will be conducted in five groups: Group 1 is 18 years and above, 
Group 2 and 5 are 6 to 17 years of age, Group 3 is 0 to 5 years of age and Group 4 is 2 to 5 
years of age. 
For Group 1: alpelisib 125 mg FCT once daily (taken with food) for adult participants age 18 
and above. Alpelisib at 250 mg once daily taken without food was shown to be effective in all 
4 adult participants with no significant safety concerns (Venot et al 2018). Since alpelisib has a 
positive food effect (50-80% exposure increases at 200-300 mg doses once daily), the current 
study proposes to use 125 mg once daily taken with food, in order to provide similar but slightly 
lower exposure than that following 250 mg once daily in fasting state. This is proposed for 
safety and tolerability reasons (e.g., diarrhea and hyperglycemia) in PROS participants as a 
long-term, possibly a life-long treatment will be required. Also, the lower inter- subject 
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A period of 16 weeks would allow identifying early signs of efficacy and safety. The 
comparison of the proportion of participants with response at Week 16 is a key secondary 
objective of this study. 
4.4 
Purpose and timing of interim analyses/design adaptations 
There is no planned interim efficacy analysis before the conduct of the primary analysis.  
The DMC (Data Monitoring Committee) will conduct periodic safety data reviews (refer to 
Section 10.2.2 and Section 12.7). 
4.5 
Risks and benefits 
Potential benefits to clinical study participants 
PROS is a serious condition with no approved pharmacological treatment targeting the 
underlying cause of the disease outside the US. Current therapy includes debulking surgery, 
amputation, and/or endovascular occlusive procedures and mainly addresses symptoms and 
complications of the disease. There is a high unmet medical need for an effective systemic 
treatment. Alpelisib is considered to be a promising treatment option for pediatric and adult 
participants with PROS and confirmed PIK3CA mutation. Treatment with alpelisib in 
overgrowth related to mutation in PI3K gene may provide a clinical benefit compared to 
available treatment options (See Section 1.1). The participants enrolled in this study are planned 
to receive alpelisib as active treatment for their disease as per treatment assignment plan (see 
Section 6.1). Based on published clinical data (Venot et al 2018) and recent results from EPIK-
P1 study, treatment with alpelisib is expected to be tolerated with a manageable safety profile. 
For further details on clinical safety, please refer to Section 1.1 and the latest version of 
[Alpelisib (BYL719) Investigator's Brochure]. 
Potential risks to clinical study participants 
Participants in this study will be carefully monitored using periodic laboratory, renal and liver 
function parameters, Electrocardiogram (ECG), bone development, teeth development, growth, 
sexual maturity, and other safety evaluations for key toxicities that have been already observed 
with alpelisib or may be observed in PROS pediatric and adult participants (see Section 8.4). 
Risks will be further minimized by adherence to inclusion/exclusion selection criteria  
(see Section 5), avoidance of prohibited medication (see Section 6.2.2), close safety monitoring 
(see Section 10), adherence to dose adjustment guidelines (see Section 6.5.1), and training of 
site personnel. An independent Data Monitoring Committee (DMC) will monitor safety data as 
outlined in the protocol. A Steering Committee (SC) comprising of Investigators, a patient 
advocate, and Novartis personnel participating in the study will ensure transparent management 
of the study according to the protocol. A Novartis Safety Management Team (SMT) will 
periodically review and evaluate all emerging data across the alpelisib program for potential 
safety signal assessment in a timely manner. 
Females of child bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 

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study and must agree that in order to participate in the study they must adhere to the 
contraception requirements outlined in the exclusion criteria. If there is any concern that the 
participant will not reliably comply to study requirements, they should not be entered or 
continue in the study. 
4.6 
Public health emergency mitigation procedures 
During a public health emergency as declared by local or regional authorities i.e., pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
may be implemented. Notification of the public health emergency as declared by local or 
regional authorities should be discussed among investigators and Novartis. All procedures 
adapted to the situation must be submitted, if required as per local regulations, through a 
protocol amendment for approval by local or regional Health Authorities and Ethics 
Committees prior to implementation of mitigation procedures. 
4.7 
Rationale for planned off-site procedures (for Netherlands only) 
Off-site procedures (e.g. fasting glucose plasma) are planned in this study to minimize burden 
on participants if unable to travel to the site, offering them increased flexibility to participate in 
the study from an off-site location (as described in Section 6.5 and defined in Section 10.1.6). 
The hybrid approach will allow participants to maintain contact with the investigator, both in 
person, during clinic visits at site, and during off-site participation. 
5 
Study Population 
It is planned to enroll approximately 192 participants in total, 78 adults and 114 children and 
adolescents. The study will first start enrolling adult and pediatric participants ≥6 years old 
treated with alpelisib/matching placebo FCT and following the implementation of Global 
Protocol Amendment 01, participants ≥2 years old treated with alpelisib FCT. Following the 
implementation of Global Protocol Amendment 05, participants 0-5 years old in Group 3 will 
be treated with alpelisib granules. 
First, a total of approximately 162 participants with PROS will be enrolled in three groups - 
N=78 participants for Groups 1 and 2 each, and N=6 for exploratory Group 4: 
• Group 1: ≥18 years old  
• Group 2: 6-17 years old  
• Group 4: ≥ 2-5 years old  
Following the implementation of Global Protocol Amendment 02 and enrollment of Group 2 is 
completed, exploratory Group 5 will be opened to enroll approximately 15 additional pediatric 
participants with PROS who will be treated with alpelisib FCT at a higher starting dose: 
• Group 5: 6-17 years old 
After completion of the primary analysis, approximately  15 additional pediatric participants 
with PROS, treated with the alpelisib granules formulation, will be enrolled in an exploratory 
Group 3: 
• Group 3: 0 to 5 years old  

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The same inclusion/exclusion criteria will apply for all groups, except for the below which are 
adjusted based on Group: 
• inclusion criterion on tissue sample collection and performance status assessment  
• exclusion criterion concerning pneumonitis, interstitial lung disease as well as 
comprehension and compliance with study instructions.  
The phenotypic variability of PROS is broad in terms of overgrowth localization, number of 
lesions, disease progression, and severity of the impact on the participants’ everyday life, 
mobility, organ function and quality of life. In order to assess the efficacy of alpelisib in PROS 
in an objective manner and consistently with the recent literature (Kuentz et al 2017), 
Keppler-Noreuil et al 2014, participants with syndromic disease and participants with isolated 
disease will be included. Criteria for inclusion will be bearing clinically relevant and measurable 
lesion(s) and confirmed mutation in the PIK3CA gene. Participants with isolated features like 
macrodactyly, megalencephaly and epidermal nevus will not be considered for inclusion, 
because these features are not considered sufficiently severe to require specific treatment and 
are unlikely to qualify for a measurable lesion. 
Participants with functional /mobility impairment can be included in the study and the changes 
will be assessed as indicated in Section 8 study visit schedule and assessments. 
The Investigator or his/her designee must ensure that all participants who meet the inclusion 
and none of the exclusion criteria during screening are offered enrollment in the study. No 
additional exclusions can be applied by the Investigator, in order to ensure that the study 
population will be representative of all eligible participants. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent and assent (when applicable) from the patient, parent, legal 
authorized representative or guardian must be obtained prior to any study related screening 
procedures are performed. 
2. Male or female patients who, at the time of informed consent, were of the below age:  
• Group 1: ≥18 years old  
• Group 2: 6-17 years old 
• Group 3: 0-5 years old 
• Group 4: ≥ 2-5 years old 
• Group 5: 6-17 years old  
3. Patients with diagnosis of PROS [according to Clinical Diagnostic Criteria for PIK3CA-
related Overgrowth Spectrum (PROS) proposed by 
Keppler-Noreuil et al 2014  (Section 16.1 - Appendix 1)] with symptomatic and /or 
progressive overgrowth and at least one measurable PROS-related lesion confirmed by 
BIRC assessment, who have syndromic disease or isolated features (with the exception of 
isolated macrodactyly, macrocephaly or epidermal nevus) at the time of informed consent. 
Patients, who previously have been receiving systemic treatment for PROS (e.g., 
mTOR inhibitors, AKT inhibitors, anti angiogenic agents), may enter the study. 

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4. Documented evidence of a somatic mutation(s) in the PIK3CA gene performed in local 
laboratories (certified, if applicable per local practices) using a DNA based test validated 
according to the local regulations at the time of informed consent. 
5. A tissue sample (fresh or archival) is to be sent to a Novartis-designated central laboratory. 
If archival tissue is not available, collection of a fresh tissue biopsy is required for 
participants in Groups 1, 2 and 5, if it is not clinically contraindicated. For participants in 
Groups 3 and 4, a fresh tissue biopsy is not mandatory. 
  
For Germany only: If archival tissue is available, it must be sent to a Novartis-designated 
central laboratory. If no archival tissue is available, obtaining a fresh tissue biopsy is 
recommended, if it is not clinically contraindicated, but is not mandatory. 
6. Karnofsky (in patients > 16 years old at study entry)/Lansky (≤16 yrs of age at study entry) 
performance status index ≥50. 
7. Adequate bone marrow and organ function (as assessed by central laboratory for eligibility: 
• Absolute neutrophil count ≥ 1.5 × 109/L 
• Platelets ≥ 100 × 109/L 
• Hemoglobin ≥ 9.0 g/dL (transfusions are allowed) 
• Calcium (corrected for serum albumin) and magnesium within normal limits or ≤Grade 
1 according to NCI-CTCAE version 4.03 if judged clinically not significant by the 
Investigator 
• Potassium within normal limits, or corrected with supplements 
• INR ≤1.5 unless anticoagulant therapy (related to PROS) is ongoing at the time of 
screening 
Note: Participants receiving anticoagulants for PROS related coagulopathy, primary or 
secondary prophylaxis of thrombosis may be included in the study.  
• Creatinine Clearance ≥ 30 mL/min using Modification of Diet in Renal Disease 
(MDRD) (≥18 years old) or creatinine-based Bedside Schwartz (˂18 years old) 
Glomerular filtration rate (GFR) equation 
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN. 
• Total bilirubin< ULN except for patients with Gilbert’s syndrome who may only be 
included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN 
• Fasting plasma glucose (FPG) ≤ 140 mg/dL (7.7 mmol/L)* and Glycosylated 
hemoglobin (HbA1c) ≤ 6.5% (both criteria have to be met) 
• Fasting Serum amylase ≤ 2 × ULN 
• Fasting Serum lipase ≤ ULN 
*For patients with FPG ≥ 100 mg/dL and/or HbA1c ≥5.7% (i.e., threshold for pre-diabetes) at 
screening, recommend lifestyle changes according to the American Diabetes Association 
(ADA) or European Association for the Study of Diabetes (EASD) guidelines, i.e., dietary 
advice (e.g., small frequent meals, low carbohydrate content, high fiber, balancing carbohydrate 
intake over the course of the day, three small meals and 2 small snacks rather than one large 
meal) and exercise. A consultation with a diabetologist is highly recommended. 

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8. Presence of at least one PROS-related measurable lesion defined as a lesion with longest 
diameter ≥2 cm, when the volume can be accurately and reproducibly assessed by MRI, and 
associated with complaints, clinical symptoms or functional limitations affecting the 
patient's everyday life. Measurability must be confirmed by BIRC before randomization. 
9. Able to swallow study drug (as assessed within 7 days before study treatment start): 
• Group 1, Group 2, Group 4 and Group 5: FCT, or as drinkable suspension when 
applicable (refer to Section 6.7.2) 
• Group 3: granules. Drug administration via feeding tube is allowed. 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Participant with only isolated macrodactyly, epidermal nevus/nevi and macroencephaly (the 
only clinical feature or a combination of any of three of them), in absence of other PROS-
related lesions at the time of informed consent. 
2. Previous treatment with alpelisib and/or any other PI3K inhibitor(s) (except treatment 
attempt, defined as the attempt to treat PROS with any of PI3K inhibitors, with treatment 
duration less than 2 weeks and stopped at least 4 weeks prior to the first dose of study 
medication with alpelisib) 
Notes: 
• patients treated with small molecules (such as mTOR inhibitors, AKT inhibitors) and/or 
anti angiogenic agents for PROS must discontinue from these specific treatments before 
any of study related assessments and for at least 4 weeks before the start of study 
treatment 
• those patients who previously received systemic treatment for PROS other than PI3K 
inhibitor(s), should recover from all toxicities related to prior therapies to Grade ≤1 
according to NCI CTCAE version 4.03, with exception for any grade of alopecia, where 
the patients are allowed to enter the study 
• in pretreated patients, all screening assessments should be performed after 
discontinuation from previous specific systemic therapy for PROS. 
3. Radiation exposure for PROS treatment purpose within the previous 12 months on those 
PROS areas which are expected to qualify for target lesions (except lesion(s) progressing 
after completion of radiotherapy) at time of informed consent. 
4. Debulking or other major surgery performed within 3 months at time of informed consent. 
5. Clinically meaningful bleeding related to PROS: Grade 2 within 14 days or Grade 3 and 
more within 28 days before study treatment start as per CTCAE v. 4.03. 
6. Clinically meaningful PROS-related thrombotic event (Grade 2 and more as per CTCAE 
v.4.03) within 30 days before informed consent, and/or sclerotherapy/embolization for 
vascular complications performed within 6 weeks before informed consent. Note: 
Participants receiving anticoagulants for PROS-related coagulopathy, primary or secondary 
prophylaxis of thrombosis may be included in the study. 
7. History of prior and or ongoing malignancy (within 5 years before informed consent except 
radically treated Carcinoma in situ of radically treated basal-cell carcinoma of skin or 

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thyroid gland well differentiated microcarcinoma or Stage 1 Wilms’ tumor of a histology 
other than anaplastic), or ongoing investigations or treatment for malignancy at time of 
informed consent. 
8. Clinically significant heart disease at time of informed consent, including: 
• History of documented congestive heart failure (New York Heart Association 
functional classification III-IV) 
• Clinically significant uncontrolled cardiac arrhythmias 
• Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome 
• Corrected QT (QTcF) at screening: >470 ms for Group 1 / >450 ms for Groups 2, 3, 4 
and 5. 
9. For participants in Groups 1, 2 and 5 (i.e., those ≥ 6 years of age): Participants with 
documented pneumonitis or interstitial lung disease at the time of informed consent and 
with impaired lung function (e.g., FEV1 (Forced expiratory volume) or DLCO 
(Diffusing Capacity of the Lung for Carbon Monoxide) ≤ 70% of predicted) that is not 
related to PROS. 
For participants in Groups 3 and 4 (i.e., those who are less than 6 years of age): Participants 
with documented or suspicious pneumonitis or interstitial lung disease based on MRI 
images at time of informed consent. 
Note: When lung function impairment is, in the opinion of the Investigator, related to PROS, 
the patient may be included but caution must be exercised. 
10. History of acute pancreatitis within 1 year before informed consent or past medical history 
of chronic pancreatitis at time of informed consent. 
11. Participants with an established diagnosis of type I diabetes mellitus or uncontrolled type II 
diabetes mellitus at time of informed consent. 
12. Known impairment of gastrointestinal (GI) function due to concomitant GI disease that may 
significantly alter the absorption of the study drug (e.g., ulcerative diseases, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) at time of 
informed consent. 
13. History of hypersensitivity to any drugs or metabolites of PI3K inhibitor or any of the 
excipients of alpelisib at time of informed consent. 
14. Known history of Steven Johnson’s syndrome, erythema multiforme or toxic epidermal 
necrolysis at time of informed consent. 
15. Known history of seizure, or epilepsy, regardless of relatedness to PROS spectrum at time 
of informed consent, when epilepsy is not controlled and/or the patient may not be switched 
to non-enzyme inducing antiepileptic drug(s) at time of informed consent. 
16. Participant with other concurrent severe and/or uncontrolled medical conditions that would, 
in the Treating Physician’s judgment, contraindicate administration of alpelisib (e.g., Active 
and/or uncontrolled severe infection, chronic active hepatitis, hepatic impairment Child-
Pugh-Score C, immuno-compromised, etc.) at time of informed consent. Participant with 
an active documented COVID-19 infection (any grade of disease severity) at time of 
informed consent may be included only when completely recovered (in accordance with 

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local guidance) and had no symptoms for at least 28 days before first dose of study 
medication. 
17. Pregnant or breastfeeding female participants at time of informed consent. 
18. Female participants of childbearing potential (see Section 8.4.3) who do not consent to use 
a highly effective method of contraception and male participants who do not consent to use 
a condom and/or a highly effective method of contraception for the duration of the study 
and for one week following discontinuation of alpelisib. Highly effective contraception is 
one of the following: 
• Total abstinence: when this is in line with the preferred and usual lifestyle of the 
participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
• Female sterilization: have has surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks before 
taking alpelisib. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow-up hormone assessment. 
• Male sterilization at least six months prior to screening. The vasectomized male partner 
should be the sole partner for the female study participant. 
• Use of oral, injected or implanted hormonal methods of contraception, or placement of 
an intrauterine device or intrauterine system, or other forms of hormonal contraception 
that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or 
transdermal hormone contraception. 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.  
If local regulations are more stringent than the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF. 
20. Participant is currently receiving any of the following medications and cannot be 
discontinued 7 days prior to the start of the treatment: 
• Strong inducers of CYP3A4 
• Inhibitors of Breast Cancer Resistance Protein (BCRP). 
21. Not able to understand and to comply with study instructions and requirements (in patients, 
legal authorized representative or guardian as applicable) at time of informed consent. 
22. Participation in a prior investigational study within 4 weeks prior to study treatment start or 
within 5 half-lives of the investigational product, whichever is longer. 
23. Participants with clinically significant worsening of PROS-related laboratory anomalies, 
physical signs and symptoms (such as, but not limited to increase of D-dimers, worsening 
of underlying pain, newly occurring swelling or redness) indicating an uncontrolled 
condition during the screening phase, particularly if systemic treatment with any other 
inhibitor of the PI3K/AKT/mTOR pathway was stopped prior to the start of study treatment. 
This includes but is not limited to hypercoagulability state in participants not receiving 
prophylactic treatment. 

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6 
Treatment 
6.1 
Study treatment 
In this study, the “study treatment” refers to alpelisib or placebo, as no other treatment beyond 
investigational drug is included in this study. The "participant" refers to the patient diagnosed 
with PROS who will be consented to the trial prior to any study procedures being performed. 
The term “investigational drug” refers to the Novartis study drug, alpelisib/BYL719 or placebo. 
Novartis Global Clinical Supply (GCS) will provide alpelisib or placebo as global clinical 
double-blind labeled supplies (alpelisib and placebo FCT as 50 mg or 125 mg, as individual 
participant supply packed in bottle) during study period 1 (Core period Week 1 to Week 16: 
Double-Blind Phase). Study drug for study period 1 (Core period Week 17 to Week 24), study 
period 2 (Extension 1) and study period 3 (Extension 2) will be provided as global clinical open-
label supplies (alpelisib as 20 mg, 50 mg, 125 mg or 200 mg, as individual participant supply 
packed in bottle).  
The FCT will be differentiated through different FCT sizes and/or shades of the color. Granules 
(Group 3 only) will be provided in 20 mg or 50 mg sachets. Alpelisib will be dosed on a flat 
scale of mg/day, based on age, and will not be adjusted to body weight or body surface area. 
Alpelisib FCT or granules will be administered orally with food on a continuous basis (see 
Section 6.7). The storage conditions will be described on the medication label. 
All dosages prescribed and dispensed to the participant and all dose changes during the study 
must be recorded on the appropriate Case Report Form (CRF). 
6.1.1 
Investigational and control drugs 
Administration of study treatment 
This study will include: 
Core period, Extension 1 and Extension 2 periods applicable to the participants ≥6 years old 
(Group 1 – ≥ 18 years, Group 2 – participants 6 to 17 years old). The participants of less than 6 
years old (Groups 3 and 4) and additional participants of 6 to 17 years old (Group 5) will be 
included in exploratory study parts. Enrollment in Group 4 will start with implementation of 
Global Protocol Amendment 01. Enrollment in Group 5 will start after implementation of 
Global Protocol Amendment 02 and enrollment in Group 2 is completed, whereas enrollment 
in Group 3 will start later (as described in Section 3). 
Study treatment in Group 1 and Group 2  
In the double-blind, randomized, placebo-controlled part, alpelisib/matching placebo will be 
administered at the assigned starting doses based on the groups. Eligible participants will enter 
the study and start treatment with alpelisib/matching placebo at 125 mg once daily p.o. in Group 
1 or 50 mg alpelisib/matching placebo once daily p.o. in Group 2. Both groups will be enrolled 
in the study in parallel. In the Core Period 1, participants will receive treatment in blinded 
fashion, with an upfront 16-week placebo-controlled period. After Week 16 those participants 
who were randomized to receive placebo will be switched to active treatment with alpelisib and 

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will receive 125 mg once daily p.o (Group 1) or 50 mg once daily p.o (Group 2). Those 
participants who were randomized to receive alpelisib will continue their treatment at the same 
dose level. When the dose of alpelisib/matching placebo was reduced during initial 16 weeks 
of treatment because of safety/tolerability concerns, the participants will continue their 
treatment at the reduced dose.  
During the initial 16 weeks of the Core period, study treatment will be given in a blinded 
fashion, starting from Week 17 of the Core period - in open-label fashion. The randomized 
treatment assignment to the treatment arms will remain blinded to participants, Investigators 
and the study team until the time of the primary analysis, when the last participant reaches 
Week 48 from randomization or discontinues earlier. 
Study treatment in Group 4 
The participants in Group 4 will receive alpelisib FCT 50 mg once daily in an open-label setting. 
Study treatment in Group 5 
The participants in Group 5 will receive alpelisib FCT 125 mg once daily in an open-label 
setting.  
Study treatment in Group 3 
The participants in Group 3 will receive alpelisib granules with an age-dependent starting dose 
and maximum dose levels for participants < 2 years of age in an open-label setting. Group 3 
will be an exploratory group (for more details, please refer to Section 3 Study Design). 
Details are presented in Table 6-1, Table 6-2, Table 6-3, Table 6-4, Table 6-5 and Table 6-6. 
Table 6-1 
Investigational and control drug - Core period Week 1 - Day 1 to Week 
16 
Group 
(Age range) 
Investigational / 
control drug 
(name and 
strength) 
Pharmaceutical 
dosage form/ 
Route of 
administration 
Frequency 
Supply type 
Group 1 
(≥ 18 years) 
(DB=Double Blind) 
DB_Alpelisib 125 
mg 
FCT/ Oral  
Once daily 
Double-Blind, label 
participant packs, 
bottles 
Group 1 
(≥ 18 years)  
DB_ Placebo 125 
mg 
FCT/ Oral  
Once daily 
Double-Blind, label 
participant packs, 
bottles 
Group 2 
(6-17 years) 
DB Alpelisib 50 mg 
FCT/ Oral  
Once daily 
Double-Blind, label 
participant packs, 
bottles 
Group 2 
(6-17 years) 
DB placebo 50 mg 
FCT/ Oral  
Once daily 
Double-Blind, label 
participant packs, 
bottles 

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Table 6-2 
Investigational drug - Core period Week 17 to Week 24 
Group 
(Age range) 
Investigational 
drug (name and 
strength) 
Pharmaceutical 
dosage form/ 
Route of 
administration 
Frequency  
Supply type 
Group 1 
(≥ 18 years) 
(OL=Open-Label) 
OL alpelisib 125 mg 
FCT/ Oral  
Once daily 
Open- label 
participant packs, 
bottles 
Group 2 
(6-17 years) 
OL alpelisib 50 mg 
FCT/ Oral  
Once daily 
Open- label 
participant packs, 
bottles 
Table 6-3 
Investigational drug - Extension 1 and Extension 2 
Group 
(Age 
range) 
Investigat
ional 
Drug 
Pharmace
utical 
Dosage 
Form/ 
Route of 
administr
ation 
Frequency 
Strength 
Dose 
escalation 
Dose  
decreasea 
Supply 
type 
Group 1 
(≥ 18 
years)  
OL 
Alpelisib 
FCT/ Oral  
Once daily 
50 mg; 
125 mg; 
200 mg 
200 mg 
or 250 mg  
50 mg or 
125 mg or 
200 mg 
Open-label 
participant 
packs, 
bottlesb 
Group 2 
(6-17 
years)  
OL 
Alpelisib 
FCT/ Oral  
Once daily 
50 mg; 
125 mg; 
200 mg 
125 mg or 
200 mg or 
250 mg 
Frequency 
changed 
(i.e.,50 mg 
QOD) or 
50 mg or 
125 mg or 
200 mg 
Open-label 
participant 
packs, 
bottlesb 
a: The dose used upon decrease will depend on the previous dose administered 
b: The randomized treatment assignment to the treatment arms will remain blinded to participants, 
Investigators and the study team until the time of the primary analysis, when the last participant completes 
Week 48 or discontinues earlier 
 
Table 6-4 
Investigational drug - Exploratory Group 3 
Group 
(Age range)a 
Investigation
al Drug 
Pharmaceutica
l Dosage Form 
Route of 
administration 
Frequency 
Strength 
Supply type 
Group 3 
(<1 month) 
OL Alpelisib 
Granules 
Oral use 
Every 
other day 
20 mg;  
50 mg;  
Open-label 
participant 
packs 
Group 3 
(1 to <6 
months) 
OL Alpelisib 
Granules 
Oral use 
Once daily 
20 mg 
50 mg;  
Open-label 
participant 
packs 
Group 3 
(6 to < 24 
months) 
OL Alpelisib 
Granules / 
FCTb 
Oral use 
Once daily 
20 mg  
50 mg 
125 mgb 
200 mgb 
Open-label 
participant 
packs, 
bottles 
Group 3 
OL Alpelisib 
Granules /  
Oral use 
Once daily 
50 mg 
Open-label 
participant 

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(2-5 years) 
FCTb 
125 mgb 
200 mgb 
packs, 
bottles 
a: dose adjustments as participants age to account for enzyme maturation are allowed (see Table 6-7) 
b: FCT used for strength > 50 mg 
Table 6-5 
Investigational drug - Exploratory Group 4 
Group 
(Age range) 
Investigational 
Drug 
Pharmaceutical 
Dosage Form 
Route of 
administration 
Strength 
Supply type 
Group 4 
(2-5 years) 
OL Alpelisib 
FCT 
Oral use 
50 mg 
125 mg; 
200 mg 
Open-label 
participant 
packs, bottles 
Table 6-6 
Investigational drug - Exploratory Group 5 
Group 
(Age range) 
Investigational 
Drug 
Pharmaceutical 
Dosage Form 
Route of 
administration 
Strength 
Supply type 
Group 5 
(6-17 years) 
OL Alpelisib 
FCT 
Oral use 
50 mg; 
125 mg; 
200 mg 
Open-label 
participant 
packs, bottles 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug is included in this study. 
6.1.3 
Treatment arms/group 
During double-blind, randomized study Period 1 “Core period Week 1 Day 1 to Week 16”, 
eligible participants aged ≥6 years old will be assigned to one of the following treatment arms 
in a 2:1 ratio: 
• Group 1: Alpelisib or matching placebo arms (125 mg QD) 
• Group 2: Alpelisib or matching placebo arms (50 mg QD) 
Both participant and Investigator will remain blinded. 
During double-blind study Period 1 “Core period Week 17 to Week 24”: 
Those participants who were randomized to receive alpelisib will continue their treatment at the 
same dose level. Those participants who were randomized to receive placebo will be switched 
to active treatment with alpelisib in a blinded fashion at the dose level received at the end of the 
placebo period. Study treatment will be given in an open-label fashion. 
• Group 1: Alpelisib (125 mg QD) 
• Group 2: Alpelisib (50 mg QD) 
The randomized treatment assignment will remain blinded for both participant and Investigator 
until last participant reaches the 48-week treatment period. 
During the open-label study period 2 - Extension 1 and 2 (Week 25 up to 5 years after 
randomization): 

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Participants (Group 1 and Group 2) will continue their treatment at the randomized dose if this 
dose was not reduced due to safety-tolerability reasons. Once a participant (Groups 1 and 2) has 
reached Week 29 then dose escalation will be allowed (Refer to Section 6.5.1) 
• Group 1: Alpelisib (50 mg, or 125 mg, or 200 mg, or 250 mg QD) 
• Group 2: Alpelisib (50 mg, or 125 mg, or 200 mg, or 250 mg QD) 
During the open-label exploratory study parts: 
• Group 3: Participants from this group will receive alpelisib granules in an open-label setting 
in doses ranging from 20 mg every other day to 50 mg daily depending on the age. Please 
refer to Table 6-7 for details on starting doses dependent on the age. Age related dosing 
adjustments up to 50 mg alpelisib p.o. daily will be allowed for participants with a starting 
dose below 50 mg p.o. daily, once they reach the age range for a higher maximum dose as 
per Table 6-7. Once a participant has reached the age of 6 years old and has reached at least 
Week 25, dose escalation will be allowed.  
Table 6-7 
Group 3 starting dose and maximum age-related dose 
Age range 
< 1 month 
≥1 month to < 6 
months 
≥6 months to < 2 
years 
≥2 years to < 6 
years 
Starting dose / 
maximum dose 
20 mg every 
other day  
20 mg once daily  
40 mg once daily  
50 mg once daily  
 
• Group 4: Participants from this group will receive 50 mg alpelisib FCT formulation once 
daily in an open-label setting. Once a participant has reached the age of 6 years old and 
has reached at least Week 25, dose escalation will be allowed. 
• Group 5: Participants from this group will receive 125 mg alpelisib FCT formulation once 
daily in an open-label setting. Once a participant has reached at least Week 25, dose 
escalation will be allowed. 
6.1.4 
Guidelines for continuation of treatment 
Refer to guidelines for management of toxicities and doses modifications instruction 
(Section 6.5.1 and Section 6.5.2). 
6.1.5 
Treatment duration 
The planned duration of alpelisib treatment in the study will be up to 5 years after study 
treatment start for all groups. 
The Treatment Period for each participant will begin on study Day 1. Participant may be 
discontinued from treatment with alpelisib earlier due to unacceptable toxicity (refer to 
Section 6.5.1 
and 
Section 6.5.2), 
BIRC-confirmed 
disease 
progression 
(refer 
to 
Section 6.1.5.1 and Section 8.3.1 for more details), death, and/or any other reason at the 
discretion of the Investigator or the participant.  
For all participants, the Core Period, Extension 1 and Extension 2 are considered. Those 
participants, who continue in the study until Week 24 and have clinical benefit from the study 
treatment at the end of Core Period, will enter Extension 1 (Week 25-48) and Extension 2 (Week 

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49 – up to 5 years) periods with no interruption in alpelisib therapy (except interruptions for 
safety reasons). Participants who did not derive sufficient clinical benefit or have progressed, 
may remain on study therapy if there are no safety concerns and the Investigators feel that 
they may benefit, from continuation. 
Participants who complete 5 years of treatment in the study and are still deriving clinical benefit 
from alpelisib based on the Investigator’s evaluation, may receive post-trial access. Post Trial 
Access (PTA) means the provision of treatment to study participants following their completion 
of study participation. Every effort will be made to continue provision of study treatment after 
5 years of total duration of study treatment. PTA will be provided until one of the following is 
met: participant no longer derives clinical benefit, Investigator discontinues treatment, launch 
or reimbursement (where applicable), treatment fails to achieve registration in the study 
participant’s country, or the clinical program is discontinued for any other reason. Mechanisms 
for provision of PTA may include an extension phase to this study, a separate extension 
protocol, a rollover protocol, provision of the Novartis investigational product in a non-study 
setting (known as post-study drug supply [PSDS]) when no further safety or efficacy data are 
required, or any other mechanism appropriate for the country. 
6.1.5.1 
Treatment beyond disease progression 
During Core period, progression of lesions must be confirmed by BIRC to make a decision on 
treatment beyond progression. Starting from Week 25 the Investigator will review the results 
of PROS lesions response assessment based on local assessments and other assessments to 
conclude, if the participant has progression of the disease, and to make treatment decision (refer 
to Section 8.3.1). The Investigator must perform an unscheduled MRI in case of suspected 
disease progression as soon as feasible and within the coming 3 months maximum in 
participants of all groups at any time point in the study. Unscheduled MRI must be submitted 
to BIRC as other lesions assessment. Any treatment that is considered necessary for the 
treatment of progression is allowed in addition to treatment with alpelisib beyond progression 
except prohibited medication (refer to Section 6.2.2).  
Participants of Group 1, Group 2 and Group 5 who have BIRC-confirmed disease progression 
by Week 16, may remain on study therapy at the same dose level if there is no safety/tolerability 
concerns, and the participant may benefit from continuation at the discretion of the Investigator, 
or discontinue. When progression is suspected on a local assessment but not confirmed by 
BIRC, the participant should remain in the study at the same dose level and undergo all required 
assessments according to evaluation schedule until progression is confirmed by BIRC at 
subsequent assessment. Participant may be discontinued if continuation of study drug until 
confirmation of progression by BIRC is not clinically acceptable or at the discretion of the 
Investigator. 
Participants of Group 1, Group 2 and Group 5 with BIRC- confirmed disease progression by 
Week 24 and later, who do not have safety/tolerability issues, may remain on study therapy at 
the discretion of the Investigator; they will also have the option to undergo dose escalation after 
28 weeks for Groups 1 and 2 and after 24 weeks for Group 5 of study treatment. The participant 
with BIRC-confirmed progression may remain on study therapy at the same or the next dose 
level, or discontinue.  

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Participants of Group 1, Group 2 and Group 5 will have a possibility to undergo dose escalation 
for response optimization purpose and continue treatment beyond progression of the disease 
(twice from 125 mg to 200 mg and from 200 to 250 mg in Groups 1 and 5, and 3 times from 50 
mg to 125 mg, from 125 to 200 mg, from 200 to 250 mg in Group 2).  
In the event of a dose increase for response optimization, an MRI has to be performed after at 
least 3 months to assess the benefit from the increased dose if further dose optimization is 
considered.  
Participants of Group 1, Group 2 and Group 5 receiving alpelisib beyond disease progression 
should undergo all required assessments according to evaluation schedule (See Table 8-2). 
Group 4 participants with disease progression by Week 24 and later, who do not have 
safety/tolerability issues, may remain on study therapy at the discretion of the Investigator; they 
will also have the option to undergo dose escalation once they have reached the age of 6 years 
old and have reached at least Week 25. The participant with progression may remain on study 
therapy at the same or the next dose level, or discontinue.  
Group 3 of 0 to 5 years old participants will be enrolled after implementation of Global Protocol 
Amendment 05. Group 3 participants with disease progression by Week 24 and later, who do 
not have safety/tolerability issues, may remain on study therapy at the discretion of the 
Investigator; they will also have the option to undergo dose escalation once they have reached 
the age of 6 years old and have reached at least Week 25. The participant with progression may 
remain on study therapy at the same or the next dose level or discontinue.   
6.2 
Other treatment(s) 
All participants will be allowed to receive concomitant medication and/or other non-medication 
treatment (e.g., rescue surgery) when clinically indicated to control comorbidities and/or 
complications of PROS. Rescue surgery is defined as a salvage intervention, and includes e.g. 
debulking surgery, orthopedic surgery, invasive vascular surgeries/procedures. As much as 
possible, surgery targeting PROS-related lesion volume reduction should be avoided. Systemic 
therapy targeting PI3K/AKT/mTOR pathway other than alpelisib and/or any investigational/not 
approved medication for PROS are not allowed during the conduct of the study. 
During the course of the study, the participant must also not receive anti angiogenic agents for 
the purpose to treat PROS. 
The participant must discontinue from specific treatment with small molecules (such as mTOR 
inhibitors, AKT inhibitors) for PROS before any of study related assessments and at least 4 
weeks before study treatment start. 
It is not allowed to receive any other investigational drugs. 
6.2.1 
Concomitant therapy 
All medications (other than alpelisib) and significant non-drug therapies (e.g., physical therapy, 
vitamins) administered during treatment should be noted in the participant’s record. In addition, 
any known prior medications, procedures, or significant non-drug therapies administered for 
the treatment of PROS should be recorded on the appropriate Case Report Forms (see also 
Section 8.2 for details). 

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The Investigator must instruct the participant to notify the site about any new medication he/she 
takes after the start of the study. 
During the course of the study, the participant may receive the following concomitant therapies: 
• Transfusions of blood and blood components 
• Pain relief medication 
• Anti-infective medications (see prohibited and cautioned medications in the 
Section 6.2.1.1 and Section 6.2.2 below). Investigators should discuss prescription of anti-
fungal, anti-viral agents with Novartis 
• Treatment for concomitant medical conditions, adverse events (see prohibited and 
cautioned medications in the Section 6.2.1.1 and Section 6.2 below) 
• Supplemental nutrition (enteral, parenteral) 
• Routine vaccinations 
Each concomitant drug must be individually assessed against all exclusion criteria and 
prohibited medication. If in doubt, the Investigator should contact the Novartis medical monitor 
before randomizing a participant or allowing a new medication to be started. If the participant 
is already enrolled, contact Novartis to determine if the participant should continue participation 
in the study. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
Medications to be used with caution are described below and listed in the Appendix in 
Table 16-1. This list is not comprehensive and is only meant to be used as a guide. Please 
contact Novartis with any questions. 
These medications should be excluded from participant use if possible. If they must be given 
based on the Investigator’s judgment, then use with caution and consider an alpelisib 
interruption, as appropriate, if the concomitant medication is only needed for a short time. 
Medications to be used with caution: 
• CYP2C9 substrates with narrow therapeutic index (NTI) (e.g., anticoagulants): In vitro 
evaluations indicated that pharmacological activity may be reduced by the CYP2C9 
induction effects of alpelisib. In the absence of clinical data, caution is recommended with 
therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative 
anticoagulants as alpelisib may reduce the clinical activity of such drugs. Alternatively, 
therapeutic anticoagulation may be accomplished using low- molecular weight heparin or 
Direct Thrombin inhibitors (DTIs) and Factor Xa inhibitors. 
• CYP2B6 sensitive substrates or CYP2B6 substrates with NTI: Based on a static 
mechanistic assessment with sensitive CYP2B6 substrates such as bupropion, a reduction 
of exposure by up to 3-fold can be expected when co-administered with alpelisib. In the 
absence of clinical data, sensitive CYP2B6 substrates (e.g., bupropion, evafirenz) or 
CYP2B6 substrates with a narrow therapeutic window should be used with caution in 
combination with alpelisib, as alpelisib may reduce the clinical activity of such drugs. 
• Selected CYP3A4 substrates: Alpelisib can be co-administered with sensitive CYP3A4 
substrates (e.g., midazolam) and CYP3A4 substrates with narrow therapeutic window (e.g., 
fentanyl). Caution is recommended when alpelisib is used in combination with CYP3A4 

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substrates that also possess an additional time dependent inhibition and induction potential 
on CYP3A4 that affects their own metabolism (refer to Table 16-2). Systemic exposures of 
such CYP3A4 auto-inhibitors and auto-inducers may be either decreased or increased 
depending on the drug and nature of auto-perpetrator potential, respectively, when alpelisib 
is co-administered, based on PBPK simulations.  
• Co-administration of alpelisib with bis-phosphonates and/or denosumab should be avoided 
since the risk of osteonecrosis increases with the combination. 
• Please refer to the latest version of [Alpelisib (BYL719) Investigator’s Brochure] for 
additional information pertaining to alpelisib.  
6.2.1.2 
Oral anti diabetic therapy 
Participants who develop hyperglycemia during the study should be treated according to the 
ADA (American Diabetes Association)/EASD (European Association for the Study of 
Diabetes) guidance. It is recommended to start treatment with metformin. Metformin is not 
recommended in participants below the age of 10 years, metformin extended release (XR) is 
not recommended in pediatric participants below the age of 18 years. Consultation with a 
diabetologist is needed to find the optimal individualized treatment for hyperglycemia, 
especially in pediatric participants under 10 years old (where international or local guidelines 
may apply). Participants receiving oral anti-diabetics which are predominantly metabolized by 
CYP2C9 and CYP2C8, including but not limited to, repaglinide, rosiglitazone, glipizide and 
tolbutamide, should be monitored with respect to their effectiveness as alpelisib was found to 
be an inducer of CYP2C9 in vitro. 
6.2.1.3 
Corticosteroids 
Chronic dosing of high levels of corticosteroids such as dexamethasone and prednisone may 
prolong or aggravate hyperglycemia (steroid-induced diabetes). Hyperglycemia is a common 
adverse drug reaction for PI3K inhibitors like alpelisib; corticosteroids should therefore be used 
with caution and participants should be closely monitored. 
6.2.1.4 
Gastric protection agents 
Alpelisib is characterized by a pH-dependent solubility. Therefore, acid reducing agents 
(ARAs, e.g., proton-pump inhibitors, H2-antagonists and antacids) may alter the solubility of 
alpelisib and hence its bioavailability. A drug-drug interaction study in human healthy 
volunteers confirmed that co-administration of alpelisib with the H2-antagonist ranitidine after 
a meal lead to a decrease in exposure by only ~20%, considered not to be clinically relevant. 
Alpelisib can be co-administered with any ARAs. 
6.2.2 
Prohibited medication 
The following medications are prohibited during treatment with alpelisib: 
This list is not comprehensive and is only meant to be used as a guide. 
• Strong inducers of CYP3A4:  

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Coadministration of alpelisib with a strong CYP3A4 inducer may decrease alpelisib 
concentration, which may decrease alpelisib activity. Avoid coadministration of alpelisib 
with strong CYP3A4 inducers. 
• Inhibitors of BCRP:  
Coadministration of alpelisib with a BCRP inhibitor may increase alpelisib concentration, 
which may increase the risk of toxicities. Avoid the use of BCRP inhibitors in participants 
treated with alpelisib. 
• Herbal Medications:  
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 
medication include, but are not limited to St. John’s Wort (Hypericum perforatum), and 
Avasimibe (see Table 16-2) or BCRP inhibitors such as Curcumin (see Table 16-3). 
Medications such as Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone, 
yohimbe, saw palmetto, black cohosh and ginseng should be avoided if possible due to their 
potential for complex interactions. Participants must stop using all herbal medications (refer 
to Table 16-2 and Table 16-3) and dietary supplements at least 7 days prior to first dose of 
study treatment. 
Other investigational and antineoplastic therapies 
In addition, the participant should discontinue from specific treatment with small molecules 
(such as mTOR inhibitors, AKT inhibitors) and/or anti angiogenic agents for PROS before any 
of study related assessments and for at least 4 weeks before the start of study treatment 
whichever comes first. 
Please refer to the latest version of [Alpelisib (BYL719) Investigator’s Brochure] for additional 
information. 
6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by Subject Number (Subject No.), that is assigned 
when the participant is first enrolled for screening and is retained as the primary identifier for 
the participant throughout his/her entire participation in the study. The Subject No. consists of 
the Site Number (Site No.) (as assigned by Novartis Rave EDC to the investigative site) with a 
sequential Subject number suffixed to it, so that each participant is numbered uniquely across 
the entire database. Upon signing the informed consent form, the participant is assigned to the 
next sequential Subject No. available. A new Informed Consent Form (ICF) will need to be 
signed if the Investigator chooses to re-screen the participant after a participant has screen 
failed, and the participant will be assigned a new Subject number.  
6.3.2 
Treatment assignment, randomization 
The assignment of a participant to alpelisib or matching placebo at the appropriate starting dose 
will be based on age using an Interactive Response Technology (IRT). Prior to dosing, all 
participants who fulfill all inclusion/exclusion criteria will be enrolled via IRT. The IRT must 

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be used for all study drug allocations as the system will specify the unique medication numbers 
for participant dispensation. 
Groups 1 and 2 (Core Period- Double blind phase) 
A total of approximately 156 eligible participants aged over 6 years old will be randomized in 
a 2:1 ratio to alpelisib or matching placebo; the starting dose will be 125 mg once daily p.o. in 
Group 1, and 50 mg once daily p.o. in Group 2.  
The Investigator or his/her delegate will contact the IRT after confirming that the participant 
fulfills all the inclusion/exclusion criteria by completing the key eligibility criteria checklist 
embedded in the system. The IRT will assign a randomization number to the participant, which 
will be used to link the participant to a treatment arm and will specify a unique medication 
number for the first package of study treatment to be dispensed to the participant. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and Investigator staff. A 
participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Global Clinical Supply (GCS) using a validated system that automates the random 
assignment of medication numbers to packs containing the study treatment. 
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office. 
Groups 3, 4 and 5 (Exploratory study parts – Open-label phase)  
In this exploratory study part, the participants of Groups 3, 4 and 5 will receive alpelisib in an 
open-label setting; no randomization will be performed. The Investigator or his/her delegate 
will contact the IRT after confirming that the participant fulfills all the inclusion/exclusion 
criteria by completing the key eligibility criteria checklist embedded in the system. 
Approximately 15, 6 and 15 eligible participants will be enrolled via IRT for treatment with 
alpelisib into Groups 3, 4, and 5, respectively.  
6.4 
Treatment blinding 
Groups 1 (≥18 years old) and 2 (6 to 17 years old) 
The clinical study team (CTT) at Novartis will remain blinded to the identity of the treatment 
assigned randomly to the treatment arms in Groups 1 and 2, from the time of 
randomization until analysis of the primary endpoint. Participants, Investigator staff, and 
persons performing the assessments including BIRC will remain blinded to the identity of the 
treatment from the time of randomization until database lock for primary analysis (when the 
last participant completes Week 48 from randomization or discontinues earlier), using the 
following methods: 
(1) Randomization data are kept strictly confidential until the time of unblinding and will not 
be accessible by anyone else involved in the study with the following exceptions: Independent 
biostatistician and programmer who will perform DMC analysis and the Bioanalysts. The 

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randomization codes associated with participants from whom PK samples are to be analyzed 
will be disclosed to Bioanalysts upon request who will keep PK results confidential until the 
point when the database is locked for primary endpoint analysis.  
(2) The identity of the treatments will be concealed by the use of study treatment that are all 
identical in packaging, labeling, schedule of administration, appearance, taste and odor. 
Confidentiality of randomization data is required to limit the occurrence of potential bias arising 
from the influence that the knowledge of treatment may have on the recruitment and allocation 
of participants. Unblinding will only occur in the case of participant emergencies (see 
Section 6.6.2). 
In rare cases when unblinding occurs because of emergency participant management, the actual 
treatment arm will not be communicated to any of the Novartis employees involved in running 
the study. Unblinding a single participant at a site for safety reasons (necessary for participant 
management) will occur via an emergency system in place at the site. As a result, the participant 
must be discontinued from the study treatment. After primary analysis, the participants, 
Investigators, Novartis employees involved in running of the study will be unblinded, BIRC 
will be kept blinded. 
At the time of safety review, the DMC will review unblinded interim reports created by an 
(independent) analysis team. More details will be provided in the DMC charter. 
Exploratory study parts: Groups 3 and 4 (less than 6 years old) and Group 5 (6 to 17 years 
old) 
Treatment will be open to participants, Investigator staff, persons performing the assessments, 
and the clinical trial team (CTT) at Novartis. 
6.5 
Dose escalation and dose modification 
6.5.1 
Dose modifications 
Dose escalation 
Dose escalation for response optimization purpose is considered in this study (Table 6-8 and 
Table 6-9). 
Dose escalation is not allowed for Group 1 and Group 2: 
• During Core period (Week 1 – Week 24). 
• First 4 weeks of Extension 1 period (Week 25 – Week 28) 
Dose escalation is allowed for Group 1 and Group 2: 
• During Extension 1 period starting from Week 29 
• During Extension 2 period, decision to escalate the dose for response optimization purpose 
will be done by the Investigator based on local assessment of lesion response and overall 
clinical response. Escalation will be allowed, when: 
• The participant does not meet criteria for lesion response based on local assessment and 
there are no safety/tolerability concerns which may preclude from treatment continuation at 
a higher dose level. 

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• The participant, in the opinion of the Investigator, did not derive sufficient clinical benefit 
(based on overall clinical response assessed by the Investigator) from previous treatment 
regardless of meeting criteria for lesion response and there are no safety/tolerability 
concerns which may preclude from treatment continuation at higher dose level. 
• The participant has BIRC-confirmed disease progression, but, in the opinion of the 
Investigator, may remain in the study and benefit from dose escalation, and there are no 
safety/tolerability concerns which may preclude from treatment continuation at higher dose 
level. 
Dose escalation is allowed for Group 4 once the participant has reached the age of 6 years old 
and has completed 24 weeks of treatment and has reached at least Week 25. Dose escalation is 
allowed for Group 5 once the participant has reached at least Week 25. Decision on dose 
escalation will be taken by the Investigator based on local assessment of PROS lesions response, 
overall clinical response, and safety/tolerability concerns which may preclude from treatment 
continuation at higher dose level. Dose escalation is allowed at a minimum of 12-week intervals. 
In Group 1 and Group 2, dose escalations are possible from Week 29 visit onwards as following: 
• Group 1: from 125 mg to 200 mg, from 200 mg to 250 mg once daily p.o. (Refer to  Table 
6-8). 
• Group 2: from 50 mg to 125 mg, from 125 mg to 200 mg, and from 200 mg to 250 mg once 
daily p.o. (Refer to Table 6-9). 
In Group 3 and 4, dose escalations are allowed for participants who reached 6 years of age 
and are possible from Week 25 onward as follows:  
• from 50 mg to 125 mg, from 125 mg to 200 mg, and from 200 mg to 250 mg once daily p.o. 
(Refer to Table 6-9).  
• For participants in Group 3, dose adjustments are allowed (please refer to Section 6.1.3 and 
Table 6-7 for details), and adjustment up to 50 mg once daily must be performed prior to 
starting with any further dose escalations. 
In Group 5, dose escalations are possible from Week 25 onwards as follows: 
• from 125 mg to 200 mg, from 200 mg to 250 mg once daily p.o. (Refer to Table 6-8). 
Table 6-8 
Dose escalation for alpelisib in Group 1 and Group 5 
Alpelisib dose level 
Adult dose  
Number of tablets & strength  
Starting dose 
125 mg/day 
1 x 125 mg FCT 
Dose level 1 
200 mg/day 
1 x 200mg FCT 
Dose level 2 
250 mg/day 
1 x 200 mg + 1 x 50 mg FCT 

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Table 6-9 
Dose escalation for alpelisib in Groups 2, 3 and 4 
Alpelisib dose level 
Pediatric dose starting at 6 
years old 
Number of tablets/ granules 
sachet & strength 
Starting dose or dose after age 
related dose adjustments  
50 mg/day 
1 x 50 mg FCT or granulesa 
Dose level 1 
125 mg/day 
1 x 125 mg FCT 
Dose level 2 
200 mg/day 
1 x 200 mg FCT 
Dose level 3 
250 mg/day 
1 x 200 mg + 1 x 50 mg FCT 
a: 50 mg granules are to be used in Group 3 only.  
 
For those participants from Groups 1 and 2, who receive the lower dose because of 
safety/tolerability concerns, re-escalation of the dose after a dose reduction is possible starting 
from Week 29 in certain conditions as defined in the dose modification guidance below. The 
Investigator should consult Novartis to make a decision to re-escalate the dose. 
For those participants from Group 3 and 4, who receive the lower dose because of 
safety/tolerability concerns, re-escalation of the dose is possible starting from Week 25, 
provided that the participant has reached the age of 6 years old and certain conditions, as defined 
in the dose modification guidance provided below, are met. The Investigator should consult 
Novartis to make a decision to re-escalate the dose. 
For those participants from Group 5, who receive the lower dose because of safety/tolerability 
concerns, re-escalation of the dose is possible starting from Week 25 in certain conditions as 
defined in the dose modification guidance below. The Investigator should consult Novartis to 
make a decision to re-escalate the dose. 
In the event of a dose increase for response optimization, an MRI has to be performed after at 
least 3 months to assess the benefit of the increased dose and if further dose optimization is 
considered. 
Monitor fasting plasma glucose (FPG) 8 and 15 days after each dose escalation, and HbA1c 3 
months after each dose escalation. Additional monitoring of FPG and HbA1c may be 
undertaken at the discretion of the Investigator, particularly for participants with at least one 
risk factor for development of severe hyperglycemia, including prediabetes/diabetes (elevated 
FPG and/or HbA1c at the upper limit of normal or above), use of concomitant systemic 
corticosteroids, and/or obesity (BMI ≥ 30). Hematology and clinical chemistry can be repeated, 
if clinically indicated, at that timeframe. Home nursing is allowed for monitoring of FPG in the 
Netherlands only. 
For the Netherlands only and at the Investigator's discretion based on benefit-risk considerations 
of the participant's clinical condition, participants who are unable to travel to the site may be 
offered the option to have certain clinical trial procedures (e.g., monitoring of FPG) performed 
at an off-site location as described in Section 10.1.6. A qualified Off-site Health Provider (OHP) 
will perform fasting glucose plasma (under the direction of the Investigator) if allowed by 
national and local/site regulations and if participant provides consent (See Section 4.7). 
 

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Dose reduction  
Dose reduction and/or interruption is allowed in all groups at any time for reasons of tolerability 
and safety. 
Generally, when dose reduction is permitted as per toxicity management guidance, maximum 
2 consequent dose reductions are possible. When the participant experiences safety concerns at 
starting dose level, only one dose reduction is permitted. Depending on the dose of alpelisib, 
the Investigator should follow the general guidance for alpelisib dose reductions sequential 
steps as described in Table 6-10, Table 6-11, Table 6-12 and Table 6-13. 
Investigators should exercise caution and consider dose interruption for safety reasons, 
especially in participants who experience adverse events of grade 3 and higher, regardless of 
their apparent relatedness to study medication, and in participants experiencing recurrent or 
prolonged adverse events. This is particularly important for pediatric participants. A combined 
approach of drug interruption with subsequent re-initiation of study medication at a reduced 
dose may be pursued. 
Dose interruption because of safety and/or other medically relevant reason may last up to 60 
days, afterward the participant may restart study therapy. When the Investigator plans to restart 
alpelisib after more than 60 days of interruption, he/she should consult the Novartis. 
The sections below provide specific guidance for management and study drug modification in 
the event of: QTcF prolongation, skin toxicity, hyperglycemia, pneumonitis, diarrhea and 
stomatitis/oral mucositis. 
When minor or major surgical invasive procedure is planned, the Investigator may make a 
decision to interrupt study medication based on clinical condition of the participant. 
Dose reduction sequential steps are described in the Table 6-10, Table 6-11, Table 6-12 and 
Table 6-13; guidelines and criteria for dose reduction/interruption/re-initiation are provided in 
the following Section 6.5.1. 
Table 6-10 
Dose reduction sequential steps for alpelisib in Group 1 
Alpelisib dose 
Reduced dose / Level -1 
Reduced dose / Level -2 
125 mg daily p.o 
50 mg daily p.o 
Not allowed 
200 mg daily p.o 
125 mg daily p.o 
50 mg daily p.o 
250 mg daily p.o 
200 mg daily p.o 
125 mg daily p.o 
Table 6-11 
Dose reduction sequential steps for alpelisib in Group 2 and 4 
Alpelisib dose 
Reduced dose / Level -1 
Reduced dose / Level -2 
50 mg daily p.o 
50 mg every other day p.o 
Not allowed 
125 mg daily p.o 
50 mg daily p.o 
50 mg every other day 
200 mg daily p.o 
125 mg daily p.o 
50 mg daily p.o 
250 mg daily p.o 
200 mg daily p.o 
125 mg daily p.o 
Table 6-12 
Dose reduction sequential steps for alpelisib in Group 5 
Alpelisib dose 
Reduced dose / Level -1 
Reduced dose / Level -2 
125 mg daily p.o 
50 mg daily p.o 
50 mg every other day 

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Alpelisib dose 
Reduced dose / Level -1 
Reduced dose / Level -2 
200 mg daily p.o 
125 mg daily p.o 
50 mg daily p.o 
250 mg daily p.o 
200 mg daily p.o 
125 mg daily p.o 
Table 6-13 
Dose reduction sequential steps for alpelisib in Group 3 
Alpelisib dose 
Reduced dose / Level -1 
Reduced dose / Level -2 
20 mg every other day p.o 
Not allowed 
Not allowed 
20 mg daily p.o 
20 mg every other day p.o 
Not allowed 
40 mg daily p.o 
20 mg daily p.o 
20 mg every other day p.o 
50 mg daily p.o 
50 mg every other day p.o  
Not allowed  
125 mg daily p.o 
50 mg daily p.o 
50 mg every other day 
200 mg daily p.o 
125 mg daily p.o 
50 mg daily p.o 
250 mg daily p.o 
200 mg daily p.o 
125 mg daily p.o 
 
6.5.1.1 
Dose adjustments for QTcF prolongation 
The Fridericia QT correction formula (QTcF) should be used for clinical decisions. When 
QTcF > 500 ms or > 60 ms change from baseline (≥ Grade 3) is detected on at least two separate 
ECGs, the Investigator should follow criteria for interruption and re-initiation of study treatment 
as per Table 6-14 below.  
Table 6-14 
Criteria for interruption and re-initiation of alpelisib/placebo treatment 
due to QTcF prolongation 
If QTcF > 500 ms or > 60 ms change from baseline (≥ Grade 3) is identified: 
• 
Assess the quality of the ECG recording and the QT value and repeat if needed 
• 
If deemed necessary, consult with a cardiologist (or qualified specialist) to confirm ECG diagnosis 
If QTcF prolongation is confirmed: 
• 
Interrupt study treatment 
• 
Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If abnormal, correct 
abnormalities before resuming study drug treatment. 
• 
Review concomitant medication use for other causes for QT prolongation (refer to crediblemeds.org for 
known QT prolonging drugs), and for drugs with the potential to increase the risk of drug exposure related 
QT prolongation 
• 
Check study drug dosing schedule and treatment compliance 
• 
Consider collecting a time-matched PK sample and record time and date of last study drug intake 
• 
Increase cardiac monitoring as indicated, until the QTcF returns to ≤ 480 ms or < 60 ms change from 
baseline 
After resolution to ≤ 480 ms / 60 ms change from baseline, re-introduce treatment at a reduced dose (if 
possible), and increase ECG monitoring 
• 
If QTcF prolongation recurs (> 500 ms / 60 ms change from baseline, i.e., ≥ Grade 3) after treatment re-
introduction, discontinue participant from study. 
6.5.1.2 
Guidelines for the treatment of alpelisib induced skin toxicity 
Consultation with a dermatologist is highly recommended for better assessment and 
management of alpelisib-induced skin toxicity. Dermatologist consult is mandated for serious 
cutaneous reactions (i.e., fulfilling seriousness criteria for AE Reporting) and for severe 

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cutaneous reactions like Stevens-Johnson-Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), 
or Erythema Multiforme (EM). Dose modification guidelines are described in  
Table 6-15. 
Table 6-15 
Criteria for interruption and re-initiation of alpelisib/placebo treatment 
due to skin toxicity 
Worst toxicity-CTCAE Grade (value) 
Dose Modifications for alpelisib/placebo 
Skin and subcutaneous tissue disorders 
Grade 1 (<10% body surface area (BSA) with active 
skin toxicity*) 
Maintain dose level 
• 
Initiate topical corticosteroids 3-4 times daily, 
preferred compounds to use are triamcinolone, 
betamethasone as long as skin toxicity is active, 
for a duration of maximum 28 days 
For participants with symptoms like burning and/or 
pruritus, add a 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  
Grade 2 (10-30% BSA with active skin toxicity*) 
Maintain dose level 
• 
Initiate topical corticosteroids 3-4x daily, preferred 
compounds to use are triamcinolone or 
betamethasone as long as skin toxicity is active, 
during max. 28 days 
• 
Consider adding systemic corticosteroids in adult 
participants. The optimal doses of systemic 
steroids in pediatric participants should be 
defined individually after a consultation with a 
dermatologist according to the local label. 
If rash resolves to ≤ G1 within 10 days, the systemic 
corticosteroid may be discontinued. 
For participants with symptoms like burning, stinging 
and/or pruritus add a non-sedating anti-histamine; 
consider adding a sedating anti-histamine at night 
Grade 3 (>30% BSA with active skin toxicity*) 
Omit alpelisib/placebo dose until rash /skin toxicity 
is no longer active but fading (G1), skin biopsy may 
be considered if part of local practice 
• Initiate topical corticosteroids 3-4x daily, preferred 
compounds to use are triamcinolone or 
betamethasone for at least 28 days 
• Add systemic corticosteroids  
If rash resolves to ≤ G1 within 10 days, systemic 
corticosteroid may be discontinued 
For participants with symptoms like burning, stinging 
and/or pruritus add a non-sedating anti-histamine 
during day time; consider adding a sedating anti-
histamine at night 
Re-start alpelisib/placebo 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 

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Worst toxicity-CTCAE Grade (value) 
Dose Modifications for alpelisib/placebo 
Skin and subcutaneous tissue disorders 
corticosteroid for at least 48 hours upon re-
challenge with alpelisib; if rash and/or pruritus do 
not reoccur within 48 hours after re-challenge with 
alpelisib, systemic corticosteroid may be 
discontinued 
For participants with symptoms like burning, stinging 
and/or pruritus an antihistamine regimen should be 
continued for a minimum of 28 days after re-challenge 
with alpelisib 
Grade 4 
(any % BSA associated with extensive superinfection, 
with IV antibiotics indicated; life-threatening 
consequences) 
• Permanently discontinue participant from 
alpelisib/placebo 
• Mandated to consult a dermatologist. Photographs 
and skin biopsy** may be considered if part of 
local practice. Treatment may follow guidelines for 
Grade 3 above with the exception of rechallenge. 
Additional measures may be taken as per local 
treatment guidance 
Any Grade of Stevens-Johnson-Syndrome/Toxic 
Epidermal Necrolysis or other SJS/TEN-like 
severe skin reactions 
• Permanently discontinue participant from 
alpelisib/placebo treatment 
• Consult dermatologist, ensure documentation by 
imaging like photographs and consider skin 
biopsy** if part of local practice.  
• Follow local treatment guidelines for SJS/TEN 
*“Active” skin toxicities: If there are no new lesions or new areas of involvement developing, and if lesion 
appearance is changing color from red to pale or light brown, it is likely the skin toxicity has begun to fade and 
is not to be considered “active” any longer. Treatment reduction can be considered for these areas. The 
appearance of skin toxicity may fade slowly, over 10 days or more but not requiring ongoing therapy. 
** Skin biopsy: skin biopsy can be performed as clinically indicated and assessed locally; no skin samples will 
be sent for central assessment. 
6.5.1.3 
Guidelines for the treatment of alpelisib induced hyperglycemia 
Always consider consultation with a diabetologist, particularly for pediatric participants, and 
recommend/reinforce lifestyle changes as per American Diabetes Association (ADA) or 
European Association for the Study of Diabetes (EASD), 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 two small snacks rather than one large meal). 
The table below provides dose management recommendations. The preferred option for treating 
alpelisib-induced hyperglycemia, in participants over 10 years old, is metformin, given its wide 
availability and well characterized safety profile. For pediatric participants under 10 years of 
age (where international or local guidelines may apply), or in case of intolerance, unavailability 
or unsuitability of metformin, it is needed to consult a diabetologist to find the optimal 
individualized treatment for hyperglycemia. Other insulin sensitizers such as thiazolidinediones 
or dipeptidyl peptidase-4 inhibitors may be used for the treatment of alpelisib-induced 
hyperglycemia in adult participants. Dose modification guidelines are described in Table 6-16. 

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Table 6-16 
Criteria for interruption and re-initiation of alpelisib/placebo treatment 
due to hyperglycemia 
Worst toxicity-CTCAE Grade (value) 
Dose Modifications for alpelisib/placebo 
Grade 1 (> ULN - 160 mg/dL) [> ULN - 8.9 mmol/L] 
For participants with baseline values between >ULN – 
140 mg/dL (ULN – 7.7 mmol/L) this applies only for 
findings > 140 mg/dL (7.7 mmol/L) 
Maintain dose level and remind participant on 
lifestyle changes. 
• If FPG < 140 mg/dl, consider adding metformin as 
per guidance below or in cooperation with 
diabetologist (for children<10 years old, a 
consultation with diabetologist to individualize 
treatment is required). 
• If FPG 140-160 mg/dl, start/intensify metformin as 
per guidance below or in cooperation with 
diabetologist (for children<10 years old, a 
consultation with diabetologist to individualize 
treatment is required). 
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 participant of 
lifestyle changes, exclude confounding factors like 
e.g., urinary tract infection, consider 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 alpelisib 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 alpelisib/placebo 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. 

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Worst toxicity-CTCAE Grade (value) 
Dose Modifications for alpelisib/placebo 
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 alpelisib-induced 
hyperglycemia given the short half-life of alpelisib. 
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 program treatment and on metformin, re-start 
alpelisib/placebo and reduce 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 
• If FPG does not resolve to Grade1 within 3-5 days 
while off program 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 participant from 
alpelisib/placebo treatment. 
Grade 4 (> 500 mg/dL) [≥ 27.8 mmol/L] 
Omit alpelisib/placebo, confirm fasting status of the 
assessment. If non-fasting, re-check within 24 hours. 
Exclude confounding factors (e.g., urinary tract 
infection). 
Should consult 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 participant from alpelisib/placebo. 
A diabetologist consultation should always be considered. 
In cases where there is rapidly increasing serum glucose suspicious of severe clinical presentation and/or 
diabetic ketoacidosis without obvious confounding factors, a diabetologist should be consulted with 
consideration of potential hospitalization and close monitoring. 
6.5.1.4 
Guidelines for treatment of alpelisib induced pneumonitis 
An early consultation with a pulmonologist is recommended at any suspicion of pneumonitis 
for an appropriate evaluation and management. Dose modification guidelines are described in 
Table 6-17. 

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Table 6-17 
Management of pneumonitis related to alpelisib/placebo with or 
without other agents in combination 
Pneumonitis 
Recommended 
Investigations 
Management of 
Pneumonitis 
Program Treatment 
Modification 
Any Grade  
Obtain appropriate 
imaging (e.g., high 
resolution CT scan) 
Consider broncho-
alveolar lavage (BAL) 
and biopsy, if clinically 
appropriate 
Infectious causes of 
interstitial lung disease 
should be ruled out 
Follow institutional 
practice for management 
of pneumonitis (e.g., 
Treatment with high dose 
corticosteroids; 
concurrent antibiotic 
therapy if infectious 
causes are suspected). 
Consultation with a 
pulmonologist is highly 
recommended 
Immediately interrupt 
alpelisib/placebo for any 
case of suspected 
pneumonitis. 
For all participants with 
confirmed pneumonitis 
alpelisib/placebo should 
be permanently 
discontinued  
6.5.1.5 
Guidelines for the treatment of alpelisib induced diarrhea 
Mild to moderate diarrhea has been reported in studies of single-agent alpelisib. Severe diarrhea 
and its clinical consequences including dehydration and acute kidney injury, as well as colitis, 
have been reported in participants treated with alpelisib. Based on the severity of diarrhea, 
alpelisib may require dose interruption, reduction, or discontinuation.  
In order to effectively manage diarrhea and mitigate the escalation in severity or duration of 
diarrhea, participant education as well as proper management of alpelisib-induced diarrhea is 
mandatory. For pediatric participants, early detection and treatment of diarrhea is particularly 
important to avoid dehydration, and consultation with a gastroenterologist is recommended. 
The Investigators and care givers should ensure appropriate hydration and nutrition of the 
participants experiencing diarrhea; standards of local practice to be applied. In pediatric 
participants the Investigator may consider immediate dose interruption and initiation of anti-
diarrhea treatment at occurrence of the first episode of diarrhea, and should ensure, that 
participants and care givers are guided how to control diarrhea in timely manner. Dose 
modification guidelines are described in Table 6-18.  
The following algorithm for treatment and management of diarrhea is based on 
Wadler et al 1998, Kornblau et al 2000. 
Table 6-18 
Criteria for interruption and re-initiation of alpelisib treatment due to 
diarrhea 
Worst toxicity-CTCAE Grade (value) 
Dose Modifications for alpelisib/placebo 
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 reduce 1 
dose level 
Grade 4 
Permanently discontinue treatment 

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Participant history of diarrhea: 
• At baseline, the participant’s history of diarrhea should be reviewed and the participant (and 
care-giver) should be appropriately informed of potential alpelisib-induced diarrhea and its 
management 
• Review previous medical history of diarrhea within the last 12 months; laxative use, colon 
surgery abdominal and pelvic irradiation, nocturnal diarrhea, pain, ulcerative colitis and 
other diarrhea-inducing diseases/conditions 
• Stop all diarrheogenic agents, otherwise exclude from program 
• Instruct participants regarding risk of developing diarrhea 
• Perform baseline clinical/laboratory studies (e.g., one could rule out carrier state of 
Salmonella spp., Clostridium difficile, Campylobacter spp., Giardia, Entamoeba, 
Cryptosporidium which can lead to opportunistic infections in immunosuppressed 
participants) 
• Explain the frequency of diarrhea and its relationship to NCI CTCAE grading (Table 6-19)  
First report of diarrhea: 
• Obtain history of onset and duration of diarrhea 
• Description of number of stools and stool composition (e.g., watery, blood, mucus in stool) 
• Assess participant for fever, abdominal pain, cramps, distension, bloating, nausea, vomiting, 
dizziness, weakness (i.e., rule out risk for sepsis, bowel obstruction, dehydration) 
• Obtain medication profile (i.e., to identify any diarrheogenic agents) and dietary profile (i.e., 
to identify diarrhea-enhancing foods) 
• Proactively look for occurrence of diarrhea. If no problems occur, instruct the participant 
and care-giver to call when a problem does arise 
Management of diarrhea: 
General Recommendation 
• Stop all lactose-containing products, alcohol 
• Stop laxatives, bulk fiber (e.g., Metamucil®) and stool softeners (e.g., docusate sodium, 
Colace®) 
• Stop high-osmolar food supplements such as Ensure Plus® and Jevity Plus® (with fiber) 
• Drink 8 to 10 large glasses of clear liquids per day (e.g., water, Pedialyte®, Gatorade®, broth) 
• Eat frequent small meals (e.g., bananas, rice, apple sauce, toast) 
It is recommended that participants are treated with loperamide (refer to the local label). 
Participants and care-givers should be instructed on the use of loperamide in order to manage 
signs or symptoms of diarrhea at home. Participants should be instructed to start oral loperamide 
at the first sign of loose stool or symptoms of abdominal pain (initial administration for adults: 
4 mg, then 2 mg every 4 hrs to a maximum of 16 mg/day; for children below 12 years, 
depending on age: 1-2 mg up to 4 times a day). These instructions should be provided at each 
visit and the treating physician should ensure that the participant understands the instruction. 
At each visit, participants should be specifically questioned regarding any experience of 

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diarrhea or diarrhea related symptoms. If symptoms were experienced, then the treating 
physician should question the participant regarding the actions taken for these symptoms. 
Intensive management of diarrhea must be instituted at the first sign of abdominal cramping, 
loose stools or overt diarrhea. 
Loperamide is the first-line treatment of diarrhea (any Grade) in this recommended algorithm. 
Persistent symptoms may require the administration of high dose loperamide followed by 
treatment with second-line agents such as opium tincture and octreotide acetate, based on 
severity and duration of diarrhea and related signs/symptoms. Another first-line treatment for 
diarrhea is diphenoxylate hydrochloride/atropine sulfate. This medication may be used in place 
of loperamide, however it is important to note that loperamide and diphenoxylate 
hydrochloride/atropine sulfate must not be used in conjunction with one another due to the risk 
of developing paralytic ileus. Upon treatment with any antidiarrheal agents, the participant’s 
response to treatment should be observed and appropriately documented.  
For colitis consider additional treatment, such as steroids. 

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Treatment of diarrhea CTCAE Grade 1 or 2 
Diarrhea CTCAE Grade 1 or 2 will be treated with standard loperamide (initial at first 
administration 4 mg, then 2 mg every 4 hrs (maximum of 16 mg/day) or after each unformed 
stool) (Table 6-19). Dosage and dosage schedule for pediatric participants should be 
individualized according to the local loperamide label.  
12-24 hours later: 
Diarrhea resolved 
• Continue instructions for dietary modification 
• Gradually add solid foods to diet 
• Discontinue loperamide after 12 hours diarrhea-free interval 
Diarrhea unresolved 
• Persisting diarrhea CTCAE Grade 1 or 2 will be treated with addition of opium tincture or 
dihydrocodeine tartrate tablets/injections with monitoring of participants condition to rule 
out dehydration, sepsis, ileus, medical check and selected workup if participant does not 
need hospitalization (see section Diarrhea workup below). Observe participant for response 
to antidiarrheal treatment. 
• Persisting diarrhea CTCAE Grade 3 or 4 may be treated with hospitalization, high dose 
loperamide (initial 4 mg, then 2 mg every 2 hours) and addition of opium tincture (DTO) or 
dihydrocodeine tartrate tablets/injections, start of IV fluids and antibiotics as needed with 
monitoring of participants condition (to rule out dehydration, sepsis, ileus) medical check 
and workup (perform appropriate additional testing). Observe participant for response. 
After 12-24 hours: 
Diarrhea resolved 
• Continue instructions for dietary modification 
• Gradually add solid foods to diet 
• Discontinue loperamide and/or other treatment after 12 hrs diarrhea-free interval 
Diarrhea unresolved 
• If diarrhea still persisting (CTCAE Grades 1 and 2) after 48 hrs with high dose loperamide 
and opiates, then admit to hospital and employ measures as for CTCAE grade 3 and 4 until 
diarrhea resolved. 
• If diarrhea still persisting and progressed to CTCAE Grades 3 and 4, employ measures 
described below. 
Treatment of diarrhea CTCAE Grade 3 or 4 
Severe diarrhea CTCAE Grade 3 or 4 may be treated with hospitalization, high dose loperamide 
(initial 4 mg, then 2 mg every 2 hrs and addition of opium tincture or dihydrocodeine tartrate 
tablets/injections, start of IV fluids and antibiotics as needed with monitoring of participants 
condition (to rule out dehydration, sepsis, ileus) medical check and workup (Table 6-19) (see 
Diarrhea workup section below). 
Observe participant for response. 

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After 12-24 hours: 
• If diarrhea persisting administer s.c. Sandostatin/octreotide (100-500 μg tid) 
• Continue IV fluids and antibiotics as needed 
• If diarrhea CTCAE Grade 3 or 4 still persists participants should receive opium tincture or 
dihydrocodeine tartrate injections s.c. or i.m. 
• If diarrhea CTCAE Grade 3 or 4 is still persisting s.c. Sandostatin/octreotide (500-1000 μg 
TID) should be administered 
• To control and/or resolve diarrhea, next cycle of treatment should be delayed by 1 or 2 
weeks. Treatment should be continued only when diarrhea resolves. 
Diarrhea workup 
Perform appropriate tests (Fine and Schiller 1999). 
Spot stool analysis 
• Collect stool separating it from urine (special containers, analysis immediately, 
exceptionally freeze samples) 
• Blood 
• Fecal leukocytes (Wright's staining and microscopy) or Clostridium difficile toxin 
• Fecal cultures including Salmonella spp., Campylobacter spp., Giardia, Entamoeba, 
Cryptosporidium (which can lead to opportunistic infections in immunosuppressed 
participants), plus Shigella and pathogenic E. coli - enterotoxigenic, enterohemorrhagic 
etc., possibly Aeromonas, Pleisiomonas (if suspected exposure to contaminated water). 
Endoscopic examinations 
Endoscopic examinations may be considered only if absolutely necessary. The bowel is likely 
to be fragile with evidence of colitis and thus great care and caution must be exercised in 
undertaking these invasive procedures: 
• Gastroscopy to obtain jejunal fluid - re. bacterial overgrowth for cultures and biopsy of 
proximal jejunum to assess extent of inflammatory jejunitis 
• Sigmoidoscopy - reassessment of colitis 
Table 6-19 
NCI CTCAE version 4.03 grading of diarrhea for participants without 
Colostomy 
Toxicity 
1 
2 
3 
4 
Diarrhea 
Increase of < 4 
stools per day over 
baseline 
Increase of 4-6 
stools per day over 
baseline 
Increase of ≥ 7 
stools per day over 
baseline; 
incontinence; 
hospitalization 
indicated; limiting 
self-care Activity of 
Daily Living (ADL) 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Diarrhea is defined as: A disorder characterized by frequent and watery bowel movements. 

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6.5.1.6 
Guidelines for the treatment of alpelisib induced stomatitis/oral 
mucositis 
For pediatric participants, early consultation with a stomatologist is recommended on suspicion 
of alpelisib-induced stomatitis for appropriate evaluation and management. Dose modification 
guidelines are described in Table 6-20. 
Table 6-20 
Criteria for interruption and re-initiation of alpelisib treatment due to 
stomatitis 
Worst toxicity-CTCAE Grade (value) 
Dose Modifications for alpelisib/placebo 
Grade 1/Tolerable Grade 2 
Maintain dose level. 
Non-alcoholic or salt water mouth wash. 
Intolerable Grade 2 or Grade 3 
First occurrence: hold until ≤ Grade 1 and reduce 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 reduce 
1 dose level. 
Grade 4 
Permanently discontinue participant from 
alpelisib/placebo. 
6.5.1.7 
Guideline for treatment of alpelisib induced pancreatitis 
If acute pancreatitis is diagnosed, initiate appropriate treatment and follow dose modification 
guidelines described in the Table 6-21. 
Table 6-21 
Criteria for interruption and re-initiation of alpelisib treatment due to 
pancreatitis. 
Worst toxicity-CTCAE Grade (value) 
Dose Modifications for alpelisib/placebo 
Grade 2 (enzymatic elevation or radiologic findings 
only) 
Maintain dose level. Initiate appropriate medical 
therapy and monitor as clinically indicated. 
Grade 3 
Omit dose until resolved to Grade ≤ 1, then resume 
treatment at decrease 1 dose level. Only 1 dose 
reduction is allowed. If toxicity recurs, permanently 
discontinue participant from alpelisib/alpelisib 
matching-placebo. 
Grade 4 
Permanently discontinue participant from 
alpelisib/alpelisib matching-placebo. 
6.5.1.8 
Investigations: alpelisib dose modifications 
Recommendations for dose reduction or dose interruption of alpelisib in the management of 
changes in the investigations when they are considered adverse events are summarized in the 
Table 6-22 and Table 6-23.  
Clinical judgment of the treating physician, including confirmation of laboratory values if 
deemed necessary, should guide the management plan of each participant based on individual 
benefit/risk assessment. 
• One dose reduction will be allowed after which treatment must be discontinued as indicated 
in the Table 6-22 and Table 6-23. 

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• After treatment is resumed at a lower dose: 
• If the same toxicity reoccurs with the same severity, treatment must be discontinued. 
• Once the AE has resolved and alpelisib dose has been reduced, the Investigator may 
consider a dose re-escalation only if it may be needed to provide optimal clinical benefit 
(based on overall response assessment) and if there are no safety/tolerability concerns which 
may preclude from treatment continuation at higher dose level. 
Table 6-22 
Criteria for interruption and re-initiation of alpelisib treatment: 
Investigations (hematologic) 
Worst toxicity-CTCAE Grade (value) 
Dose Modifications for alpelisib/placebo 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 1.5 x 109/L) 
Grade 2 (ANC < 1.5 - 1.0 x 109/L) 
• Maintain dose level. 
• Maintain dose level and monitor as clinically 
indicated. 
Grade 3 (ANC < 1.0 - 0.5 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then resume at 
the next lower dose level. 
Grade 4 (ANC < 0.5 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then resume at 
the next lower dose level. 
Discontinue from study in the event of recurrence. 
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 decrease 1 dose level. 
Discontinue from study in the event of recurrence. 
Thrombocytopenia 
Grade 1 (PLT < LLN - 75 x 109/L) 
Grade 2 (PLT < 75 - 50 x 109/L) 
Maintain dose level. 
Maintain dose level and monitor as clinically 
indicated. 
Grade 3 (PLT < 50-25 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then resume at 
the next lower dose level. 
Grade 4 (PLT < 25 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then resume at 
the next lower dose level. 
Discontinue from study in the event of recurrence. 
Table 6-23 
Criteria for interruption and re-initiation of alpelisib treatment: 
Investigations (other) 
Worst toxicity-CTCAE Grade (value) 
Dose Modifications for alpelisib/placebo 
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 decrease 1 dose 
level. 
Grade 3 (> 3.0 – 6.0 x ULN) 
Permanently discontinue participant from study drug. 
Grade 4 (> 6.0 x ULN) 
Permanently discontinue participant from study drug. 
Investigations (Hepatic) 
Isolated total Bilirubin elevation (for participants with Gilbert Syndrome these dose modifications apply 
to changes in direct bilirubin only) 

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Worst toxicity-CTCAE Grade (value) 
Dose Modifications for alpelisib/placebo 
Grade 1 (>ULN - 1.5 x ULN) 
No dose adjustment is required. Initiate appropriate 
medical therapy and monitor as clinically indicated. 
Grade 2 (> 1.5 - 3.0 x ULN) 
Interrupt dose until recovery to Grade ≤ 1 and resume 
at the same dose if resolved in ≤ 14 days or resume 
at the next lower dose level if resolved in > 14 days. 
Grade 3 (>3.0 - 10.0 x ULN) 
Interrupt dose until recovery to Grade ≤ 1, then 
resume at the next lower dose level. 
Grade 4 (>10.0 x ULN) 
Permanently discontinue. 
Isolated AST or ALT elevation 
Grade 1 (>ULN - 3.0 x ULN) 
Grade 2 (>3.0 - 5.0 x ULN) 
No dose adjustment is required. Initiate appropriate 
medical therapy and monitor as clinically indicated. 
Grade 3 (>5.0 - 20.0 x ULN) 
Interrupt dose until recovery to Grade ≤ 1, then 
resume at the next lower dose level. 
Grade 4 (>20.0 x ULN) 
Permanently discontinue. 
Combined ALT/AST and TBIL elevation 
Please see specific instructions in Section 6.5.2.1 
Investigations (Metabolic) 
Asymptomatic amylase and/or lipase elevation 
  
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level. 
Grade 2 (> 1.5 - 2.0 x ULN) 
Maintain dose level. 
Grade ≥ 3 (> 2.0 x ULN) 
• 
Omit dose until resolved to baseline, then 
• 
If resolved in ≤ 14 days, maintain dose level. 
• 
If resolved in > 14 days, then decrease 1 dose 
level. 
Note: 
• 
In cases of isolated amylase elevations only, 
dosing may be maintained provided amylase 
fractionation demonstrates that pancreatic 
amylase is ≤ Grade 1. Monitor total amylase (and 
continue to assess fractionated amylase). 
Note: Withhold study treatment for acute onset of 
new or progressive unexplained abdominal 
symptoms, such as severe pain or vomiting; and 
perform diagnostic procedures (e.g., abdominal CT 
scan or ultrasound) to exclude pancreatic pathology. 
  
Investigations (any other) 
  
Other adverse events 
  
Grade 1 or 2 
Maintain dose level. 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then decrease 
1 dose level. 
Grade 4 
Permanently discontinue participant 
from alpelisib/alpelisib matching-placebo. 
For additional details on the safety profile of alpelisib, please refer to the [alpelisib 
(BYL719) Investigator's Brochure]. 
6.5.2 
Follow-up for toxicities 
All participants must be followed up for safety (adverse events and serious adverse events) for 
30 days following the last dose of study treatment (alpelisib). 

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Participants whose treatment is interrupted or permanently discontinued due to an adverse event 
or a clinically significant laboratory value must be followed until resolution or stabilization of 
the event, whichever comes first. Further guidelines and recommendations for the management 
of specific study treatment induced toxicities are provided below. 
6.5.2.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Participants with transaminase increase combined with an increase of total bilirubin (TBIL) 
may be indicative of potential DILI, these cases should be considered as clinically important 
events. 
In general, any increase of serum aminotransferases to > 3 x ULN should be followed by repeat 
testing within 48 to 72 hours. 
If total bilirubin is elevated > 2 x ULN, fractionation into direct and indirect bilirubin is 
required. 
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and TBIL 
value; participants meeting any of the following criteria will require further follow-up as 
outlined below: 
• For participants with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 
x ULN combined with TBIL > 2.0 x ULN (For participants with Gilbert syndrome: doubling 
of direct bilirubin) 
• For participants with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN] 
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in participants without bone pathology, or 
elevation of ALP liver fraction in participants with bone pathology. 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or alkaline phosphatase 
(ALP) elevation is due to cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) 
liver injury. 
In the absence of cholestasis, these participants should be immediately discontinued from study 
treatment, and repeat Liver function test (LFT) testing as soon as possible, preferably within 48 
hours from the awareness of the abnormal results. The evaluation should include laboratory 
tests, detailed history, physical assessment, and the possibility of liver metastasis or new liver 
lesions, obstructions/compressions, etc. 
Upon presentation 
• Obtain PK sample to determine exposure to study drug and metabolites. 
• Perform comprehensive medical history including cardiac disease, blood transfusions, i.v. 
drug abuse, travel, work, alcohol intake, and full clinical examination for evidence of acute 
or chronic liver disease, cardiac disease and infection etc. 

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• History of concomitant drug use (including nonprescription medications and herbal and 
dietary supplement preparations), alcohol use, recreational drug use, special diets, and 
chemicals exposed to within one month of the onset of the liver injury. 
• Exclude other causes of liver disease. 
Participant monitoring: 
• Repeat liver chemistry tests within 48-72 hours. 
• Retest frequency can decrease to weekly or less if abnormalities stabilize, drug has been 
discontinued, and the participant is asymptomatic. 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before the diagnosis of DILI is confirmed (see 
Table 6-24). Liver biopsy has limited value in the diagnosis of DILI as histopathological 
findings in DILI can resemble many other liver conditions. However, biopsy can be useful to 
establish an alternative diagnosis especially if other tests are inconclusive. 
Table 6-24 
Alternative causes of liver disease 
Disease 
Assessment 
Hepatitis A, B, C, E 
Immunoglobulin M (IgM) anti-HAV; Hepatitis B virus 
surface antigen (HBsAg), IgM anti-HBc, HBV DNA; 
anti-HCV, HCV RNA, IgM & IgG anti-HEV, HEV RNA 
CMV, HSV, EBV infection 
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG 
anti-EBV 
Autoimmune hepatitis 
Antinuclear Antibodies (ANA) & Anti Smooth Muscle 
Antibody (ASMA) titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
Ethanol history, gammaGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
Medical history: acute or chronic congestive heart 
failure, hypotension, hypoxia, hepatic venous 
occlusion. Ultrasound or MRI. 
Biliary tract disease 
Ultrasound or MRI, Endoscopic Retrograde 
Cholangiopancreatography (ERCP) as appropriate. 
Wilson disease 
Caeruloplasmin 
Hemochromatosis 
Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
Alpha-1-antitrypsin 
Following appropriate causality assessments, as outlined above, the causality of the drug is 
estimated as “probable” i.e., > 50% likely, if it appears greater than all other causes combined. 
All cases confirmed on repeat testing that meet the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant” and thus, meet the definition of SAE and should be reported as a SAE using the 
term “potential treatment-induced liver injury.” All events should be followed up with the 
outcome clearly documented. 
6.5.2.2 
Management of pneumonitis 
Alpelisib is associated with pneumonitis/interstitial lung disease. 
Closely monitor all participants for signs and symptoms of pneumonitis. 

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All participants will be routinely asked about and observed for the occurrence of adverse events 
including new or changed pulmonary symptoms (consistent with lung abnormalities). 
Participants who are suspected to have developed pneumonitis should interrupt study treatment 
immediately and undergo appropriate imaging (high resolution CT scan); broncho-alveolar 
lavage (BAL) and biopsy should be considered if clinically appropriate. Infectious causes of 
interstitial lung disease should be ruled out. Investigators should follow institutional practice 
for 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. 
After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently 
discontinue treatment with alpelisib/placebo and promptly initiate appropriate treatment and 
supportive measures. 
6.5.2.3 
Guidelines for the treatment of alpelisib induced skin toxicity 
Skin toxicity is a class-effect observed with PI3K inhibitors. 
Close monitoring of potential skin reactions will be performed at each planned visit and will be 
reported as adverse event. The most frequent skin adverse events reported are: maculopapular 
rash (only a minority present acneiform rash); pruritus and dry skin. The onset is typically 
within the first 2 months of starting treatment and is reversible with adequate concomitant 
medications and alpelisib treatment interruption/reduction, if needed. Skin reactions may 
improve over several weeks. Consultation with a dermatologist is highly recommended for 
better assessment and management of alpelisib-induced skin toxicity at any grade, and 
mandated if a severe cutaneous reaction like Stevens-Johnson-Syndrome, Toxic Epidermal 
Necrolysis or Erythema multiforme is suspected. 
Workup for skin toxicities includes skin photography, a complete blood count with differential, 
and a full chemistry panel. A paired skin biopsy may be obtained as clinically indicated (from 
both affected and an unaffected skin area) for local histopathology assessment to further assess 
the skin toxicity, especially to confirm suspected diagnosis of any severe cutaneous reactions. 
In case of Grade 3/4 skin toxicity or any grade of severe cutaneous reactions, Novartis 
recommends that photographs are taken and a skin biopsy is performed as clinically indicated 
and assessed locally.  
At the Investigator’s discretion, non-sedating antihistamines (e.g., cetirizine (Zyrtec©), 
fexofenadine (Allegra), loratadine (Claritin) may be used as prophylactic treatment to reduce 
severity of rash, especially for participants with a history of atopy such as allergic rhinitis, 
asthma, atopic dermatitis or drug allergies. 
Recommended therapies for skin toxicity events include: 
• Topical steroids Triamcinolone or Betamethasone 3-4 times daily for at least 28 days. 
Consider spray, lotion, or cream preparation for ease of application on trunk. For scalp 
involvement, consider a foam preparation. Ensure that at least 240 g are dispensed. 
• GABA analogs: Gabapentin 300mg every 8 hours, Pregabalin 50-75 mg every 8 hours 
(adjust as tolerated). Please refer to the local labels and apply local standards of care as 

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needed to optimize treatment for skin toxicity. Depending on participant’s clinical condition 
be aware of potential and common adverse effects observed with GABA agonists such as: 
somnolence, dizziness and peripheral edema among others adverse events.  
For grade 4 skin events, alpelisib/placebo treatment must be permanently discontinued without 
any re-challenge. 
Dry skin has been reported. It is recommended that participants with dry skin use mild and 
fragrance free soaps and detergents. 
Although preclinical experiments demonstrated that alpelisib has no potential phototoxic effect, 
it is recommended to caution participants to avoid sun exposure during treatment with alpelisib, 
especially when they already have experienced rash or other skin toxicities as the increased 
blood flow of the skin may worsen skin symptoms. Participants should be advised to take 
measures to protect themselves from direct exposure to sunlight, including the wearing of 
sunglasses as well as the regular use of sunscreen, hats, long-sleeve shirts and long pants when 
outdoors. 
6.5.2.4 
Guidelines for the treatment of alpelisib-induced hyperglycemia 
Alpelisib, like other PI3K inhibitors, may affect glucose homeostasis which could result in 
increases of plasma glucose and insulin resistance (Busaidy et al 2012). Alpelisib induced 
hyperglycemia is generally manageable with adequate antidiabetic treatment. Alpelisib induced 
hyperglycemia typically occurs within the first month of treatment. Participants with pre-
diabetes (i.e., FPG ≥100 mg/dl or ≥5.6 mmol/L; HbA1c ≥ 5.7%) and those with an established 
diagnosis of type 2 diabetes mellitus should be monitored carefully, thus allowing an early 
detection and prompt management of increases in FPG while on alpelisib/placebo treatment. 
However, even participants with FPG within normal limits at screening may develop alpelisib-
induced hyperglycemia. Participants should always be instructed to follow dietary guidelines 
provided by the American Diabetes Association (ADA) or European Association for the Study 
of Diabetes (EASD), 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 and exercise, as appropriate. 
Detailed guidelines for the management of alpelisib induced hyperglycemia are provided in 
Table 6-16. 
This includes early administration of metformin. Metformin may be titrated to a daily dose of 
1000 mg BID. Local standard clinical practice may be followed. Fasting plasma glucose may 
be performed both locally and/or centrally for rapid availability for safety evaluation and 
management guidance. Special attention should be paid to the risk of hypoglycemia in 
participants interrupting alpelisib treatment and concomitantly receiving insulin and/or 
sulfonylureas. Due to the short half-life of alpelisib, all glucose lowering medications should 
be discontinued when alpelisib is stopped. Consultation with a diabetologist is highly 
recommended for better assessment and management of alpelisib-induced hyperglycemia.  
6.5.2.5 
Follow-up on amylase or lipase elevation (CTCAE Grade 3) 
Participants with amylase or lipase elevation ≥ CTCAE Grade 3 must be tested weekly (or more 
frequently if clinically indicated) until values return to ≤ Grade 1. After resumption of dosing, 

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continue to test weekly for one additional cycle. If no reoccurrence of ≥ Grade 2 event, continue 
monitoring every cycle. 
An exception to these follow-up guidelines will be made for cases of isolated amylase elevations 
in which amylase fractionation demonstrates that pancreatic amylase is ≤ Grade 1. In such cases, 
total amylase and fractionated amylase should be monitored weekly (or more frequently if 
clinically indicated) for 4 weeks. If pancreatic amylase remains ≤ Grade 1, subsequent 
monitoring must be performed at least every 4 weeks (or more frequently if clinically indicated). 
Participants who discontinue study treatment due to pancreatic toxicity must be monitored 
weekly (or more frequently if clinically indicated) until the event resolves to ≤ grade 1 or 
stabilization occurs (no CTCAE grade change over 4 weeks). 
If amylase and/or lipase elevations are accompanied by new or progressive unexplained 
abdominal symptoms such as severe pain or vomiting, withhold study treatment, then perform 
diagnostic procedures (e.g., abdominal CT scan or ultrasound) to exclude pancreatic pathology. 
Please also refer to Table 6-23: Criteria for interruption or re-initiation of alpelisib treatment.  
6.5.2.6 
Guidelines for hypersensitivity 
Alpelisib is associated with hypersensitivity reactions, including anaphylaxis. These are 
manifested by symptoms including, but not limited to, dyspnea, flushing, rash, fever or 
tachycardia. Alpelisib/placebo should be permanently discontinued and should not be re-
introduced in participants with serious hypersensitivity reactions. Appropriate treatment should 
be promptly initiated. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
The Investigator must promote compliance for alpelisib/placebo by instructing the participant 
to take the study treatment exactly as prescribed and by stating that compliance is necessary for 
the participant’s safety and the validity of the study. The participant must also be instructed to 
contact the Investigator if he/she is unable for any reason to take the study treatment as 
prescribed. Compliance will be assessed by the Investigator and/or study personnel using pill 
counts and information provided by the participant. This information should be captured in the 
source document at each visit. All study treatment dispensed and returned must be recorded in 
the Drug Accountability Log. 
PK parameters (measures of treatment exposure) will be determined in participants treated with 
alpelisib, as detailed in Section 8.5.2. 
6.6.2 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is absolutely necessary to treat the 
participant safely. Most often, study treatment discontinuation without knowledge of the 
possible treatment assignments is generally sufficient to treat a study participant who presents 
with an emergency condition. Emergency treatment code breaks are performed using the IRT. 
When the Investigator contacts the system to break a treatment code for a participant, he/she 

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must provide the requested participant identifying information and confirm the necessity to 
break the treatment code for the participant. The Investigator will then receive details of the 
investigational drug treatment for the specified participant and a fax or email confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
study team that the code has been broken. 
It is the Investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The Investigator will provide: 
• protocol number 
• name (if available) 
• participant number 
In addition, the Investigator will inform the participant how to contact his/her backup in cases 
of emergency when he/she is unavailable. 
Study treatment must be discontinued once emergency unblinding has occurred. If a participant 
is unblinded, he/she must be discontinued from the study.  
6.7 
Preparation and dispensation 
Participants will be provided with an adequate supply of study drug for self-administration at 
home, including instructions for administration, until at least their next scheduled study visit 
(see Table 6-25). Participants will receive alpelisib/placebo on an outpatient basis. 
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, delivery 
of Investigational Medicinal Product (IMP) directly to a participant's home may be permitted 
(if allowed by local or regional health authorities and ethics committees as appropriate) in the 
event the Investigator has decided that an on-site visit by the participant is no longer appropriate 
or possible, and that it is in the interest of the participant’s health to administer the study 
treatment without performing an on-site visit. The on-site visit would be replaced with a 
remote/virtual assessment. Implementation will need to be discussed with Novartis. The 
dispatch of IMP (alpelisib/placebo) from the site to the participant’s home remains under the 
accountability of the Investigator. Each shipment/provisioning will be for a maximum of 4 
weeks supply for the first year of treatment or every 24 weeks during subsequent visits after 
Week 48. In this case, regular phone calls or virtual contacts (at the time of every scheduled 
visit or more frequently if needed) will occur between the site and the participant for 
instructional purposes, safety monitoring, and discussion of the participant´s health status until 
the participants can again visit the site. 
The Investigator or responsible site personnel must instruct the participant or caregiver to take 
the study drugs as per protocol. Study drug(s) will be dispensed to the participant by authorized 
site personnel only. All dosages prescribed to the participant and all dose changes during the 
study must be recorded on the Dosage Administration Record CRF. 
The study medication packaging has a 2-part label. A unique medication number is printed on 
each part of this label which corresponds to the dose. Responsible site personnel will identify 
the study treatment package(s) to dispense to the participant by using the IRT and obtaining the 
medication number(s). Site personnel will add the participant number on the label. Immediately 

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before dispensing the package to the participant, site personnel will detach the outer part of the 
label from the packaging and affix it to the source document (Drug Label Form) for that 
participant’s unique participant number. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug and the medication number but no 
information about the participant. 
Table 6-25 
Preparation and dispensation 
Study 
treatment 
Dispensing 
Preparation 
Alpelisib 
For Groups 1, 2, 4 and 5 
participants, the FCT in 
bottles (50 mg, 125 mg, 200 
mg) are dispensed by study 
personnel on an outpatient 
basis and oral instruction on 
dose administration will be 
provided by the Investigator 
or responsible site 
personnel. 
Participants (or parents or 
caregivers) will be provided 
with adequate supply of 
study treatment for self-
administration at home until 
at least their next scheduled 
study visit. 
 
 
For Group 3, granules in 
sachets applicable for 20 mg 
and 50 mg dose are 
dispensed by study 
personnel on an outpatient 
basis and oral instruction on 
dose administration will be 
provided by the Investigator 
or responsible site 
personnel. 
Participants (or parents or 
caregivers) will be provided 
with adequate supply of 
study treatment for self-
administration at home until 
at least their next scheduled 
study visit. 
In participants with swallowing dysfunction (including pediatric 
participants who are unable to swallow), alpelisib FCTs can be 
administered as drinkable suspension by crushing the tablets 
under water with a spoon. The drinkable suspension prepared 
from the film-coated crushed tablets must not be administered 
through feeding tubes. 
Procedure for alpelisib oral suspension using FCT: Place 
alpelisib tablets in a glass containing 50 -150 ml of still water 
and let the mixture stand for 5 minutes, then stir and crush the 
tablets with the help of a spoon until a suspension is obtained. 
Gently stir the suspension with the spoon and drink the full 
amount immediately after stirring. Discard the oral suspension 
if it is not administered within 60 minutes after preparation. If 
any solid residue remains visible, add approximately 20– 50 ml 
of still water to the same cup, stir with the same spoon to 
resuspend any remaining residue and administer the entire 
contents of the cup. Repeat the procedure if necessary. 
Beverages other than still water should not be used to make 
the suspension. 
Procedure for alpelisib oral granules: 20 mg, 2 x 20 mg and 50 
mg sachets can be poured directly onto the tongue and 
swallowed with 60-120 mL of water, or mixed with 1 – 3 
teaspoon of water, milk, apple juice, applesauce or yogurt 
followed by a 40 mL rinse. Infants can be dosed with an oral 
syringe, but not a bottle due to particulates in the suspension. 
Once mixed with a food vehicle, granules should be consumed 
within 2 hours. Administration of granules through feeding 
tubes (sizes 8 Fr (length 125 cm to 160 cm) to 12 Fr (length 
125 cm) for nasogastric tubes consisting of silicone or 
polyurethane, and 12 Fr to 24 Fr for gastric tube consisting of 
silicone) is allowed.  
 
 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment 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 
site personnel have access. Upon receipt, all study treatment must be stored according to the 

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instructions specified on the labels and in the latest version of [Alpelisib (BYL719) 
Investigator's Brochure]. Clinical supplies are to be dispensed only in accordance with the 
protocol. Technical complaints are to be reported to the respective Novartis Country 
Organization (CO) Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The Investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the study. Participants will be 
asked to return all unused study treatment and packaging at the end of the study or at the time 
of discontinuation of study treatment. 
Document destruction of unused study treatment, drug labels and packaging is allowed as 
appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. 
Otherwise, at the conclusion of the study, and as appropriate during the course of the study, the 
Investigator will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the Investigator folder at each site. 
6.7.1.2 
Handling of additional treatment 
No other treatment beyond investigational drug is included in this study (Section 6.1.2) 
6.7.2 
Instruction for prescribing and taking study treatment 
Dosing and treatment schedule will be performed according to Section 6.1. 
All kits of study treatment assigned by the IRT will be recorded in the IRT system.  
6.7.2.1 
Alpelisib/placebo administration 
The Investigator or responsible site personnel should instruct the participant to take the study 
drugs as per protocol (promote compliance). Drug accountability must be performed on a 
regular basis. Participants will be instructed to return unused study drugs to the site monthly. 
The site personnel will ensure that the appropriate dose of each study drug is administered at 
each visit and will provide the participant with the correct amount of drugs for subsequent 
dosing. 
Participant should be instructed to take the dose of alpelisib once daily at approximately the 
same time each day immediately after food (preferably in the morning after breakfast), except 
on the days blood collection is scheduled at the clinic, at which time the participants should 
take their doses at the clinic at any later point of time (please refer to Section 6.7.2.2). 
Alpelisib/placebo must be taken immediately after a meal or snack, any type of food is 
acceptable. If, for any reason, a breakfast (or other meal) was not consumed, then the participant 
should take study treatment with a glass of still water immediately after a snack. If this happens 
on days of PK sampling, it should be documented in the eCRF. 

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Alpelisib granules can be poured directly onto the participant’s tongue and swallowed with a 
glass of water or mixed with another vehicle (Table 6-25). Please refer to Appendix 7 for details 
on administration of study drug granules.  
Alpelisib/placebo FCT should be taken with a glass of an appropriate 150 ml volume of still 
water. Refer to preparation details in Table 6-25. Alpelisib/placebo FCT should be swallowed 
whole (tablets should not be chewed, or split prior to swallowing). Tablets that are broken, 
cracked, or otherwise not intact should not be ingested. In participants with swallowing 
dysfunction (including pediatric participants who are unable to swallow), alpelisib/placebo FCT 
can be administered as drinkable suspension by crushing the tablets under water with a spoon. 
Administration of FCT or granules by mouth or through feeding tubes (sizes 8 Fr (length 125 
cm to 160 cm) to 12 Fr (length 125 cm) for nasogastric tubes consisting of silicone or 
polyurethane, and 12 Fr to 24 Fr for gastric tube consisting of silicone) is allowed for Group 3 
only. A minimum dispersion volume of 40 mL should be used. When using feeding tubes, co-
administration with medium caloric food is recommended to reduce the risk for hyperglycemia.  
If a dose of alpelisib/placebo is missed, it can be taken immediately after food and within 9 
hours after the time it is usually administered. After more than 9 hours, the dose should be 
skipped for that day. On the next day, alpelisib should be taken at its usual time. If the participant 
vomits after taking the alpelisib/placebo dose, the participant should not take an additional dose 
on that day and should resume the usual dosing schedule the next day, at the usual time. 
Vomiting during a treatment must be reported in the adverse events section of the eCRF. 
During the treatment phase, the participant or caregiver/legal guardian should record if the dose 
was taken or not in the alpelisib/placebo participant dosing diary. 
6.7.2.2 
Additional dosing guidelines for scheduled visit days 
On days when pre-dose fasting safety samples are collected as described in Table 8-2 and Table 
8-3 and Section 8.5, participants should be instructed to arrive at the site in fasted state. The 
following additional guidelines should be followed: 
• On scheduled visit days, participants must take study treatment in the clinic under the 
supervision of the Investigator or designee. On all other days participants will take 
alpelisib at home 
• The participants must take alpelisib immediately after food 
• ECG measurement should always occur before dosing of alpelisib 
• If a pre-dose PK sample should be obtained, then the sample should be collected after the 
ECG and before dosing of alpelisib 
• Pre-dose PK samples should be drawn prior to dosing. The sampling time of the PK 
samples and the dosing time must be precisely recorded in the eCRF. Furthermore, the 
date and time of alpelisib dose on the day before the PK assessment must be precisely 
recorded in the eCRF 
• Post-dose PK samples should be collected after dosing of alpelisib 
• ECG and PK sample collection will be performed according to Section 8.4.2 and 
Section 8.5.2 
Please refer to Figure 6-1 for the study drug administration on scheduled visit days. 

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A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. Participants might be asked to complete an optional questionnaire to provide feedback 
on their clinical trial experience. 
A participant can be re-screened, for more details please refer to Section 6.3.1. 
As per Section 4.6, during a public health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, the Investigator 
may conduct the informed consent discussion remotely (e.g. telephone, videoconference) if 
allowable by a local Health Authority. Guidance issued by local regulatory bodies on this aspect 
prevail and must be implemented and appropriately documented (e.g. the presence of an 
impartial witness, sign/dating separate ICFs by trial participant or their legally authorized 
representative and person obtaining informed consent, etc).  
In case Home Nursing is implemented during the COVID-19 pandemic or for monitoring of 
FPG (in the Netherlands only), a separate Home Nursing consent document must be 
implemented in addition to the main ICF.  
8 
Visit schedule and assessments 
Assessment schedule Table 8-2 and Table 8-3 lists all of the assessments when they are 
performed. An "X" in the table denotes the assessments to be recorded in the clinical database 
or received electronically from a vendor. An "S", the assessments that are in the participant’s 
source documentation only and do not need to be recorded in the clinical database. 
All data obtained from these assessments must be supported in the participant’s source 
documentation. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-2 and Table 8-3) or as close to the designated day/time as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation. Participants who discontinue 
from study treatment are requested to return for the end of treatment visit as soon as possible, 
and attend the Safety follow-up visit as indicated in the Assessment Schedule. Participants who 
discontinue from study or withdraw their consent/oppose the use of their data/biological 
samples should be scheduled for a final evaluation visit if they agree as soon as possible, at 
which time all of the assessments listed for the end of treatment visit will be performed. At this 
visit, all dispensed investigational product should be reconciled, and the adverse event and 
concomitant medications not previously reported must be recorded on the eCRF. 
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e., pandemic, epidemic or natural disaster that limits or prevents on-site study visits, alternative 
methods of providing continuing care may be implemented by the Investigator as the situation 
dictates. Phone calls, virtual contacts (e.g. teleconsultation) or visits by site staff/ off-site 
healthcare professional(s) staff to the participant´s home if allowable by a local health authority 
and depending on operational capabilities, can replace on-site study visits, for the duration of 
the disruption until it is safe for the participant to visit the site again. If the Investigator delegates 
tasks to an off-site healthcare professional, the Investigator must ensure the individual(s) is/are 

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qualified and appropriately trained to perform assigned duties. The Investigator must oversee 
their conduct and remain responsible for the evaluation of the data collected. 
During the course of the study, test procedures should occur on schedule whenever possible as 
per allowable visit windows specified in Table 8-1 below. 
Table 8-1 
Allowable visit windows 
All assessments during treatment (other than MRI and 
digital photos for disease and response evaluation) 
+/- 7 days (during Year 1 until visit Week 48 included/ 
Core Period and Extension 1); 
+/- 14 days (Starting from visit Week 48 
excluded/Extension period 2) 
PK sampling 
Please refer to Table 8-11, Table 8-12, Table 8-13 
and Table 8-14 in Section 8.5.2.1 
Disease assessment 
MRI/digital photos  
Screening: -42 to -1 days; 
Weeks 16, 24, 40: +/- 7 days; 
Week 48: -7/+30 days; 
Weeks 72, 96 (+/-30 days); 
Starting from visit Week 48 excluded/Extension period 
2): -/+ 30 days 
End of treatment 
< 14 days after permanent discontinuation of study 
treatment 
End of Study (30 days post-treatment safety follow-up 
visit) 
+/- 3 days 
 

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Table 8-2 
Assessment Schedule (≥ 2 years of age)  
Period 
Screenin
g 
Core / Exploratory (Treatment)  
Extension 1 / Exploratory 
(Treatment) 
Extension 2 / Exploratory (Treatment) 
Visit Name 
Screenin
g 
Wee
k 1 - 
Day 
1 
Wee
k 2 - 
Day 
1 
Wee
k 3 - 
Day 
1 
Wee
k 4 
Wee
k 8 
Wee
k 12 
Wee
k 16 
Wee
k 
17-
Day 
1 
Wee
k 20 
Wee
k 24 
Wee
k 28 
Wee
k 32 
Wee
k 36 
Wee
k 40 
Wee
k 44 
Wee
k 48  
Wee
k 72 
Wee
k 96 
Wee
k 
120 
Wee
k 
144 
Wee
k 
168 
Wee
k 
192 
Wee
k 
216 
Days 
-42 
to -1 
-28 
to -
1 
1 
8 
15 
28 
56 
84 
112 113 140 168 196 224 252 280 308 336 504 672 840 1008 1176 1344 1512 
Informed 
consent 
X 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
IRT registration S 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
IRT 
randomization 
(except Groups 
3, 4 and 5)  
  
  
X 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demography 
X 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion / 
Exclusion 
criteria 
  
X 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Eligibility 
Checklist 
(within IRT) 
  
  
S 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Prior PROS 
disease history; 
Prior PROS 
therapies; Prior 
PROS 
surgeries 
X 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical 
history/current 
X 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

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Period 
Screenin
g 
Core / Exploratory (Treatment)  
Extension 1 / Exploratory 
(Treatment) 
Extension 2 / Exploratory (Treatment) 
Visit Name 
Screenin
g 
Wee
k 1 - 
Day 
1 
Wee
k 2 - 
Day 
1 
Wee
k 3 - 
Day 
1 
Wee
k 4 
Wee
k 8 
Wee
k 12 
Wee
k 16 
Wee
k 
17-
Day 
1 
Wee
k 20 
Wee
k 24 
Wee
k 28 
Wee
k 32 
Wee
k 36 
Wee
k 40 
Wee
k 44 
Wee
k 48  
Wee
k 72 
Wee
k 96 
Wee
k 
120 
Wee
k 
144 
Wee
k 
168 
Wee
k 
192 
Wee
k 
216 
Days 
-42 
to -1 
-28 
to -
1 
1 
8 
15 
28 
56 
84 
112 113 140 168 196 224 252 280 308 336 504 672 840 1008 1176 1344 1512 
medical 
conditions 
Prior 
medications 
X 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Non-drug 
therapies / 
Surgical and 
medical 
procedures 
X 
  
Continuous up to 30 days after the last dose of study treatment 
Concomitant 
medications 
X 
  
Continuous up to 30 days after the last dose of study treatment 
Subject 
disposition 
X  
  
X 
Performance 
Status 
(Karnofsky (in 
patients > 16 
years old / 
Lansky ≤ 16 
years old) 
  
X 
X 
X 
 
X 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Height 
  
X 
X1 
  
 
  
  
X1 
  
X1 
  
X1 
  
  
X1 
  
  
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
Body Weight 
  
X 
X 
X 
 
X 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
  
X 
X 
X 
 
X 
X 
X 
  
X 
X 
X  
X 
X 
X  
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
Physical 
Examination 
  
S11  S  
  
 
  
  
S11 
  
  
  
S11 
  
  
S11 
  
  
S11 
S11 
S11 
S11 
S11 
S11 
S11 
S11 

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Period 
Screenin
g 
Core / Exploratory (Treatment)  
Extension 1 / Exploratory 
(Treatment) 
Extension 2 / Exploratory (Treatment) 
Visit Name 
Screenin
g 
Wee
k 1 - 
Day 
1 
Wee
k 2 - 
Day 
1 
Wee
k 3 - 
Day 
1 
Wee
k 4 
Wee
k 8 
Wee
k 12 
Wee
k 16 
Wee
k 
17-
Day 
1 
Wee
k 20 
Wee
k 24 
Wee
k 28 
Wee
k 32 
Wee
k 36 
Wee
k 40 
Wee
k 44 
Wee
k 48  
Wee
k 72 
Wee
k 96 
Wee
k 
120 
Wee
k 
144 
Wee
k 
168 
Wee
k 
192 
Wee
k 
216 
Days 
-42 
to -1 
-28 
to -
1 
1 
8 
15 
28 
56 
84 
112 113 140 168 196 224 252 280 308 336 504 672 840 1008 1176 1344 1512 
Hematology 
  
X 
X 
X 
 
X 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical 
Chemistry 
  
X 
X 
X 
 
X 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting Plasma 
Glucose 
(central) 
 
X 
X 
X 
X10 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1C 
  
X 
  
  
 
  
  
X 
  
  
  
X 
  
  
X 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
Panel (INR, 
PTT, APTT) 
  
X 
  
  
 
  
  
X2 
  
  
  
X2 
  
  
  
X2 
  
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
Hepatitis 
Screen 
  
X 
as clinically indicated 
Urine 
pregnancy test 
(local)  
  
  
 
  
 
S 
S 
S 
  
S 
S 
S 
S 
S 
S 
S 
S 
S 
Monthly15 (S) 
Serum 
pregnancy test 
(central) 
  
X 
S12 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Whole-body 
MRI, Digital 
photography of 
PROS related 
X 
  
  
  
 
  
  
  
X 
  
  
X 
  
  
  
X 
  
X 
X 
X 
 
X 
 
X 
 

Novartis 
 
Confidential 
 
Page 130 of 223 
Amended Protocol Version No.05 (Clean) 
 
Protocol No. CBYL719F12201 
 
Period 
Screenin
g 
Core / Exploratory (Treatment)  
Extension 1 / Exploratory 
(Treatment) 
Extension 2 / Exploratory (Treatment) 
Visit Name 
Screenin
g 
Wee
k 1 - 
Day 
1 
Wee
k 2 - 
Day 
1 
Wee
k 3 - 
Day 
1 
Wee
k 4 
Wee
k 8 
Wee
k 12 
Wee
k 16 
Wee
k 
17-
Day 
1 
Wee
k 20 
Wee
k 24 
Wee
k 28 
Wee
k 32 
Wee
k 36 
Wee
k 40 
Wee
k 44 
Wee
k 48  
Wee
k 72 
Wee
k 96 
Wee
k 
120 
Wee
k 
144 
Wee
k 
168 
Wee
k 
192 
Wee
k 
216 
Days 
-42 
to -1 
-28 
to -
1 
1 
8 
15 
28 
56 
84 
112 113 140 168 196 224 252 280 308 336 504 672 840 1008 1176 1344 1512 
lesions for 
Groups 1 and 2 
Overall clinical 
response 
assessment for 
Groups 1 and 2 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
Whole-body 
MRI, Digital 
photography of 
PROS related 
lesions for 
Group 4 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
X 
 
X 
 
Overall clinical 
response 
assessment for 
Group 4 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
X 
 
X 
 
Whole-body 
MRI, Digital 
photography of 
PROS related 
lesions for 
Group 5 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
X 
 
X 
 
Overall clinical 
response 
assessment for 
Group 5 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
X 
 
X 
 

Novartis 
 
Confidential 
 
Page 131 of 223 
Amended Protocol Version No.05 (Clean) 
 
Protocol No. CBYL719F12201 
 
Period 
Screenin
g 
Core / Exploratory (Treatment)  
Extension 1 / Exploratory 
(Treatment) 
Extension 2 / Exploratory (Treatment) 
Visit Name 
Screenin
g 
Wee
k 1 - 
Day 
1 
Wee
k 2 - 
Day 
1 
Wee
k 3 - 
Day 
1 
Wee
k 4 
Wee
k 8 
Wee
k 12 
Wee
k 16 
Wee
k 
17-
Day 
1 
Wee
k 20 
Wee
k 24 
Wee
k 28 
Wee
k 32 
Wee
k 36 
Wee
k 40 
Wee
k 44 
Wee
k 48  
Wee
k 72 
Wee
k 96 
Wee
k 
120 
Wee
k 
144 
Wee
k 
168 
Wee
k 
192 
Wee
k 
216 
Days 
-42 
to -1 
-28 
to -
1 
1 
8 
15 
28 
56 
84 
112 113 140 168 196 224 252 280 308 336 504 672 840 1008 1176 1344 1512 
Electrocardiogr
am (ECG) 
  
X 
X  
  
 
X 
X 
X 
X 
  
  
X 
  
  
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
Echocardiogra
phy 
  
X 
  
  
 
  
  
  
X2 
  
  
X2 
  
  
  
X2 
  
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
Spirometry4 for 
Groups 1, 2 
and 5  
  
X 
  
  
 
  
  
  
X2 
  
  
X2 
  
  
  
X2 
  
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
Walking 
distance test13 
(except Groups 
3 and 4)  
  
X 
  
  
 
X2 
X2 
  
X2 
  
  
X2 
  
  
  
X2 
  
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
Archival tissue 
for central 
PIK3CA 
mutation 
testing or fresh 
biopsy 5 
X 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
PROMIS profile   
  
X 
  
 
X 
  
  
X 
  
X 
X 
X 
X 
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
Patient Global 
Impression of 
Symptom 
Severity  
  
  
X 
X 
 
X 
X 
  
X 
  
X 
X 
X 
X 
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 

Novartis 
 
Confidential 
 
Page 132 of 223 
Amended Protocol Version No.05 (Clean) 
 
Protocol No. CBYL719F12201 
 
Period 
Screenin
g 
Core / Exploratory (Treatment)  
Extension 1 / Exploratory 
(Treatment) 
Extension 2 / Exploratory (Treatment) 
Visit Name 
Screenin
g 
Wee
k 1 - 
Day 
1 
Wee
k 2 - 
Day 
1 
Wee
k 3 - 
Day 
1 
Wee
k 4 
Wee
k 8 
Wee
k 12 
Wee
k 16 
Wee
k 
17-
Day 
1 
Wee
k 20 
Wee
k 24 
Wee
k 28 
Wee
k 32 
Wee
k 36 
Wee
k 40 
Wee
k 44 
Wee
k 48  
Wee
k 72 
Wee
k 96 
Wee
k 
120 
Wee
k 
144 
Wee
k 
168 
Wee
k 
192 
Wee
k 
216 
Days 
-42 
to -1 
-28 
to -
1 
1 
8 
15 
28 
56 
84 
112 113 140 168 196 224 252 280 308 336 504 672 840 1008 1176 1344 1512 
Patient 
Reported 
Outcome Diary 
 
Start at screening and continuous daily until 
week 166 
  
Daily 
  
  
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
Trial Feedback 
Questionnaire 
 
 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S 
 
 
 
 
 
 
 
Adverse 
Events 
X 
  
Continuous up to 30 days after the last dose of study treatment 
Dental 
assessment 
(<18 years old) 
X 
  
  
  
 
  
  
  
  
  
  
X 
  
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
Hospitalization
s for PROS-
related reasons 
X 
  
Continuous up to 30 days after the last dose of study treatment 
Bone 
development 
assessment 
(<18 years old) 
7 
X8 
  
  
  
 
  
  
  
  
  
  
X9 
  
  
  
  
  
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
Assessment of 
sexual 
X 
  
  
  
 
  
  
  
  
  
  
X 
  
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 

Novartis 
 
Confidential 
 
Page 133 of 223 
Amended Protocol Version No.05 (Clean) 
 
Protocol No. CBYL719F12201 
 
Period 
Screenin
g 
Core / Exploratory (Treatment)  
Extension 1 / Exploratory 
(Treatment) 
Extension 2 / Exploratory (Treatment) 
Visit Name 
Screenin
g 
Wee
k 1 - 
Day 
1 
Wee
k 2 - 
Day 
1 
Wee
k 3 - 
Day 
1 
Wee
k 4 
Wee
k 8 
Wee
k 12 
Wee
k 16 
Wee
k 
17-
Day 
1 
Wee
k 20 
Wee
k 24 
Wee
k 28 
Wee
k 32 
Wee
k 36 
Wee
k 40 
Wee
k 44 
Wee
k 48  
Wee
k 72 
Wee
k 96 
Wee
k 
120 
Wee
k 
144 
Wee
k 
168 
Wee
k 
192 
Wee
k 
216 
Days 
-42 
to -1 
-28 
to -
1 
1 
8 
15 
28 
56 
84 
112 113 140 168 196 224 252 280 308 336 504 672 840 1008 1176 1344 1512 
maturation 
(Tanner 
staging 6 to 
<18 years old)  
IRT Study Drug 
Dispensation 
  
  
S 
  
 
S 
S 
S 
  
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Participant 
Dosing Diary 
  
  
Start at D1 and continues until last dose (S) 
Meal record 
  
  
See Section 8.5.2 for time points of blood collection for alpelisib PK assessment and Section 6.7.2.1 for more details on meal record 
Blood sample 
for Alpelisib PK 
sampling 
  
  
See Section 8.5.2 for time points of blood collection for alpelisib PK assessment applicable for Groups 1&2 (Table 8-11), Group 3  (Table 8-
12), Group 4 (Table 8-13) and Group 5 (Table 8-14). 
Alpelisib/Place
bo 
  
  
Daily 
 
 
 
Period 
Extension 2 / Exploratory (Treatment) End of Study Treatment (Non-Treatment) 
Safety Follow up / End of Study 
Visit Name 
Week 240 
Week 264/End of Study Treatment  
Safety Follow up 
Days 
1680 
1848 
Last dose +30 
Informed consent   
  
  
IRT registration 
  
  
  

Novartis 
 
Confidential 
 
Page 134 of 223 
Amended Protocol Version No.05 (Clean) 
 
Protocol No. CBYL719F12201 
 
Period 
Extension 2 / Exploratory (Treatment) End of Study Treatment (Non-Treatment) 
Safety Follow up / End of Study 
Visit Name 
Week 240 
Week 264/End of Study Treatment  
Safety Follow up 
Days 
1680 
1848 
Last dose +30 
IRT 
randomization 
(except Groups 3, 
4 and 5)  
  
  
  
Demography 
  
  
  
Inclusion / 
Exclusion criteria 
  
  
  
Eligibility 
Checklist (within 
IRT) 
  
  
  
Prior PROS 
disease history; 
Prior PROS 
therapies; Prior 
PROS surgeries 
  
  
  
Medical 
history/current 
medical 
conditions 
  
  
  
Prior medications   
  
  
Non-drug 
therapies / 
Surgical and 
medical 
procedures 
Continuous up to 30 days after the last 
dose of study treatment 
X 
Continuous up to 30 days after 
the last dose of study treatment 
Concomitant 
medications 
Continuous up to 30 days after the last 
dose of study treatment 
X 
Continuous up to 30 days after 
the last dose of study treatment 
Subject 
disposition 
X 
X 
X 
Performance 
Status (Karnofsky 
(in patients > 16 
X 
X 
X 

Novartis 
 
Confidential 
 
Page 135 of 223 
Amended Protocol Version No.05 (Clean) 
 
Protocol No. CBYL719F12201 
 
Period 
Extension 2 / Exploratory (Treatment) End of Study Treatment (Non-Treatment) 
Safety Follow up / End of Study 
Visit Name 
Week 240 
Week 264/End of Study Treatment  
Safety Follow up 
Days 
1680 
1848 
Last dose +30 
years old / Lansky 
≤ 16 years old) 
Body Height 
X1 
X1 
X1 
Body Weight 
X 
X 
X 
Vital Signs 
X  
X 
X 
Physical 
Examination 
S11 
S11 
S11 
Hematology 
X 
X 
X 
Clinical Chemistry X 
X 
X 
Fasting Plasma 
Glucose (central) X 
X 
X 
HbA1C 
X 
X 
X 
Coagulation 
Panel (INR, PTT, 
APTT) 
X2 
X2 
  
Hepatitis Screen 
as clinically indicated 
Urine pregnancy 
test (local)  
Monthly15 (S) 
  
  
Serum pregnancy 
test (central) 
  
X12 
X12 
Whole-body MRI, 
Digital 
photography of 
PROS related 
lesions for Groups 
1 and 2 
X 
X 
  
Overall clinical 
response 
X 
X 
 

Novartis 
 
Confidential 
 
Page 136 of 223 
Amended Protocol Version No.05 (Clean) 
 
Protocol No. CBYL719F12201 
 
Period 
Extension 2 / Exploratory (Treatment) End of Study Treatment (Non-Treatment) 
Safety Follow up / End of Study 
Visit Name 
Week 240 
Week 264/End of Study Treatment  
Safety Follow up 
Days 
1680 
1848 
Last dose +30 
assessment for 
Groups 1 and 2 
Whole-body MRI, 
Digital 
photography of 
PROS related 
lesions for Group 
4 
X 
X 
 
Overall clinical 
response 
assessment for 
Group 4 
X 
X 
 
Whole-body MRI, 
Digital 
photography of 
PROS related 
lesions for Group 
5 
X 
X 
 
Overall clinical 
response 
assessment for 
Group 5 
X 
X 
 
Electrocardiogram 
(ECG) 
X 
X 
X 
Echocardiography X2 
X2 
  
Spirometry4 for 
Groups 1, 2 and 5 X2 
X2 
  
Walking distance 
test (except 
Groups 3 and 4)  
X2 
X2 
  
Archival tissue for 
central PIK3CA 
  
  
  

Novartis 
 
Confidential 
 
Page 137 of 223 
Amended Protocol Version No.05 (Clean) 
 
Protocol No. CBYL719F12201 
 
Period 
Extension 2 / Exploratory (Treatment) End of Study Treatment (Non-Treatment) 
Safety Follow up / End of Study 
Visit Name 
Week 240 
Week 264/End of Study Treatment  
Safety Follow up 
Days 
1680 
1848 
Last dose +30 
mutation testing 
or fresh biopsy 5 
PROMIS profile 
X 
X 
  
Patient Global 
Impression of 
Symptom Severity 
X 
X 
  
Patient Reported 
Outcome Diary 
X 
X 
  
Trial Feedback 
Questionnaire 
 
S 
 
Adverse Events 
Continuous up to 30 days after the last 
dose of study treatment 
X 
Continuous up to 30 days after 
the last dose of study treatment 
Dental 
assessment (<18 
years old) 
X 
X 
 
Hospitalizations 
for PROS-related 
reasons 
Continuous up to 30 days after the last 
dose of study treatment 
X 
Continuous up to 30 days after 
the last dose of study treatment 
Bone 
development 
assessment (<18 
years old) 7 
X9 
X9 
 
Assessment of 
sexual maturation 
(Tanner staging 6 
to <18 years old) 
X 
X 
 

Novartis 
 
Confidential 
 
Page 138 of 223 
Amended Protocol Version No.05 (Clean) 
 
Protocol No. CBYL719F12201 
 
Period 
Extension 2 / Exploratory (Treatment) End of Study Treatment (Non-Treatment) 
Safety Follow up / End of Study 
Visit Name 
Week 240 
Week 264/End of Study Treatment  
Safety Follow up 
Days 
1680 
1848 
Last dose +30 
IRT Study Drug 
Dispensation 
S 
  
  
Participant Dosing 
Diary 
Start at D1 and continues until last dose 
(S) 
  
  
Meal record 
See Section 8.5.2 for time points of 
blood collection for alpelisib PK 
assessment and Section 6.7.2.1 for 
more details on meal record 
  
  
Blood sample for 
Alpelisib PK 
sampling 
See Section 8.5.2 for time points of 
blood collection for alpelisib PK 
assessment applicable for Groups 1&2 
(Table 8-11), Groups 3 & 4 (Table 8-12 
and Table 8-13) and Group 5 (Table 8-
14) 
  
  
Alpelisib/Placebo Daily 
  
  
X Assessment to be recorded in the clinical database or received electronically from a vendor. 
1 <18 yrs only. 
2 Only if impairment associated with PROS identified at screening. 
3 Only if PROS-related clinically meaningful alteration at screening. 
4 Pulmonary Function Test; Spirometry will not be performed in Groups 3 and 4. 
5 If archival block or slides is not available, a fresh biopsy is required for participants in Groups 1, 2 and 5, if it is not clinically contraindicated. For participants in Groups 
3 and 4, a fresh tissue biopsy is not mandatory.  
  
For Germany only: If archival tissue is available, it must be sent to a Novartis-designated central laboratory. If no archival tissue is available, obtaining a fresh tissue 
biopsy is recommended, if it is not clinically contraindicated, but is not mandatory. 
6 Starting 7 days prior to the first dose of study treatment. 
7 Includes assessment of growth plate abnormalities (knee) and skeletal bone age (wrist, hand). 
8 Either X-rays or MRIs of knee, wrist, hand should be performed at screening.  
9 Bone development assessments are required per scheduled protocol timepoints. If there is evidence of thickening or changes in the growth plate at screening, then 
further assessment of bone development should be based on x-rays, as clinically indicated. X-rays can be replaced by MRIs according to institutional standard or if there 
is any clinical contraindication for further assessment of bone development after screening. 
10 Test may be done locally and results of the local laboratory are to be recorded in the eCRF. 

Novartis 
 
Confidential 
 
Page 139 of 223 
Amended Protocol Version No.05 (Clean) 
 
Protocol No. CBYL719F12201 
 
Period 
Extension 2 / Exploratory (Treatment) End of Study Treatment (Non-Treatment) 
Safety Follow up / End of Study 
Visit Name 
Week 240 
Week 264/End of Study Treatment  
Safety Follow up 
Days 
1680 
1848 
Last dose +30 
11 Physical Examination findings for extremities examined are to be recorded in the eCRF. 
12 May be replaced by urine test done locally if participants cannot have a serum pregnancy test done during a public health emergency as declared by Local or Regional 
authorities. 
13 Walking distance test will not be performed in Groups 3 and 4. 
15 Monthly home pregnancy test are allowed 
 
Table 8-3 
Assessment schedule (less than 2 years of age) 
Period 
Screening Core / Exploratory (Treatment)  
Extension 1 / Exploratory 
(Treatment) 
Extension 2 / Exploratory (Treatment) 
Visit Name 
Screening 
Wk 
1 - 
Day 
1 
Wk 
2 - 
Day 
1 
Wk 
3 - 
Day 
1 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
16 
Wk 
17-
Day 
1 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 
36 
Wk 
40 
Wk 
44 
Wk 
48  
Wk 
72 
Wk 
96 
Wk 
120 
Wk 
144 
Wk 
168 
Wk 
192 
Wk 
216 
Days 
-42 
to -1 
-28 
to -1 
1 
8 
15 
28 
56 
84 
112 113 140 168 196 224 
252 280 308 336 504 
672 
840 
1008 1176 1344 1512 
Informed consent 
X 
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
IRT registration 
S 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demography 
X 
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion / 
Exclusion criteria 
  
X 
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Eligibility Checklist 
(within IRT) 
  
  
S 
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Prior PROS 
disease history; 
X 
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

Novartis 
 
Confidential 
 
Page 140 of 223 
Amended Protocol Version No.05 (Clean) 
 
Protocol No. CBYL719F12201 
 
Period 
Screening Core / Exploratory (Treatment)  
Extension 1 / Exploratory 
(Treatment) 
Extension 2 / Exploratory (Treatment) 
Visit Name 
Screening 
Wk 
1 - 
Day 
1 
Wk 
2 - 
Day 
1 
Wk 
3 - 
Day 
1 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
16 
Wk 
17-
Day 
1 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 
36 
Wk 
40 
Wk 
44 
Wk 
48  
Wk 
72 
Wk 
96 
Wk 
120 
Wk 
144 
Wk 
168 
Wk 
192 
Wk 
216 
Days 
-42 
to -1 
-28 
to -1 
1 
8 
15 
28 
56 
84 
112 113 140 168 196 224 
252 280 308 336 504 
672 
840 
1008 1176 1344 1512 
Prior PROS 
therapies; Prior 
PROS surgeries 
Medical 
history/current 
medical conditions 
X 
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Prior medications 
X 
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Non-drug 
therapies / 
Surgical and 
medical 
procedures 
X 
 
Continuous up to 30 days after the last dose of study treatment 
Concomitant 
medications 
X 
 
Continuous up to 30 days after the last dose of study treatment 
Subject disposition 
X 
 
X 
Performance 
Status (Lansky ≤ 
16 years old) 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Length and 
head 
circumference 
 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
Examination 
 
S9 
S 
 
 
 
 
S9 
 
 
 
S9 
 
 
S9 
 
 
S9 
S9 
S9 
S9 
S9 
S9 
S9 
S9 
Hematology 
 
X 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

Novartis 
 
Confidential 
 
Page 141 of 223 
Amended Protocol Version No.05 (Clean) 
 
Protocol No. CBYL719F12201 
 
Period 
Screening Core / Exploratory (Treatment)  
Extension 1 / Exploratory 
(Treatment) 
Extension 2 / Exploratory (Treatment) 
Visit Name 
Screening 
Wk 
1 - 
Day 
1 
Wk 
2 - 
Day 
1 
Wk 
3 - 
Day 
1 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
16 
Wk 
17-
Day 
1 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 
36 
Wk 
40 
Wk 
44 
Wk 
48  
Wk 
72 
Wk 
96 
Wk 
120 
Wk 
144 
Wk 
168 
Wk 
192 
Wk 
216 
Days 
-42 
to -1 
-28 
to -1 
1 
8 
15 
28 
56 
84 
112 113 140 168 196 224 
252 280 308 336 504 
672 
840 
1008 1176 1344 1512 
Clinical Chemistry 
 
X 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting Plasma 
Glucose (central) 
 
X 
 
X 
X8 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1C 
  
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation Panel 
(INR, PTT, APTT) 
  
X1 
 
 
 
 
 
X2 
 
 
 
X2 
 
 
 
X2 
 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
Whole-body MRI, 
Digital 
photography of 
PROS related 
lesions  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
X 
 
X 
 
Overall clinical 
response 
assessment  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
X 
 
X 
 
Electrocardiogram 
(ECG) 
 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Echocardiography 
 
X 
 
 
 
 
 
 
X2 
 
 
X2 
 
 
 
X2 
 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
Archival tissue for 
central PIK3CA 
mutation testing or 
fresh biopsy 4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROMIS profile 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 

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Period 
Screening Core / Exploratory (Treatment)  
Extension 1 / Exploratory 
(Treatment) 
Extension 2 / Exploratory (Treatment) 
Visit Name 
Screening 
Wk 
1 - 
Day 
1 
Wk 
2 - 
Day 
1 
Wk 
3 - 
Day 
1 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
16 
Wk 
17-
Day 
1 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 
36 
Wk 
40 
Wk 
44 
Wk 
48  
Wk 
72 
Wk 
96 
Wk 
120 
Wk 
144 
Wk 
168 
Wk 
192 
Wk 
216 
Days 
-42 
to -1 
-28 
to -1 
1 
8 
15 
28 
56 
84 
112 113 140 168 196 224 
252 280 308 336 504 
672 
840 
1008 1176 1344 1512 
Patient Global 
Impression of 
Symptom Severity  
 
 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Trial Feedback 
Questionnaire 
 
 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S 
 
 
 
 
 
Adverse Events 
X 
 
Continuous up to 30 days after the last dose of study treatment 
Dental 
assessment (<18 
years old) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Hospitalizations for 
PROS-related 
reasons 
X 
 
Continuous up to 30 days after the last dose of study treatment 
Bone development 
assessment (<18 
years old) 5 
X6 
 
 
 
 
 
 
 
 
 
 
X7 
 
 
 
 
 
X7 
X7 
X7 
X7 
X7 
X7 
X7 
X7 
IRT Study Drug 
Dispensation 
 
 
S 
 
 
S 
S 
S 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Participant Dosing 
Diary 
 
 
Start at D1 and continues until last dose (S) 
Meal record 
 
 
See Section 8.5.2 for time points of blood collection for alpelisib PK assessment and Section 6.7.2.1 for more details on meal record 

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Period 
Extension 2 / Exploratory (Treatment) 
End of Study Treatment (Non-Treatment) 
Safety Follow up / End of Study 
Visit Name 
Week 240 
Week 264/End of Study Treatment 
Safety Follow up 
Days 
1680 
1848 
Last dose +30 
Informed consent 
  
  
  
IRT registration 
  
  
  
Demography 
  
  
  
Inclusion / Exclusion 
criteria 
  
  
  
Eligibility Checklist 
(within IRT) 
 
 
 
Prior PROS disease 
history; Prior PROS 
therapies; Prior PROS 
surgeries 
 
 
 
Medical history/current 
medical conditions 
 
 
 
Prior medications 
 
 
 
Non-drug therapies / 
Surgical and medical 
procedures 
Continuous up to 30 days after the last dose 
of study treatment 
X 
Continuous up to 30 days after the last dose of 
study treatment 
Period 
Screening Core / Exploratory (Treatment)  
Extension 1 / Exploratory 
(Treatment) 
Extension 2 / Exploratory (Treatment) 
Visit Name 
Screening 
Wk 
1 - 
Day 
1 
Wk 
2 - 
Day 
1 
Wk 
3 - 
Day 
1 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
16 
Wk 
17-
Day 
1 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 
36 
Wk 
40 
Wk 
44 
Wk 
48  
Wk 
72 
Wk 
96 
Wk 
120 
Wk 
144 
Wk 
168 
Wk 
192 
Wk 
216 
Days 
-42 
to -1 
-28 
to -1 
1 
8 
15 
28 
56 
84 
112 113 140 168 196 224 
252 280 308 336 504 
672 
840 
1008 1176 1344 1512 
Blood sample for 
Alpelisib PK 
sampling 
 
 
See Section 8.5.2 for time points of blood collection for alpelisib PK assessment applicable for Group 3 (Table 8-12) 
Alpelisib 
 
 
Every other day or Daily 

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Period 
Extension 2 / Exploratory (Treatment) 
End of Study Treatment (Non-Treatment) 
Safety Follow up / End of Study 
Visit Name 
Week 240 
Week 264/End of Study Treatment 
Safety Follow up 
Days 
1680 
1848 
Last dose +30 
Concomitant 
medications 
Continuous up to 30 days after the last dose 
of study treatment 
X 
Continuous up to 30 days after the last dose of 
study treatment 
Subject disposition 
X 
X 
X 
Performance Status 
(Lansky ≤ 16 years old) 
X 
X 
X 
Body Length and head 
circumference 
X 
X 
X 
Body Weight 
X 
X 
X 
Vital Signs 
X 
X 
X 
Physical Examination 
S9 
S9 
S9 
Hematology 
X 
X 
X 
Clinical Chemistry1 
X 
X 
X 
Fasting Plasma 
Glucose (central)1 
X 
X 
X 
HbA1C 
X 
X 
X 
Coagulation Panel 
(INR, PTT, APTT) 
X2 
X2 
 
D-dimer and fibrinogen1 
X3 
X3 
 
Whole-body MRI, 
Digital photography of 
PROS related lesions 
X 
X 
 
Overall clinical 
response assessment  
X 
X 
 
Electrocardiogram 
(ECG) 
X 
X 
X 
Echocardiography 
X2 
X2 
 
Archival tissue for 
central PIK3CA 
 
 
 

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Period 
Extension 2 / Exploratory (Treatment) 
End of Study Treatment (Non-Treatment) 
Safety Follow up / End of Study 
Visit Name 
Week 240 
Week 264/End of Study Treatment 
Safety Follow up 
Days 
1680 
1848 
Last dose +30 
mutation testing or 
fresh biopsy 4 
PROMIS profile 
X 
X 
 
Patient Global 
Impression of Symptom 
Severity  
X 
X 
 
Trial Feedback 
Questionnaire 
 
S 
 
Adverse Events 
Continuous up to 30 days after the last dose 
of study treatment 
X 
Continuous up to 30 days after the last dose of 
study treatment 
Dental assessment 
(<18 years old) 
X 
X 
 
Hospitalizations for 
PROS-related reasons 
Continuous up to 30 days after the last dose 
of study treatment 
X 
Continuous up to 30 days after the last dose of 
study treatment 
Bone development 
assessment (<18 years 
old) 5 
X7 
X7 
 
IRT Study Drug 
Dispensation 
S 
 
 
Participant Dosing 
Diary 
Start at D1 and continues until last dose (S) 
 
 
Meal record 
See Section 8.5.2 for time points of blood 
collection for alpelisib PK assessment and 
Section 6.7.2.1 for more details on meal 
record 
 
 

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Period 
Extension 2 / Exploratory (Treatment) 
End of Study Treatment (Non-Treatment) 
Safety Follow up / End of Study 
Visit Name 
Week 240 
Week 264/End of Study Treatment 
Safety Follow up 
Days 
1680 
1848 
Last dose +30 
Blood sample for 
Alpelisib PK sampling 
See Section 8.5.2 for time points of blood 
collection for alpelisib PK assessment 
applicable for Group 3 (Table 8-12) 
 
 
Alpelisib 
Every other day or Daily 
 
 
X Assessment to be recorded in the clinical database or received electronically from a vendor. 
1 Coagulation assessment are ONLY required at screening in case of history of coagulopathy. 
2 Only if impairment associated with PROS identified at screening. Coagulation panel should not be assessed on the same day as hematology (including HbA1C) and 
chemistry panels. 
3 Only if PROS-related clinically meaningful alteration at screening. 
 
 
4 Fresh tissue biopsy not mandatory for participants in Groups 3.  
  
For Germany only: If archival tissue is available, it must be sent to a Novartis-designated central laboratory. If no archival tissue is available, obtaining a fresh tissue biopsy 
is recommended, if it is not clinically contraindicated, but is not mandatory. 
5 Includes assessment of growth plate abnormalities (knee) and skeletal bone age (wrist, hand). 
6 Either X-rays or MRIs of knee, wrist, hand should be performed at screening.  
7 Bone development assessments are required per scheduled protocol timepoints. If there is evidence of thickening or changes in the growth plate at screening, then 
further assessment of bone development should be based on x-rays, as clinically indicated. X-rays can be replaced by MRIs according to institutional standard or if there is 
any clinical contraindication for further assessment of bone development after screening. 
8 Test may be done locally and results of the local laboratory are to be recorded in the eCRF. 
9 Physical Examination findings for extremities examined are to be recorded in the eCRF. 

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8.1 
Screening 
Participants diagnosed with PROS will be consented to the study prior to any study procedures 
being performed. If the participant has been previously treated with systemic PROS-targeting 
therapy, the participant should be discontinued from this treatment before study-related disease 
evaluations at screening (see Section 6.2.2). 
Screening period will begin once the participant has signed the study Informed Consent and 
will be a maximum of 42 days (Day -42 to Day -1). 
Whole-body MRI and other images (e.g., digital photography) will be collected and sent to 
BIRC for review. The Investigators should put all efforts to perform images as early as possible 
during screening. Transfer of images and submission of supplemental clinical information 
should occur as early as Day -42 and no later than Day -15. 
Technical aspects on imaging are provided in the Vendor Site Manual. 
For participants who may have had procedures previously performed as part of the participant’s 
routine disease care (prior to signing study informed consent), the following procedures can be 
used providing that the procedure fulfill the protocol mandated requirements and a proper 
documentation in participant’s file is available: 
• Any imaging assessments within 42 days of start of treatment  
• For eligibility purpose,  
• local laboratory report confirming PIK3CA mutation(s) will be used. The Investigator 
should ensure, that the report from the local laboratory is available and maintained in 
the participant’s source documents. PIK3CA mutation(s) confirmation is required at 
time of inform consent. The participant will be randomized based on local laboratory 
results, a confirmation of PIK3CA mutation(s) by the central laboratory is not 
required. 
• Archival tissue (refer to Table 8-15 in Section 8.5.3.1 for the number of slides required) 
must be provided to be sent to the central laboratory for testing of PIK3CA mutations. 
It is strongly recommended to provide a tissue sample and/or slides in which the initial 
PIK3CA determination was made by the local laboratory, when an archival tissue 
sample is not available, a fresh biopsy is required for participants in Groups 1, 2 and 5, 
if it is not clinically contraindicated, and tissue to be sent to the central laboratory. For 
participants in Groups 3 and 4, if no archival tissue is available, a fresh tissue biopsy is 
not mandatory. 
 
For Germany only: If no archival tissue is available, obtaining a fresh tissue biopsy is 
recommended, if it is not clinically contraindicated, but is not mandatory. 
Details are provided in the Laboratory Manual. 
The written informed consent must be obtained prior to the performance of any screening 
evaluations. Screening procedures are outlined in the visit evaluation schedule (Table 8-2 and 
Table 8-3) including blood samples tested as needed, and assessment of inclusion and exclusion 
criteria. 

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The Investigator or his/her designee must review the results of all screening evaluations, to 
ensure that all inclusion and exclusion criteria have been satisfied prior to enrollment of the 
participant into the study. 
All study procedures should be performed within 42 days (or within 28 days) before treatment 
initiation on Day 1. Screening laboratory assessments may be performed within 28 days of 
treatment initiation, Central Laboratory will be used. When screening laboratory assessments 
are performed within 7 days of treatment initiation, they will not be repeated at Week 1 Day 1. 
A participant who has a laboratory test result(s) that does not satisfy the entrance criteria may 
have the test(s) repeated. These tests may be repeated as soon as the Investigator believes the 
retest result is likely to be within the acceptable range to satisfy the entrance criteria, and can 
be completed within the 28 days screening period. In this case, the participant will not be 
required to sign another ICF, and the original participant ID assigned by the Investigator will 
be used. 
All baseline assessments should be performed on Day 1 as per Table 8-2 and Table 8-3. 
Laboratory assessments performed within 7 days of Day 1 are not required to be repeated at 
Week 1 Day 1. 
A participant is considered a screen failure in the event that the laboratory test(s) cannot be 
available within the screening period, or the retest(s) do not meet the entry criteria or the 
participant’s medical condition has changed significantly during the screening period so that 
the inclusion/exclusion criteria are no longer met (more details are outlined in Section 5). 
Laboratory results from the central laboratory are the only one to be used to determine 
participant’s eligibility to the study with the exception of local PIK3CA results. 
A new study ICF will need to be signed if the Investigator chooses to re-screen the participant 
after a participant has screen failed and a new participant ID will be assigned. All required 
screening activities must be performed when the participant is rescreened for participation in 
the study. An individual participant may only be rescreened once for the study. 
Participants from Groups 1 and 2 meeting all inclusion and none of exclusion criteria will be 
randomized to receive either alpelisib or placebo. Participants from Groups 3, 4, and 5 meeting 
all inclusion and none of exclusion criteria will be enrolled to receive alpelisib treatment in an 
open-label fashion. 
8.1.1 
Eligibility screening 
Following IRT registration at screening, participant eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
The eligibility checklist form must be completed in IRT by the Investigator or designee on Day 
1 prior to starting the treatment phase and receiving the first dose of study drug. Verification of 
all eligibility criteria must be done prior to contacting IRT. After the eligibility has been checked 
in IRT and confirmed that the participant is eligible for the study, then the participant can be 
assigned to a dose based on age and enrolled/randomized into the treatment phase of the study. 
Please refer and comply with detailed guidelines in the IRT manual. 

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8.1.2 
Information to be collected on screening failures 
Participants who sign the informed consent form and subsequently are found to be ineligible 
will be considered a screen failure. 
The reason for screen failure should be recorded on the Disposition CRF page. The 
demographic information, informed consent, and inclusion/exclusion and Disposition pages 
must also be completed for screen failure participants. No other data will be entered into the 
clinical database for participants who are screen failures, unless the participant experienced a 
serious adverse event during the screening phase (see Section 8.4). 
If the participant fails to be randomized/start treatment, the IRT must be notified within 2 days 
of the screen fail, that the participant was not randomized/enrolled in the treatment phase. Data 
and samples collected from participants prior to screen failure may still be analyzed. 
Participants who are randomized and fail to start treatment, e.g., participants randomized in 
error, will be considered an early terminator. The reason for early termination should be 
recorded on the appropriate eCRF. 
8.2 
Participant demographics/other baseline characteristics 
Participant demographic and baseline characteristics data will be collected on all enrolled 
participants: 
• Demography (gender, age, race and ethnicity as allowed by local regulations, height [or 
length and head circumference for 0-2 years of age] and weight). Participant race and 
ethnicity are collected and analyzed to identify variations in safety or efficacy due to these 
factors as well as to assess the diversity of the study population as required by Health 
Authorities. 
• Disease baseline characteristics including diagnosis, anatomic and functional extent of 
disease, prior PROS history (including clinical manifestation of PROS, disease extent and 
PROS related functional impairment), prior PROS therapies and previous/ foreseen surgical 
and/or other interventions. 
• Medical History other than PROS; Current medical conditions present before signing the 
informed consent. Investigators will have the discretion to record clinically significant 
laboratory abnormalities on the appropriate eCRF whenever, in their judgment, the test 
abnormality occurred prior to the informed consent signature. 
• Prior/concomitant therapy. 
• Availability of archival tissue for central testing of PIK3CA mutations. When archival tissue 
sample is not available, a fresh biopsy is required for participants in Groups 1, 2 and 5, if it 
is not clinically contraindicated. For participants in Groups 3 and 4, a fresh tissue biopsy is 
not mandatory (See details in Section 8.5.3).  
• Clinical Outcome Assessments including participant-reported outcome questionnaires (see 
Section 8.5.1).  
Furthermore, the following assessments will be performed to assess the eligibility of the 
participant: 
• Vital signs including body temperature, blood pressure and pulse 
• Karnofsky or Lansky performance status 

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• ECG (12 lead, in triplicate) 
• Cardiac imaging (echocardiography) 
• Lung function test (spirometry) (not applicable for Groups 3 and 4 and replaced by chest 
MRI images) 
• Disease evaluation (anatomic and functional extent of the disease) 
• Laboratory evaluations  
• Complete physical examination (including neurologic assessment of central and peripheral 
nervous systems as per local standards, as well as assessment of functioning of 
extremities)  
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF. 
8.3 
Efficacy 
The phenotypic variability of PROS is broad in terms of the overgrowth localization, number 
of lesions and affected limb/trunkal sites, disease progression, and severity of the impact on the 
participant everyday life, mobility, organ function and quality of life. Standard criteria for 
response assessment are not yet established. Primary efficacy in the study will be determined 
based on radiological response of PROS lesions assessed by BIRC. 
Definition of target and non-target lesions 
Target lesion is defined as anatomically reproducibly defined tissue(s) masses, which may be 
composed of one or several tissue types, and can be accurately measured by imaging technique 
MRI. Target lesion(s) (up to 3) should be identified at screening, be at least 2 cm in the longest 
diameter at baseline (for each selected lesion) and may be further reproducibly assessed by 
MRI. All selected target lesions must be associated with at least one of the following: 
participant's complaints, clinical symptoms, impaired organ function, functional limitations 
affecting participant's everyday life. Clinically meaningful PROS-related vascular anomalies 
(for instance, vascular malformations) may qualify for target lesion when they may be 
accurately measured (by volumetric technique). Macrocephaly must not qualify for target 
lesion. The volume of these lesions will be measured at each MRI assessment during the study. 
The same imaging modality must be used throughout the study. 
All lesions which do not qualify for target, measurable or not, will be considered non-target, to 
demonstrate response for anatomic PROS lesions and/or anatomic areas affected by the disease. 
In addition to MRI, the Investigator may select the other additional appropriate, accurate and 
informative method(s) to evaluate the response objectively: imaging technique and/or digital 
photography accompanied with measuring with caliper/ruler when applicable. 
Non-target lesions are all other PROS-related anatomic changes (lesions, affected limb/trunkal 
areas, organomegaly) and may include the following: 

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MRI-measurable non-target lesions 
All anatomic lesions other than selected as target and may be measured at radiologic assessment 
(at least 2 cm in the longest diameter at baseline, the volume may be further reproducibly 
assessed by MRI). 
Other non-target lesions 
Anatomic lesions, limb/trunkal areas affected by PROS, organomegaly when they may be 
measured only by caliper/ruler (e.g., circumference of changed limb or body part) 
Truly non-measurable lesions (e.g., small lesions less than 2 cm on MRI, superficial visual 
lesions, masses, organomegaly, PROS-related enlargement of anatomic area identified by 
physical exam that is not measurable by reproducible imaging technique) 
Selection of target and non-target lesions at screening: 
Whole-body MRI without contrast is mandated at baseline. In addition, focused MRI imaging 
may be required to adequately assess small anatomic areas with PROS lesions. All images 
(MRI, digital photography) will be submitted to BIRC and reviewed centrally. Review of the 
screening MRI will assess and confirm the presence of at least one lesion qualifying for target 
and this will be communicated to the site before randomization. When the Investigator 
disagrees on the presence or absence of target lesion, an adjudication process will apply. The 
adjudicator will make a final decision. (Additional details will be described in the BIRC 
Charter). 
8.3.1 
Evaluation of response of PROS lesions 
Definitions of response and progression of PROS lesions: 
Response of PROS lesions will be determined based on response of target lesion(s) (changes in 
volume will be assessed by MRI) and non-target lesions (assessed by MRI, digital photography, 
manual measurements with caliper/ruler, clinical examination of superficial visual lesions 
including size, thickness, circumference, coloration, other applicable parameters based at the 
discretion of the Investigator). The same modality must be used throughout the study. 
For primary efficacy, the response of PROS lesions will be evaluated by BIRC. It is defined as 
achieving ≥ 20% reduction from baseline in the sum of target lesion volumes (1 to 3 target 
lesions, via BIRC) confirmed by a subsequent imaging assessment performed at least 4 weeks 
after the onset of the response, provided that none of the individual target and/or MRI-
measurable non-target lesions has ≥ 20% increase from baseline and in absence of progression 
of other non-target lesions and without new lesions. 
For secondary efficacy in Groups 1 and 2, the response of PROS lesions will be evaluated by 
BIRC in similar way at Weeks 16, 24, 40, 48, 72, 96 and then every 48 weeks during the study. 
For exploratory Group 3, the response of PROS lesions will be evaluated by BIRC in similar 
way at Weeks 24, 48, 72, 96 and then every 48 weeks during the study. 

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For exploratory Group 4, the response of PROS lesions will be evaluated by BIRC in similar 
way at Weeks 24, 48, 72, 96 and then every 48 weeks during the study. 
For exploratory Group 5, the response of PROS lesions will be evaluated by BIRC in similar 
way at Weeks 16, 24, 48, 72, 96 and then every 48 weeks during the study. 
If disease progression is suspected for any patients, an MRI must be taken as soon as feasible 
and within the coming 3 months maximum. 
Progression of PROS lesions will be recorded when at least one of the following criteria are 
met: 
• Increase of ≥ 20 % of the volume of target and/or MRI-measurable non-target PROS lesions 
relative to baseline at any timepoint of efficacy evaluation, otherwise to nadir (defined as 
best achieved response) 
• Progression of other non-target PROS lesions 
• Appearance of a new PROS lesion(s) (when the new lesion is at least 1 cm long and clearly 
attributed to PROS) 
Relative to other non-target lesions, response of each of non-target lesion identified at screening 
will be assessed individually during BIRC review, then the reviewer will make a conclusion if 
overall level of non-target disease burden decreased or increased meaningfully and evaluate the 
status of all non-target lesions as improvement, stable, progression. 
Evaluation of PROS lesions for response by BIRC:  
The Investigators will send all MRI and other images (including but not limited to digital 
photographs), as well as information about clinical relevance of PROS lesions to 
BIRC performing central imaging review for the study. Two radiologists at BIRC (each will be 
a qualified different independent reader from the designated vendor) will perform their own 
review of images (e.g., MRI, digital photographs) to assess response of PROS lesions (both 
target and non-target, occurrence of new lesion(s)) throughout the study. In case of 
disagreement between the two readers, an adjudication will be performed. An adjudicator will 
review the assessment of both readers and will make a final decision about the evaluation of 
PROS lesion response. These evaluations will be independent and will be used for the purpose 
of primary and secondary endpoints. 
BIRC evaluations will not be communicated to the Investigator (unless the Investigator suspects 
progression and specifically request BIRC to confirm the fact of radiologic progression). A 
process of keeping independence of reviewers will be applied and defined in the BIRC charter. 
Evaluation of overall clinical response (by Investigators):  
The Investigators will review the MRI and other images (including but not limited to digital 
photographs), assess the PROS lesion radiological response applying the above response 
criteria, will review the results from other assessments performed at response evaluation time 
point, and make their clinical judgement on overall clinical response: if the condition of the 
participant, in general, has been improved, remained stable, or worsened compared to Baseline 
assessment. Clinical management of the patients will be based on the Investigator assessment 
of the radiological response combined with assessment of the participants' general condition.  

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Improvement will be registered when ALL of the following criteria are met: 
• Reduction in PROS lesions (by local review) 
• Clinical improvement (by Investigator, clinically relevant improvement in at least one of 
the following: participant's complains, clinical symptoms, impaired organ function, 
functional limitations affecting patient's everyday life 
• Absence of PROS-related severe or life-threatening complications 
Worsening will be registered when at least ONE of the following criteria are met: 
• Growth in PROS lesions qualifying for progression (by local review) 
• Clinical deterioration (assessed by the Investigator, clinically relevant worsening in at least 
one of the following: patient's complains, clinical symptoms, impaired organ function, 
functional limitations affecting participant's everyday life 
• PROS-related severe or life-threatening complications (assessed by the Investigator; 
including but not limited to rescue surgery, bleeding Grade ≥2, thromboembolic event 
Grade ≥2, uncontrolled severe or life threatening organ dysfunction, other severe medical 
event, which is, in opinion of the Investigator, certainly caused by progressing PROS) 
The overall clinical response will be assessed as stable disease when none of the above are met.  
Clinical management of the participants will be based on the Investigator assessment of overall 
clinical response combining the radiological response as assessed locally and assessment of the 
participant’s general condition. If Investigator suspect a radiological progression of the PROS 
lesions as defined above at any timepoint of efficacy evaluation, Investigator must require BIRC 
to confirm the radiological progression in an expedited fashion. If radiological progression is 
not confirmed by BIRC, the patient should continue study treatment until next PROS lesion 
assessment if not clinically contra-indicated. If radiological progression is confirmed by BIRC, 
Investigator will assess the clinical condition of the patient. Progression of the disease 
corresponds to the worsened condition of the participant per Investigator’s assessment of 
overall clinical response. For more information on treatment beyond progression, please refer 
to Section 6.1.5.1 
Methods of evaluation for PROS lesions  
Magnetic Resonance Imaging (MRI):  
Whole-body MRI without contrast is proposed to be the primary method for the assessment of 
the changes in the volumes of the lesions and is mandatory at baseline. Whole-body MRI is also 
recommended to be performed at all scheduled imaging time points. If this is not feasible, at 
least the lesions identified at baseline by the Investigator should be captured. Additionally, 
focused MRI imaging may be required to adequately assess small anatomic areas with PROS 
lesions. MRI is a precise and sensitive imaging method to detect volumetric changes in different 
types of tissues, which may be affected by the disease (fibro-fatty, muscular, and/or bony 
overgrowth). MRI is also the preferable imaging in pediatric participants, as it does not expose 
to radiation. MRI may also apply to assessment of non-target lesions when the Investigator 
considers it the most appropriate, informative and accurate method. For small and truly non-
measurable PROS lesions, MRI will still be a preferred method of assessment. 

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Technical aspects on imaging are provided in the Vendor Site Manual. 
For Groups 1 and 2, MRI of the whole-body will be performed at screening, at Week 16, 24, 
40, 48, 72, 96 and then at other time points of response assessment. For Group 3 and 4, MRI of 
the whole-body will be performed at screening, at Week 24, 48, 72, 96 and then at other time 
points of response assessment. For Group 5, MRI of the whole-body will be performed at 
screening, at Week 16, 24, 48, 72, 96 and then at other time points of response assessment. At 
the End of treatment, an MRI will also be performed for all participants if not performed within 
last 8 weeks during Year 1 (until visit Week 48 included), and within last 3 months during Year 
2 - Year 5. 
At any time during the study, if disease progression is suspected for any participants, an MRI 
must be taken as soon as feasible and within the coming 3 months maximum.  
In addition, in the event of a dose increase for response optimization, an MRI has to be 
performed after 3 months to assess the benefit of the increased dose and to potentially guide for 
further optimization.  
In the event of a surgery due to PROS lesions, an MRI must be performed, prior to the 
procedure. No additional MRI is required if an existing MRI was already performed within 4 
weeks of the surgical procedure. 
PROS lesions, which are defined as non-target (e.g., non-measurable vascular anomalies, skin 
lesions, superficial visual lesions, enlargement of anatomic area related to PROS spectrum) and 
may not be assessed by MRI, should be evaluated with the use of digital photography 
accompanied with measurements by caliper/ruler when applicable. 
Digital photography:  
Digital photographs will include: 
• Images of the whole-body (front, both sides, back) 
• Images of the body parts changed due to PROS when applicable 
• Images of PROS-related skin/superficial visual lesions and/or other lesions which may not 
be assessed by MRI 
Photographs should be taken by a high resolution digital camera (≥3 megapixels), a caliper or 
ruler should be included in the photo whenever possible. The photographs will be performed at 
screening and repeated further at response evaluation time points and at the End of treatment. 
These digital photographs will be used solely to document the response to study treatment of 
PROS-related target non-measurable and non-target anatomic lesions changing the body parts 
as well as response of skin/superficial visual anatomic lesions. These digital photographs should 
be sent to the central review facility for review and archiving. 
The imaging assessment collection plan is presented in Table 8-4. 
Table 8-4 
Imaging Assessment Collection Plan 
Assessment 
Screening/Baseline 
Treatment 
• 
Whole-body MRI 
• 
Digital photography 
Mandated within 42 days prior 
to randomization 
For Groups 1 and 2: Mandated, 
at Week 16, 24, 40 (+/- 7 days); 

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Assessment 
Screening/Baseline 
Treatment 
• Linear measurement with 
scale/ruler when applicable 
at Week 48 (- 7/+30 days); 
at Week 72, 96 (+/-30 days);and every 
48 weeks (+/- 30 days) thereafter until 
Week 264 (End of Treatment). 
For Group 3 and 4: Mandated, 
at Week 24 (+/- 7 days); 
at Week 48 (- 7/+30 days); 
at Week 72, 96 (+/-30 days); 
and every 48 weeks (+/- 30 days) 
thereafter until Week 264 (End of 
Treatment). 
For Group 5: Mandated, 
at Week 16, 24 (+/- 7 days); 
at Week 48 (- 7/+30 days); 
at Week 72, 96 (+/-30 days); 
and every 48 weeks (+/- 30 days) 
thereafter until Week 264 (End of 
Treatment). 
 
8.3.2 
Other assessments for PROS 
Assessment of changes in symptoms and complications/comorbidities associated with 
PROS over time. 
Information on complaints, PROS-related symptoms, PROS-related complications (including 
taken treatment measures) and comorbidities will be collected at baseline and then at every time 
point for response assessment. In participants with cardiac function, pulmonary function 
impaired because of PROS, echocardiography (see Section 8.4.2.1) and spirometry  
(see Section 8.5.5) will be performed as a part of efficacy assessment(s), to demonstrate changes 
from baseline. 
Assessment of the frequency of hospitalizations/surgeries  
Information about the frequency of healthcare visits/hospitalizations, surgeries, invasive 
procedures, interventions due to PROS, surgeries (including type and intent, e.g., rescue 
surgery, radical surgery) and/or actions other than study treatment required to manage PROS 
(including avoidance/delay in planned disease-related surgery) will be collected at baseline and 
then at every time point for response assessment. The Investigators may in addition collect all 
other information about PROS-related treatment considered medically relevant. 
Assessment of mobility and a need to use additional tools to enable mobility 
Assessment of mobility will be performed at screening and then for those participants who have 
PROS-related impairment of mobility after 4 and 8 weeks of initial treatment, and then at 
efficacy assessment time points. In addition to 2 Min Walking Distance Test, information on 
the participant need to use additional supporting tools to enable mobility (for instance, walking 

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stick, moving chair), will be collected when applicable. Walking Distance Test will not be 
performed in participants in Groups 3 and 4 (less than 6 years old).  
8.3.3 
Blinded Independent Review Committee (BIRC) assessment 
BIRC is set up for this study with the mission to evaluate efficacy data related to PROS lesions 
response in the study. The central review of the images will be carried out in a blinded fashion. 
The decision regarding participant management will remain with the Investigators. Imaging 
data will be centrally collected and checked for quality by an imaging Contract Research 
Organization (CRO) designated by Novartis. This CRO has been contracted to provide an 
independent selection of target and non-target PROS lesions at screening and evaluation of 
PROS lesions for response in each participant enrolled in this study. The assessment of the 
presence or absence of a measurable lesion qualifying for target by BIRC will be provided to 
Investigator during the screening period to confirm PROS lesion-specific eligibility of the 
patient. The BIRC assessment of PROS lesion response during the study treatment will not be 
communicated to the Investigator. The only exception will be when the Investigator will require 
BIRC to confirm a disease progression suspected on the local assessment of the MRI. A process 
of keeping independence of reviewers will be applied and defined in the charter. The clinical 
management of the patient will be based on the PROS lesions radiological response assessed 
by the Investigator (except Core period of the study where progression of the lesions must be 
confirmed by BIRC for making treatment decision) and the associated clinical manifestations.  
Details on the independent central imaging review process will be described in BIRC Charter.  
8.3.4 
Appropriateness of efficacy assessments 
Substantial efforts over the past 20 years were invested in the clinical delineation of mosaic or 
segmental overgrowth disorders; in particular, preliminary recommendations for a uniform 
approach to a clinical evaluation of PROS were determined as an outcome of the workshop in 
Bethesda, Maryland, in September 2013. The clinical diagnostic criteria for PROS will be 
utilized to assess all spectrum of findings related to the disease at screening in our study 
(Keppler-Noreuil et al 2016). 
The uniformed protocols on PROS disease evaluation, definitions for clinical severity of 
disease, as well as criteria defining key characteristics of PROS lesions for further evaluation 
of response, and criteria for response assessment are not established. Disease assessments in 
routine clinical practice vary depending on participant characteristics, site experience and local 
practices. Because of these reasons and taking into consideration the high variability of the 
disease phenotype, methods of efficacy assessments selected for this study are expected to cover 
all clinically relevant characteristics of the disease. 
The primary/key secondary objectives are to demonstrate the efficacy of alpelisib as measured 
by the proportion of participants with confirmed objective response (primary) and response at 
Week 16 (key secondary) by BIRC for Group 2 (6 - 17 yr-old) and for Group 1 (≥ 18 yr-old). For 
details, please refer to Section 2, Table 2-1, Section 8.3, Section 12. 
Evaluation of PROS lesions for response will be done by BIRC with the use of MRI and digital 
photography. MRI will be the primary and preferred method of response evaluation. This highly 
informative method allows performing volumetric measurements in an accurate, reproducible 

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and consistent manner. It is acknowledged that it might be difficult to collect the volumes for 
all existing PROS lesions/areas, digital photographs will be also performed with the purpose to 
collect information on changes in existing visual PROS lesions and get supporting information 
about changes in disease burden. When possible, linear measurements will accompany digital 
photos. All images will be reviewed centrally by a BIRC. Methods of PROS lesions evaluation 
for response in this study are consistent with published case series and evaluations utilized in 
other studies in PROS indication.  
Overall clinical response will be assessed by the Investigators. They will make the conclusion 
based on response of PROS anatomic lesions/affected areas assessed locally and their 
assessment of other clinical parameters in the individual participants as following: 
• Changes in PROS-related symptoms and complications/comorbidities based on clinical 
evaluation, supported by other examinations (e.g., echocardiography to be used in those 
participants who have at screening LVEF clinically meaningful decreased due to PROS, 
spirometry to be used when lung function is affected due to PROS) 
• Information about type and outcome of hospitalizations for PROS when happens 
• Information about type and outcome of surgery to manage PROS when happens 
In addition, patient reported outcomes will be assessed with usage of PRO measures with 
evidence to support their content validity in PROS [Worst Pain Intensity (adapted from BPI and 
Wong-Baker Faces Scale) as collected with the PRO Diary, PROMIS profile (Patient Reported 
Outcome Measurement Information System), participant Global Impression of Symptom 
Severity] 
. 
The study considers a possibility to individualize the plan of assessments in the individual 
participants based on existing signs of the disease, after evaluation of disease burden during 
screening and making a conclusion on clinical relevance of the certain findings. For additional 
information, and the details please refer to Section 4.1, Section 8.3, Section 8.5. 
8.4 
Safety 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
Safety will be monitored by assessing physical examination, vital signs, performance status 
(refer to Table 8-5), ECG,5 cardiac function evaluation by echocardiography/ECHO, laboratory 
testing (hematology, coagulation, serum chemistry, and urinalysis6) as well as routine safety 
monitoring of AEs and SAEs. For details on adverse event collection and reporting, refer 
to Section 10. 
CTCAE version 4.03 will be used throughout the study to allow pooling of safety data at the 
alpelisib program level. 

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As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented. Regular phone or virtual 
calls will occur (at the time of every scheduled visit or more frequently if needed) or visits by 
site staff/home nursing service to the participant´s home depending on local regulations and 
capabilities, for safety monitoring and discussion of the participant´s health status until the 
participant can again visit the site.  
Table 8-5 
Assessments & Specifications 
Assessment 
Specification 
Physical 
examination 
A complete physical examination will include the examination of general appearance, 
skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, vascular, and neurological. If indicated based on medical 
history and/or symptoms, rectal, external genitalia, breast, and pelvic exams will be 
performed. 
Physical examination will include information on clinical manifestations of PROS. 
Complications of PROS depend on the anatomical site and extent of overgrowth, and 
may include functional impairment amongst other manifestations all of which may be 
debilitating, and cause early mortality. 
A short physical exam will be done at all visits as indicated in Table 8-2, Table 8-3 and 
Table 8-1, starting during treatment except where a complete physical examination is 
required. It will include at least the examination of general appearance and vital signs 
(blood pressure [Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)] and 
pulse). If indicated based on symptoms, additional exams will be performed. Information 
for all physical examinations must be included in the source documentation at the study 
site. Clinically relevant findings that are present prior to signing informed consent must be 
recorded on the appropriate CRF. Significant findings made after signing informed 
consent which meet the definition of an Adverse Event must be recorded as an adverse 
event. 
Vital signs 
Vital signs include blood pressure (supine position preferred when ECG is collected), 
pulse measurement, and body temperature. 
During the COVID-19 pandemic that limits or prevents on-site study visits or if visits by 
site staff to a participant’s home are not feasible, the measurements of vital signs may be 
modified by Novartis and will be communicated to the Investigator (e.g., local vital sign 
measurements).  
Height and weight 
Height in centimeters (cm) [or length and head circumference for 0-2 years of age] and 
body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, but without shoes) will be 
measured as specified in Table 8-2, Table 8-3 and Table 8-1. 
Performance status 
Performance status will be assessed at baseline and then at every efficacy assessment time 
points, to document changes in performance status measured with use of Karnofsky/Lansky 
scores as described in Table 8-2 and Table 8-3. 
8.4.1 
Laboratory evaluations 
Clinical laboratory analyses (hematology, biochemistry, coagulation, fasting lipid 
panel/glucose, HbA1C and pregnancy test) are to be performed by the central laboratory 
designated by Novartis as outlined in Table 8-6 and as per assessment schedule in Table 8-2 
and Table 8-3. In case of urgent safety management of hyperglycemia, fasting plasma glucose 
assessment may be allowed locally according to the schedule of assessments and collection plan 

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For assessment of participants’ eligibility to the study, only laboratory results 
from the central laboratory will be used 
At any time during the study, abnormal laboratory parameters which are clinically relevant and 
require an action to be taken with study treatment (e.g., require dose modification and/or 
interruption of study treatment, lead to clinical symptoms or signs, or require therapeutic 
intervention), whether specifically requested in the protocol or not, will be recorded on the 
eCRF page. Additional analyses are left to the discretion of the Investigator. 
Visit windows as per Table 8-1 are allowed. Novartis must be provided with a copy of the local 
laboratory’s certification (if applicable), and a tabulation of the normal ranges and units of each 
parameter collected in the eCRF. Any changes regarding normal ranges and units for laboratory 
values assessed during the study must be reported via an updated tabulation indicating the date 
of revalidation. Additionally, if at any time a participant has laboratory parameters obtained 
from a different laboratory, Novartis must be provided with a copy of the certification and a 
tabulation of the normal ranges and units for this laboratory as well. The Investigator is 
responsible for reviewing all laboratory reports for participants in the study and evaluating any 
abnormalities for clinical significance. 
Table 8-6 
Central clinical laboratory parameters collection plan 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, Differential 
(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, (absolute value 
preferred, %s are acceptable) 
Fasting Chemistry 
Albumin, Alkaline phosphatase, ALT, AST, Gamma-glutamyl-transferase (GGT), 
Lactate dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, Phosphorus, 
Chloride, Sodium, Potassium, Creatinine, Creatine kinase, Direct Bilirubin, Indirect 
Bilirubin, Total Bilirubin, Total Protein, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, 
Amylase, Lipase, Glucose 
Fasting Lipid panel 
Total Cholesterol, Low density lipoprotein (LDL), High density lipoprotein 
(HDL), Triglycerides 
Coagulation 
International normalized ratio [INR]), Partial thromboplastin time (PTT) or Activated 
partial thromboplastin time (APTT), 
 
Additional tests 
Hepatitis at screening (except for participants < 2 years of age), HbA1c 
Pregnancy Test 
for women of child-
bearing potential 
Serum human chorionic gonadotropin (hCG) (central laboratory at screening, EOT 
and 30 days safety follow up), serum (local laboratory at Week 1 Day 1), urine (at 
other visits) 
8.4.2 
Electrocardiogram (ECG) 
Electrocardiograms (ECGs) must be recorded after 10 minutes rest in the supine position to 
ensure a stable baseline. ECGs are to be performed in triplicate with a minimal interval of 1 
minute between the end of one trace and the start of another. The preferred sequence of 
cardiovascular data collection during study visits is ECG collection first, followed by vital 
signs, and blood sampling. The Fridericia QT correction formula (QTcF) must be used for 
clinical decisions. 
Triplicate 12 lead ECGs are collected at each time point (as specified in7 Table 8-7) with ECG 
machines available at the site. Pre-dose ECGs should be performed on the day of the visit; time 
window should allow to perform ECG in triplicate, review it and assess QTcF before dosing. 

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Visit 
Day 
Timing 
ECG type 
Safety Follow-up 
Last dose + 30 
Anytime 
12 Lead, Triplicate 
Unscheduled or Unplanned sample 
Anytime 
12 Lead, Triplicate 
Interpretation of the tracing will be made locally by a qualified physician and documented on 
the appropriate CRF. Each ECG tracing should be labeled with the study number, participant 
initials (where regulations permit), participant number, date, and kept in the source documents 
at the study site. Clinically significant abnormalities present at screening should be reported on 
the appropriate CRF. Clinically significant findings detected at screening must be discussed 
with Novartis prior to enrolling the participant in the study. New or worsened clinically 
significant findings occurring after informed consent must be recorded as adverse events. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the Investigator at 
any time during the study as clinically indicated. Local cardiologist ECG assessment may also 
be performed at any time during the study at the discretion of the Investigator. 
Paper ECGs should be appropriately labeled and the original kept in the source documents at 
the study site. If an unscheduled ECG is performed at an external medical facility, a copy of the 
ECG should be obtained and a copy kept in the source documents at the study site. 
Clinically significant ECG abnormalities present at screening should be reported on the 
appropriate CRF. New or worsened clinically significant findings occurring after informed 
consent must be recorded as adverse events. 
8.4.2.1 
Cardiac imaging: Echocardiography 
An echocardiography is an ultrasound of the heart, which uses high-pitched sound waves to 
produce an image of the heart. It is used to evaluate cardiac chamber size, wall thickness, wall 
motion, valvular anatomy, valve motion, the proximal great vessels and the pericardium. A 
wide variety of cardiac diseases can be diagnosed echocardiographically, the severity of the 
disease ascertained and a prognosis for life derived. Echocardiography has increased the 
diagnostic accuracy of noninvasive cardiac evaluation and provides a tool for the monitoring of 
diagnostic and therapeutic procedures. 
The left ventricular ejection fraction (LVEF) will be evaluated by echocardiography at 
Screening and at EOT. Additional cardiac imaging during treatment is to be performed if 
indicated by clinical signs or symptoms. 
In those participants, who have PROS-related clinically relevant decrease of LVEF and are 
considered eligible after a consultation with Novartis, echocardiography will be used as a part 
of efficacy assessment for secondary endpoints (for more details, please refer to Section 8.3.2). 
The same imaging modality should be used. 
8.4.3 
Pregnancy and assessments of fertility 
A condom and/or highly effective methods of contraception is required for all sexually active 
male participants to prevent them from fathering a child AND to prevent delivery of study 
treatment via seminal fluid to their partner from the date of receiving alpelisib until at least one 
week after the last dose received. In addition, male participants should not donate sperm during 
this time. 

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All pre-menopausal women of child-bearing potential who are not surgically sterile will be 
required to use highly effective contraception (see Section 5.2) and have pregnancy testing. 
When pregnancy testing is required, a serum pregnancy test (central laboratory) will be 
performed at screening, EOT and 30 days safety follow up, a serum (local laboratory) at Week 
1 Day 1 and urine pregnancy test at other visits.  
Any local positive serum test needs to be confirmed with a central serum test. If positive, the 
participant must be discontinued from study treatment. 
Additional pregnancy testing might be performed if requested by local requirements. If a 
positive pregnancy test is obtained in between study visits, the participant must immediately 
notify the Investigator. 
If participants cannot visit the site to have serum pregnancy tests during a public health 
emergency as declared by Local or Regional authorities i.e., pandemic, epidemic or natural 
disaster, that limits or prevents on-site study visits, urine pregnancy test kits may be used. 
Relevant participants can perform the urine pregnancy test at home and report the result to the 
site. It is important that participants are instructed to perform the urine pregnancy test first and 
only if the test result is negative proceed with the administration of the study treatment. A 
communication process should be established with the participant so that the site is informed 
and can verify the pregnancy test results (e.g., following country specific measures). 
Assessments of Fertility 
Females of child-bearing potential are defined as all females physiologically capable of 
becoming pregnant. This includes pediatric participants who are menarchal or who become 
menarchal during the study. All menarchal girls and their parents/caregivers should be informed 
about the potential risks of pregnancy and the need to prevent pregnancy during the study. 
Female participants of child-bearing potential who are or might become sexually active, must 
be informed of the potential teratogenic risk with alpelisib and the need for highly effective 
contraception to prevent pregnancy while on alpelisib therapy. 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child-
bearing potential must also be available as source documentation in the following cases: 
1. Surgical bilateral oophorectomy without a hysterectomy 
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, Follicle Stimulating Hormone (FSH) 
testing is required of any female participant regardless of reported reproductive/menopausal 
status at screening/baseline. 
For females in the pediatric groups, an assessment of fertility should be made at the discretion 
of the Investigator, but in all girls of the age of 16 years and above. 

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8.4.4 
Other safety evaluations 
Height/length and Body Mass Index (BMI) will be assessed in pediatric participants, using 
the standard deviation scores (SDS, also called z-score), growth velocity and velocity SDS. 
SDS will be calculated based on published referenced height/length and BMI information. 
Sexual maturation assessment will be performed in all pediatric participants (6 to < 18 
years old at time of informed consent); assessments of sexual maturation will be performed 
using the Tanner Staging scale. Additional Tanner Staging assessments will be based on the 
score at screening and subsequent scores: 
• Stage 5 = no additional Tanner Staging assessments needed 
Stage 4 or less = continue Tanner Staging assessments per Table 8-2 and Table 8-3 
Dental development will be assessed in all pediatric participants (<18 years) by a qualified 
physician. If needed, further follow-up assessments should be performed by a qualified 
specialist, such as a dentist or a maxillofacial surgeon. For participants that turn 18 years of age 
while on trial, dental assessments may be discontinued at the discretion of the Investigator. A 
routine method of visual evaluation will be used. Panoramic radiographs are not mandated but 
may be performed as per local standards when clinically indicated. Management of any 
participant experiencing treatment-related dental effects will be handled at the Investigator’s 
discretion. 
Bone development will be assessed in all pediatric participants (<18 years) by a qualified 
specialist, such as a site radiologist. At screening, a baseline X-ray with anteroposterior/lateral 
views will be performed to assess growth plate abnormalities (knee/wrist) and skeletal bone age 
(wrist, hand, knee) according to Greulich-Pyle standards (Greulich and WW and Pyle 1959, 
Sasaki et al 2002, Tomei E. et al 2011 and Hojreh et al 2018). When the extremities of the 
participant are affected by PROS, it is recommended to use contralateral side for evaluations, 
when not affected - left side of the body. It is expected that MRI will be used for further 
assessments of bone development during the study; repeated X-rays of knee(s), wrist(s), hand 
should only be performed in case clinically significant changes are detected by MRI. The 
baseline X-rays should be used as reference images for comparison and assessment of the 
suspected changes. If there is evidence of thickening or changes in the growth plate, further 
assessment of bone development should be based on X-rays, as clinically indicated. When 
evaluations may not be performed with use of MRI scans, X-rays of appropriate anatomic areas 
should be considered. 
X-rays can be replaced by MRIs according to institutional standard or if there is any clinical 
contraindication. 
Assessments of growth, bone/dental development and sexual maturation will be performed 
locally in appropriate groups at screening, then every 6 months and at the End of Treatment 
visit (if not assessed during last 3 months). Bone development assessments may be stopped 
when participant reaches skeletal maturity or Tanner stage 5. 
All findings should be recorded and assessed for clinical significance; clinically significant 
abnormalities should be reported as adverse events. 

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If clinically significant changes in growth, bone/dental development, and sexual maturation are 
observed, the Investigator should reassess the risk/benefit ratio of continued alpelisib treatment 
and discuss with the Sponsor on a case-by-case basis. 
8.4.5 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population. 
8.5 
Additional assessments 
8.5.1 
Clinical Outcome Assessments (COAs) 
The participant-perceived effects of treatment with alpelisib will be assessed though changes in 
patient-reported outcomes measures (PROMs), as the basis of a secondary endpoints in this 
study. These PROMs will assess concepts including pain intensity, physical functioning, mental 
health, social functioning, fatigue, sleep, and shortness of breath. The inclusion of such PROMs 
will enable a better understanding of how treatment with alpelisib impacts health and wellbeing, 
with reports coming directly from the participant (or, when the participant is unable to self-
report, as recorded by the caregiver). Participant input should inform which domains should be 
measured in a clinical study protocol (Patrick et al 2011). Novartis conducted a targeted 
literature review and cognitive debriefing interviews with participants with PROS, to support 
the content validity of each measure, to demonstrate that they are comprehensive, relevant, and 
understandable to the specific ages and patient populations while also detecting the 
heterogeneity across the PROS patient populations. 
The PROMs will be included on PRO Diaries implemented on electronic patient-reported 
outcomes (ePRO) devices given to each participant (or caregiver). Pain and dyspnea-related 
questions will be collected on a daily basis from home, starting in the screening period (starting 
7 days prior the first dose of study treatment) through Week 16, and again starting at Week 20 
though Week 24, as well as at other times as indicated in the VES. The other health-related 
quality of life (HRQoL) measures will also be implemented on the ePRO devices and will 
appear for completion at baseline and specified time points during the study. 
The following PROMs are included in the PRO Diary on the ePRO device: 
• In this study, the BPI item that assesses worst pain intensity in the past 24 hours will be 
used. Participants respond to the item on an 11-point response scale ranging from 0 (no 
pain) to 10 (pain as bad as you can imagine). An item pertaining to pain interference with 
general activity in the past 24 hours asks participants to respond to the item on an 11-point 
response scale ranging from 0 (does not interfere) to 10 (completely interferes). The 
participant will indicate the location of pain and where it hurts the most on a modified 
BPI diagram. A separate item will allow the participant to indicate the type of pain 
experienced. Additional questions on worst pain intensity, location and type of pain will 
also be asked, if the participant wishes to answer these questions for an additional area of 
pain experienced. Adult and pediatric participants 12 years of age and older will report pain 
with these questions (Cleeland 2009). 
• For children 3-11 years old, the Wong-Baker FACES® Pain Rating Scale of pain 
interference will be asked in place of the BPI worst pain intensity question. This scale is a 
single-item that includes simple line drawings of 6 faces, each depicting an increasing 

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amount of pain. It has reliability and validity for use in children 3-18 years of age. Each face 
is associated with both a numeric rating and a descriptor (ranging from 0, “no hurt” to – 10 
“hurts worst”). Children will be asked to choose the face that best describes their level of 
pain (Wong and Baker 1988). 
• Two items on Dyspnea Severity will also be included to assess the degree to which 
participants felt short of breath while completing various physical activities. One item asks 
about shortness of breath when walking up 10 stairs and another asks about shortness of 
breath when talking while walking. Each has a recall period of the past 24 hours and includes 
5 response options: no shortness of breath (0), mildly short of breath (1), moderately short 
of breath (2), severely short of breath (3), and I did not do this. Participants 12 years and 
older will be asked to respond to these items.  
For the assessment of pain and dyspnea, participants (or their caregivers) will be asked to 
complete these items on the PRO Diary on the ePRO devices every evening starting in the 
screening period (starting 7 days prior the first dose of study treatment) through Week 16, and 
again starting at Week 20 through Week 24. Participant (or their caregivers) will be alerted for 
their completion prior to the time interval during which the assessment should be completed. 
The following PROMs will be included at Baseline and other specified times during the study: 
A Patient Global Impression of Symptom Severity item will be used to understand the overall 
severity of symptoms experienced and clinical meaningfulness of treatment effects experienced 
during this study. This item includes 5 response options: no symptoms, mild, moderate, severe, 
and very severe.  
The PROMIS Profiles are a group of PROMIS short forms measuring different domains of 
HRQoL from the patient-Reported Outcomes Measurement Information System (PROMIS) 
system (Ader and Deborah 2007). The PROMIS-29 plus 2 Profile v2.1 is designed for adults 
≥18 years of age, and includes 29 items across 7 domains (4 items per domain): depression, 
anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to 
participant in social roles and activities (corresponding to PROMIS Short Forms 6a/b); the 27th 
and 28th items are the “plus 2” and assess cognitive function abilities and the 29th item assesses 
pain intensity. All items except those related to physical function are answered in reference to 
the past 7 days; the physical function items do not have a specific recall period. All items include 
5 response options, except for the pain intensity item, which has 11 response options 
(Cella et al 2019). 
The PROMIS Pediatric-25 Profile v2.0 is designed for self-report by children; The PROMIS 
Parent-Proxy-25 Profile v2.0 is designed for completion by a parent or caregiver observer on 
behalf of children unable to record for themselves. Four items are included for each of the 
following domains: depressive symptoms, anxiety, physical function-mobility, pain 
interference, fatigue, and peer relationships (corresponding to PROMIS pediatric Short Forms 
6a/b); the 25th item assesses pain intensity. All items are answered in reference to the past 7 
days and include 5 response options, except for the pain intensity item, which has 11 response 
options. The content of the child self-report and parent/caregiver versions are identical, except 
for minor modifications to account for differences in responders (e.g., “I felt worried” vs “My 
child felt worried”). The PROMIS Pediatric-25 Profile v2.0 will be completed by children 12 

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and older, and the PROMIS Parent-Proxy-25 Profile v2.0 will be completed by 
parents/caregiver for children under 12 years of age. 
Unlike the adult PROMIS Profile, the pediatric and parent-proxy PROMIS profile does not 
include a sleep disturbance domain. In order to achieve similar content coverage across the 
COAs administered to adults, children, and parent versions, the PROMIS Pediatric and Parent-
Proxy Sleep Disturbance Short Form 4a will also be included for pediatrics and parent-proxies. 
The short form includes 4 items that assess difficulty falling asleep, sleeping through the night, 
problems with sleep, and trouble sleeping. Each item is answered in reference to the past 7 days 
and includes 5 response options. 
These health-related quality of life measures will be collected at baseline and specified time 
points during the study (refer to the Table 8-2 and Table 8-3). The participants (or their 
caregivers) should be asked to complete their PRO measure(s) on the ePRO device at the 
scheduled visit before any clinical assessments are conducted. Participant’s refusal to complete 
all or any part of a PRO measure should be documented in the study data capture system and 
should not be captured as a protocol deviation. Handling of protocol deviations can be modified 
if needed per study protocol. 
Participant questionnaires should be completed in the language most familiar to the participant, 
and participants should be given sufficient space and time to complete the PRO measure(s). 
Table 8-8 and Table 8-9 below provide details on the PRO versions given by age range.  

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Table 8-8 
Daily Diary: Starting at Screening period, then at specified time points 
in Table 8-2 and Table 8-3 
Concept of 
interest 
Adult Self-report 
(≥18 years old) 
Child Self-report 
(≥12-17 years old) 
Child report with 
Parent/Caregiver 
Assistance (3-11 
years old) 
Parent/Caregiver 
report (<12 years 
old) 
Pain intensity 
BPI Worst Pain 
Item  
Brief Pain 
Inventory, Worst 
Pain Item  
Wong Baker 
FACES Pain Scale  
NA 
Pain interference 
Pain interference 
with activity 
Pain interference 
with activity item 
NA 
NA 
Pain location 
BPI pain diagram 
(areas that hurt, 
and where hurts 
most) 
BPI pain diagram 
(areas that hurt, 
and where hurts 
most) 
NA 
NA 
Pain type 
BPI pain type item  
BPI pain type item  
NA 
NA 
Dyspnea 
Dyspnea Severity, 
2 items 
Dyspnea Severity, 
2 items 
NA 
NA 
Table 8-9 
PRO measures on ePRO Device by age range: Starting at Week 1 Day 
1 then at specified time points in Table 8-2 and Table 8-3 
Concept of 
interest 
Adult Self-report 
(≥18 years old) 
Child Self-report 
(≥12-17 years old) 
Child Report with 
Parent/Caregiver 
Assistance (3-11 
years old) 
Parent/Caregiver 
Reporter (<12 
years old) 
  
PRO measure 
Global Impression 
of severity of 
symptoms 
Single item on the overall severity of 
PROS1 
NA 
Single item on the 
overall severity of 
PROS1 
Physical function 
PROMIS-29+2 
Profile v2.1 
PROMIS Pediatric-
25 Profile v2.0 
NA 
PROMIS-Parent-
Proxy-25 Profile 
v2.0 
Fatigue 
Ability to participate 
in social/peer 
relationships2 
Pain interference 
Pain severity 
Anxiety 
Depression 
Cognitive function 
NA 
NA 
NA 
Sleep disturbance3 
PROMIS Pediatric 
Short Form v1.0 - 
Sleep Disturbance 
4a 
NA 
PROMIS Parent 
Proxy Short Form 
v1.0 -Sleep 
Disturbance 4a 
1 While the overall content of these items will be identical across the adult, child, and parent-proxy measures, 
minor changes to item wording were made (and tested) to make it relevant for the intended group (e.g., 
modifying "how would you rate your overall symptoms" to "how would you rate your child's overall symptoms"). 
2 Domain "ability to participate in social roles and activities" is assessed for adults, while "peer relationships" is 
assessed for children/parent-proxy. 
3 Sleep disturbance is assessed in the PROMIS-29 Profile v2.1 using the PROMIS Sleep Disturbance Short 

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Concept of 
interest 
Adult Self-report 
(≥18 years old) 
Child Self-report 
(≥12-17 years old) 
Child Report with 
Parent/Caregiver 
Assistance (3-11 
years old) 
Parent/Caregiver 
Reporter (<12 
years old) 
Form 4a. Sleep disturbance is not assessed on the PROMIS pediatric or parent profile version, and thus a 
separate short form assessment is needed. 
Trial Feedback Questionnaire (TFQ) 
This study will include an option for participants (or parent/caregiver) to complete an 
anonymized questionnaire, ‘Trial Feedback Questionnaire’. The intention of this questionnaire 
is to collect participant feedback on their clinical study experience. Individual participant level 
responses will not be reviewed by Investigators. Responses would be used by Novartis to 
understand where improvements can be made in the clinical study process. This questionnaire 
does not collect data about the participant's disease, symptoms, treatment effect or adverse 
events and is therefore considered as outside of the clinical trial data, therefore would not be 
study data. The TFQ data will be stored in the Vendor’s database, separate from the clinical 
trial database, and will not be part of the clinical trial database and study Clinical study report 
(CSR) and is outside scope of Data Review and Cleaning/ Reconciliation by Data Management 
personnel. Should any spontaneous information be collected about AEs, this would be 
transferred to the safety database.  

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During the COVID-19 pandemic that limits or prevents on-site study visits, or if visits by site 
staff to a participant’s home are not feasible, the Clinical Outcome Assessments may be 
collected remotely (through e.g., ePRO devices, web portal, or telephone interviews) depending 
on local regulations, technical capabilities, and following any applicable training in the required 
process. 
8.5.2 
Pharmacokinetics 
Blood samples for PK evaluation will be collected from all participants who receive at least one 
dose of study treatment. PK blood sampling will be performed in each study period as indicated 
in the Visit Evaluation Schedule (Table 8-2 and Table 8-3), PK blood collection log for Groups 
1 and 2 (Table 8-11), Groups 3 (Table 8-12), Group 4 (Table 8-13) and Group 5 (Table 8-14). 
Complete dosing information, including the date and time of actual blood draw and time of the 
last study treatment dose prior to the sampling (24-h clock time), should be obtained on all 
sampling days and recorded on the PK CRF and/or Contract Research Organization (CRO) 
requisition form(s). Sampling problems will be noted in the relevant field in the eCRF and on 
appropriate source documentation. 
An additional blood sample (unscheduled) should be collected in the event that a participant 
experiences an AE which requires premature termination from the study treatment. The 
unscheduled PK blood sample must be obtained whenever possible and as soon as possible after 

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Week 
Day 
Scheduled Time 
Point 
Dose Reference ID§  
PK Sample 
No 
Sample 
Volume 
(mL) 
20 
1 
3 h post-dose ± 30 min 
2 
-  
107 
2 
After 28*** 
1 
Pre-dose/0 h* 
3 
12 
108+ 
2 
After 28*** 
1 
3 h post-dose ± 30 min 
3 
 - 
109+ 
2 
Anytime 
Unscheduled 
151+ 
1001+ 
2 
* Pre-dose samples should be obtained within 30 minutes before administration of alpelisib dose, and within 
22-26 hours after the last dose the participant received prior to the collection of the pre-dose (trough) sample. 
PK blood samples collected before 3 hours post-dose must be collected within ± 10 minutes from the 
scheduled time point, while samples collected 3 hours post-dose and later may be collected within ± 30 
minutes from the scheduled time point. 
** The 24 hours post-dose sample should be collected 24 hours (± 2 h) after the dose administered on Week 
17 Day 1, and within 30 minutes before administration of next alpelisib dose on Week 17 Day 2. 
***After Week 28, only for participants who had dose escalation, PK sampling is planned at the next scheduled 
visit that will occur at least 4 weeks after each dose escalation. 
+ Additional samples may be collected due to additional dose escalations and/or safety observations; Refer to 
Lab manual for naming conventions.  
§ For the PK Pre-dose samples, the actual date and time of administration of the previous dose of alpelisib 
should be recorded with appropriate dose reference ID as indicated in the above table. The dose reference ID 
“1" is for the alpelisib dose administered on Week 17 Day 1. The dose reference ID "2, 3" is for the alpelisib 
dose administered on study day visit. The dose reference ID "10, 11, 12" is for the previous alpelisib dose the 
participant received prior to the collection of the PK Pre-dose sample. The dose reference ID “20” is for the 
alpelisib dose taken on Week 17 Day 2. 

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8.5.4 
Imaging 
Imaging in this study will be performed as part of primary/secondary/
objectives 
and will also be used as a safety assessment. The methods for assessment and recording are 
specified in the Section 8.3 and Section 8.4. 
The coded medical images will be used primarily for analysis as described in this protocol; 
however, the images may also be used for the development and evaluation of new analysis 
methods directly related to the area of research that this study covers. 
8.5.5 
Lung function assessment 
Spirometry testing will be performed for Groups 1, 2 and 5 according to the American Thoracic 
Society guidelines (Miller et al 2005, Graham et al 2019) at screening to assess participants’ 
eligibility for the study and as detailed in the assessment schedule (Table 8-2 and Table 8-3). 
The same spirometry equipment should be used for all assessments performed by a participant. 
Where possible the same technician should perform the assessment for an individual participant 
during the study. 
The following spirometry measurements will be collected and recorded: 
• FVC, forced vital capacity 
• FVCPP, percent predicted forced vital capacity 
• FEV1, forced expiratory volume in 1 second 
• CO, diffusion capacity of lung for CO  

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Spirometry will be performed in all participants in Groups 1, 2 and 5 at screening, and then 
when clinically indicated. In those participants, who have pulmonary function affected by 
PROS at baseline, spirometry will be performed at efficacy assessment time points (please refer 
to Section 8.3.2).  
Spirometry will not be performed in participants in Groups 3 and 4 (less than 6 yrs old). Instead 
of spirometry measurement, to assess these pediatric participants’ eligibility for the study, chest 
MRI images will be used and participants with documented or suspicious pneumonitis or 
interstitial lung disease based on MRI images at time of informed consent will not be eligible. 
9 
Study discontinuation and completion 
9.1 
Discontinuation and completion 
9.1.1 
Study treatment discontinuation and study discontinuation 
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study drug administration). Decision 
on study treatment discontinuation can be done by either the participant or the Investigator in 
the absence of disease progression or unacceptable toxicities. 
The Investigator must discontinue study treatment for a given participant if he/she believes that 
continuation would negatively impact the participant's well-being. 
Study treatment must be discontinued under the following circumstances: 
• Adverse event or laboratory abnormalities requiring permanent discontinuation of study 
treatment as per Section 6.5 
• Progressive disease (except conditions allowing to continue study treatment beyond 
progression as defined in a Section 6.1.5.1)  
• Protocol deviation that results in significant risk to participant’s safety 
• Participant/guardian decision 
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment section (see 
Section 6.2.2) 
• Any situation in which continued study participation might result in a safety risk to the 
participant 
• Following emergency unblinding (except the case when retrospectively the AE/SAE led to 
emergency unblinding is not considered related to the study treatment) 
• Study terminated by Novartis 
If discontinuation from study treatment occurs, the Investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation from study treatment and 
record this information. 
Participant who discontinues from study treatment agree to return for the End of Treatment and 
follow-up visits indicated in the Assessment Schedule (refer to Section 8). 

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If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the 
participant. This telephone contact should preferably be done according to the study visit 
schedule. 
The Investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
If discontinuation occurs because treatment code has been broken, please refer to details in the 
Emergency breaking of treatment code in Section 6.6.2. 
For the participants who discontinue from study treatment for reasons other than death, lost to 
follow-up, or withdrawal of consent/opposition to use data/biological samples, safety follow-
up assessments must continue after study treatment discontinuation and End of Treatment 
assessments. 
9.1.1.1 
Replacement policy 
No replacements will be needed. 
9.1.2 
Discontinuation from study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. 
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in the assessment table (refer to Section 8). 
9.1.3 
Withdrawal of informed consent  
Withdrawal of consent/opposition to use of data and/or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and only when a 
participant: 
• Explicitly requests to stop use of their data. 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts). 
This request should be as per local regulations (e.g. in writing) and recorded in the source 
documentation. 
Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g. to respond to data queries) and potentially other country-specific restrictions. It is therefore 
very important to ensure accurate recording of withdrawal vs. discontinuation based on the 
protocol definitions of these terms. 
In this situation, the Investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/exercise data privacy rights and record this information. The Investigator shall clearly 

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document if the participant has withdrawn his/her consent for the use of data in addition to a 
study discontinuation. 
Study treatment must be discontinued and no further assessments conducted and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of consent 
/exercise data privacy rights should be made as detailed in the assessment table (refer to Table 8-
2 and Table 8-3). 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition.  
Further details on withdrawal of consent or the exercise of participants’ data privacy rights are 
included in the corresponding informed consent form. 
9.1.4 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the Investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g., dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed. 
9.1.5 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the participant welfare and safety. Should early termination be 
necessary, participants must be seen as soon as possible (instructions will be provided to the 
Investigator for contacting the participant, when the participant should stop taking drug and 
when the participant should come for a final visit) and treated as a participant who discontinued 
from study treatment (see Section 9.1.1). The Investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the participant’s interests. The Investigator or Novartis, depending on the local 
regulation, will be responsible for informing IRBs/IECs of the early termination of the study. 
9.2 
Study completion and post-study treatment 
Study completion is defined as when the last participant, regardless of study period, finishes 
their study Completion visit and any repeat assessments associated with this visit have been 
documented and followed-up appropriately by the Investigator or, in the event of an early study 
termination decision, the date of that decision. 

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(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative). 
The Investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on study related medical 
questions or problems. 
Once screening procedures start, all AEs per the description below (inclusive of SAEs) will be 
captured as adverse events. The occurrence of adverse events must be sought by non-directive 
questioning of the participant at each visit during the study. Adverse events also may be detected 
when they are volunteered by the participant during or between visits or through physical 
examination findings, laboratory test findings, or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (if the event is serious refer to Section 10.1.2): 
1. The Common Toxicity Criteria (CTC) AE grade (version 4.03). Adverse events will be 
assessed and graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version, including Grade 5 (Death related to AE). Grade 5 (Death related to AE) 
will be used in assessment of AEs to comply with CTCAE grading. Information about deaths 
will be collected through the appropriate eCRF page. 
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression of 
underlying illness (i.e., progression of the study indication) the assessment of causality will 
usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a lack of 
efficacy or progression of underlying illness are not caused by the study drug, they happen 
in spite of its administration and/or both lack of efficacy and progression of underlying 
disease can only be evaluated meaningfully by an analysis of groups, not on a single 
participant 
3. Its duration (start and end dates) or if the event is ongoing, and the outcome of not 
recovered/not resolved must be reported 
4. Whether it constitutes a SAE (see Section 10.1.2) for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment. All adverse events must be treated 
appropriately. Treatment may include one or more of the following 
• Dose not changed 
• Dose Reduced/ re-escalation 
• Drug interrupted/permanently discontinued 
6. Its outcome (i.e., recovery status or whether it was fatal) 
If the event worsens the event should be reported a second time in the eCRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement 
to a lower grade is determined a new entry for this event should be reported in the eCRF noting 
the start date when the event improved from having been Grade 3 or Grade 4. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 

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Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g., continuing at the end of the study), and assessment must be made at each 
visit (or more frequently as necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcomes.  
Progression of PROS (including fatal outcomes), if documented according to the protocol, 
should not be reported as a serious adverse event, except if the Investigator considers that 
progression of PROS is related to study treatment. 
Adverse events separate from the PROS progression (i.e., thromboembolic event at time of 
progression) will be reported as per usual guidelines used for such events with proper attribution 
regarding relatedness to the drug. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participants 
with the underlying disease. 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  

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• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• 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 
• is medically significant, e.g., defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
Treatment-emergent elevations in AST or ALT (>3x ULN) in combination with total 
bilirubin >2x ULN or jaundice in the absence of cholestasis (defined as ALP < 2 ULN) or other 
causes of hyperbilirubinemia can be an indicator of severe drug induced liver injury (Hy’s 
Law).  For this reason, a potential Hy’s Law case requires expedited reporting, and will be 
handled as a serious unexpected adverse event (assessing it as medically significant in the 
absence of any other seriousness criteria). It must be reported as an SAE to the sponsor promptly 
(i.e., even before all other possible causes of liver injury have been excluded). Reporting should 
include all available information, especially that needed for evaluating the diagnosis, severity 
and likelihood that the study treatment caused the reaction. For participant monitoring and to 
better understand potential etiologies, the Investigator must initiate a close follow-up until 
complete resolution of the problem and completion of all attempts to obtain supplementary data. 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.  
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective of if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after the last administration of study treatment 
must be reported to Novartis safety immediately, without undue delay, but under no 
circumstances later than within 24 hours of obtaining knowledge of the events (Note: If more 
stringent, local regulations regarding reporting timelines prevail). Detailed instructions 

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regarding the submission process and requirements are to be found in the Investigator folder 
provided to each site. 
Information about all SAEs is collected and recorded on the eCRF: all applicable sections of 
the form must be completed in order to provide a clinically thorough report. 
SAEs will be followed until resolution or until clinically relevant improvement or stabilization. 
SAEs occurring after the participant has provided informed consent until the time the participant 
is deemed a Screen Failure must be reported to Novartis. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
Investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). A SAE occurring at a different time interval or otherwise 
considered completely unrelated to a previously reported one must be reported separately as a 
new event. 
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 study treatment, Novartis 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 study treatment 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 EU Clinical Trial 
Regulation 536/2014 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the 30-day period following the last administration of study 
treatment should only be reported to Novartis Safety if the Investigator suspects a causal 
relationship to study treatment, unless otherwise specified by local law/regulations. 
10.1.4 
Pregnancy reporting 
If a female study participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the Investigator to collect and report information regarding the 
pregnancy. To ensure participant safety, each pregnancy occurring after signing the informed 
consent 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 and reported by the Investigator to Novartis. Pregnancy follow-
up should be recorded on the same form and should include an assessment of the possible 
relationship to the study treatment and pregnancy outcome. Any SAE experienced during 
pregnancy must be reported. 

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If a female partner of a male trial participant who took study treatment in this study becomes 
pregnant, pregnancy outcome should be collected. Consent to report information regarding 
these pregnancy outcomes should be obtained from the mother. 
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not they are associated with an AE/SAE. Study 
treatment errors and uses outside of what is foreseen in the protocol, including misuse or abuse, 
will be collected and reported in the safety database irrespective of it being associated with an 
AE/SAE within 24 hours of Investigator’s awareness. 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.1.6 
Off-site procedures (for Netherlands only) 
At the Investigator's discretion and based on benefit-risk considerations of the participant's 
clinical condition, qualifying participants may be offered the option to have certain clinical trial 
procedures performed at an off-site location (Section 6.5). 
One or more of the following elements may be implemented to support off-site visits: 
• Telephone contacts (when applicable) 
• Fasting Glucose self-monitoring using standard self-tests, where locally allowed 
• Off-site HealthCare Professionals (OHP) 
• Source Data Collection 
Procedures for off-site visits utilizing the above listed elements are further detailed in a separate 
manual(s) provided to the sites participating in the off-site visits. 
• Off-site training manual 
• Site guidance 
The off-site procedures will be utilized in certain countries and sites as determined by protocol 
needs, if Sponsor allows, and based on national and local/site regulations. 
Participants, that the investigator identifies as suitable for off-site visits, must provide informed 
consent (Optional consent for activities that may be done outside of the study site.) 

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The following conditions must be met for off-site visits to take place: 
• Off-site visits may occur during the study for fasting glucose plasma assessments 
• If the participant suffers from either (1) a severe AE or an SAE (possibly related to study 
medication), and/or (2) any concurrent medical conditions which, in the opinion of the 
Investigator, could cause unacceptable safety risks, then the participant must resume the 
on-site visits. The participant may resume the off-site visits when, based on the 
Investigator’s judgment, there are no further safety risks for the participant. 
10.1.6.1 Responsibility of Investigator oversight of off-site activities 
Procedures that are performed off-site remain under the oversight of the investigator, who 
retains accountability for the conduct of all safety and efficacy assessments delegated to an 
OHP, and will ensure the rights, safety, and wellbeing of participants. This includes the 
following (including, but not limited to): 
• the identification, management and reporting of AEs and SAEs are performed in 
accordance with the protocol and applicable regulations 
• verification that OHPs have appropriate qualifications, training, and experience to 
successfully conduct off-site procedures 
• source data collected off-site are reviewed and evaluated in a timely manner 
• the investigator or delegate is available to be contacted by the OHP if any issues or 
concerns are noted during an off-site visit 
• where relevant, the investigator or delegate will be present by phone for a portion of the 
off-site visit to support the physical examination. 
The off-site healthcare professionals will be provided by a third-party vendor sourced by 
Novartis. Where a site wishes to use off-site healthcare professionals that are not provided by 
Novartis this must be agreed with Novartis before use. 
10.1.6.2 Responsibility of OHPs 
Any issues or safety concerns identified by the OHP will be promptly communicated to the 
investigator or delegate according to a pre-defined communication plan. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
For liver safety monitoring guidelines, please refer to the Section 6.5.2.1. 
10.2.2 
Data Monitoring Committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical study, including the site 
Investigators participating in the study. The DMC will be formed prior to the randomization of 
the first participant and will assess at defined intervals the progress of a clinical study, safety 
data and recommend to Novartis whether to continue, modify, or terminate a study. 

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Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between Novartis and the DMC. 
10.2.3 
Steering Committee 
The Steering Committee (SC) will be established comprising Investigators participating in the 
study, i.e., not being members of the DMC, a patient advocate and Novartis representatives 
from the Clinical study Team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical study team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the steering committee will be defined in the steering committee charter. 
11 
Data Collection and Database management 
Monitoring strategy, methods, responsibilities, and requirements are provided in the monitoring 
plan. Details may include definition of study critical data items and processes (e.g. risk-based 
initiatives in operations and quality such as risk management and mitigation strategies and 
analytical risk-based monitoring), including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of Novartis. No records may be transferred to 
another location or party without written notification to Novartis. 
11.1 
Data collection 
All data captured for this study will have an external originating source (either written or 
electronic) with the eCRF not being considered as source. 
Designated Investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements. Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the Investigator staff. 
The Investigator/designee is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
Investigator must certify that the data entered are complete and accurate. 
After final database lock, the Investigator will receive copies of the participant data for 
archiving at the investigational site.  

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All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated Investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Safety laboratory assessments, PK 
 samples drawn during the 
course of the study will be collected from the Investigator sites and sent to the Novartis 
designated central laboratory for processing. The laboratory results will be sent electronically 
to Novartis (or a designated CRO). 
Imaging data used for PROS lesions assessments will be collected at the sites, transmitted to a 
designated vendor for centralized analysis, quality control, as well as further processing and 
data reconciliation. It will be prospectively reviewed by a blinded independent review 
committee (BIRC). 
PRO data collected using an electronic tablet device will be documented into a separate study-
specific vendor database supplied and managed by a designated vendor. All PRO data will be 
sent electronically to Novartis personnel (or a designated CRO). 
Randomization codes and data about all study treatment (s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study primary analysis at Week 48 or upon 
request of Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate for primary analysis at Week 48, the database until Week 48 will be 
locked and the treatment codes will be unblinded and made available for data analysis. Final 
database lock will be declared after Week 240 (i.e., once LPLV is achieved at Safety Follow-
up/End of Study). Any changes to the database after that time can only be made after written 
agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a 
Novartis/representative will review the protocol and data capture requirements (i.e., eSource 

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12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data, including disease characteristics, will be listed and 
summarized descriptively by age group and treatment arm for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected 
parameters, 25th and 75th percentiles will also be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term, by age group and treatment arm. 
12.3 
Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
The duration of exposure to alpelisib and placebo, as well as the dose intensity (computed as 
the ratio of actual cumulative dose received and actual duration of exposure) and the relative 
dose intensity (computed as the ratio of dose intensity and planned dose intensity) will be 
summarized by means of descriptive statistics using the safety set. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized according to the Anatomical Therapeutic Chemical (ATC) 
classification system, by age group and treatment arm. 
The number of participants with dose adjustments (either dose increase for response 
optimization purpose, or reductions, interruption, or permanent discontinuation) and the reasons 
will be summarized by age group and treatment arm, and all dosing data will be listed. 
12.4 
Analysis of the primary estimand(s) 
The primary objective is to demonstrate the efficacy of alpelisib based on the proportion of 
participants randomized to the alpelisib treatment with a confirmed objective response by BIRC 
in the pediatric (6-17 years old; Group 2) or in the adult (≥ 18 years old; Group 1) groups 
(multiple primary endpoints). 
12.4.1 
Definition of primary estimand(s) 
The primary efficacy variable of the study is the proportion of participants randomized to 
alpelisib achieving confirmed objective response, where response is based on 
• achieving ≥ 20% reduction from baseline in the sum of target lesion volumes (1 to 3 target 
lesions, assessed by MRI by BIRC), provided that none of the individual target lesions 
has ≥ 20% increase from baseline and in absence of progression of non-target lesions and 
without new lesions. Confirmation of response requires a subsequent imaging assessment 
performed at least 4 weeks after the onset of the response. 
Refer to Section 12.4.3 for handling of intercurrent events and Section 12.4.4 for handling of 
missing values. 
Analysis of the primary endpoint will be performed in each of Groups 1 and 2. 

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12.4.2 
Statistical model, hypothesis, and method of analysis 
The primary analysis will be based on data from the FAS - BYL719 for Groups 1 and 2 
respectively. The study will be declared positive if at least one of the two primary null 
hypotheses can be rejected. 
In order to conserve the overall type-1 error (one-sided level of significance of α=0.025) in 
testing multiple hypotheses, an alpha split with a graphical gate-keeping approach will be 
implemented based on the graphical multiple testing procedure as described in Section 12.5.1.1. 
A confirmed response rate of 15% or less is considered “as insufficient” level of efficacy for 
the proposed participant population. Please refer to details in this Amendment rationale 01 for 
the threshold for futility (updated from 35% to 15%). For the primary analysis, the following 
statistical hypotheses will be tested based on the exact binomial distribution: 
• H1 (Group 1): H01: pBYL ≤ 0.15 vs. HA1: pBYL > 0.15 
• H2 (Group 2): H02: pBYL ≤ 0.15 vs. HA2: pBYL > 0.15 
where pBYL is the confirmed objective response rate on alpelisib in the Groups 1 and 2, 
respectively.  
The primary null hypothesis will be rejected based on the probability of obtaining the observed 
confirmed objective response rate under a binomial distribution with underlying parameter p0 
=0.15 at the appropriate α-level governed by the graphical gatekeeping procedure described in 
Section 12.5.1 and Figure 12-1. With a total of 52 participants, if 15 or more confirmed 
responses are observed (observed confirmed objective response rate of 28.8%, lower bound of 
the 97.5% CI exceeding 15%), the null hypothesis will be rejected at a one-sided α/2= 0.0125. 
Confirmed objective response rates in Groups 1 and 2 will be summarized using descriptive 
statistics (N, %) along with 2-sided exact 100(1-2αi)% confidence interval (CI) (Clopper-
Pearson exact method), where αi corresponds to the appropriate α-level adjusted for multiple 
testing. 
12.4.3 
Handling of remaining intercurrent events of primary estimand 
The primary analysis will account for different intercurrent events as explained in the 
following:  
a. participants discontinuing treatment prior to confirmation of response: Classified as a non-
responder 
b. participants receiving surgery as a rescue therapy for any PROS lesions (target or other) 
prior to confirmation of response: Classified as a non-responder 
12.4.4 
Handling of missing values not related to intercurrent event 
The primary efficacy variable is confirmed objective response. Confirmation of response 
requires a subsequent imaging assessment performed at least 4 weeks after the onset of the 
response. Additional details on handling of missing scans will be provided in the SAP. 

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12.4.5 
Supplementary analysis 
The primary endpoint will be summarized and reported for the following subgroups, if there are 
enough participants in each category allowing such analysis: 
• Age (6-11 years; 12-17 years) 
• Gender 
• Mutation type (as assessed locally) 
• PROS syndrome (e.g., CLOVES, Klippel-Trenaunay syndrome (KTS)) 
• Lesion type (e.g., vascular, adipose) 
Forest plots (response rate, 95% CI) will be produced to graphically depict the treatment effect 
estimates in different subgroups. Further supplementary analysis may be documented in the 
SAP. 
12.4.6 
Sensitivity analyses for primary endpoint/estimand 
Sensitivity analysis (including potential analyses to assess the impact of COVID-19 pandemic 
if applicable) may be documented in the SAP. 
12.5 
Analysis of secondary endpoints/estimands 
The analysis of secondary endpoints will be performed by age group and treatment arm. Periods 
defined based on pre- and post- switch of treatment will be considered for the analyses. 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
The FAS will be used for all analyses in this section. 
12.5.1.1 Key secondary estimand(s) 
The key secondary objective is to demonstrate the efficacy of alpelisib based on the comparison 
of the proportion of participants achieving response at Week 16 with alpelisib versus placebo 
in Groups 1 or 2. 
The key secondary analysis will be based on data from the FAS for Groups 1 and 2 respectively. 
Definition of key secondary estimand(s) 
A similar definition of response described for the primary efficacy variable in Section 12.4.1 
will be used for the key secondary efficacy variable, using response at Week 16 instead of 
confirmed objective response. Participants who had a missing/non-evaluable radiological 
assessment at Week 16 will be considered as non-responders for the calculation of the key 
secondary efficacy variable. Handling of intercurrent events will be done as described for the 
primary estimand in Section 12.4.3: Instead of confirmed objective response for the primary, 
Week 16 will be considered for the key secondary estimands. 
Statistical model, hypothesis, and method of analysis 
The following statistical hypotheses will be tested 
• H3 (Group 1): H03: pBYL,W16 ≤ pPBO,W16 vs. HA3: pBYL,W16 > pPBO,W16 

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• H4 (Group 2): H04: pBYL,W16 ≤ pPBO,W16 vs. HA4: pBYL,W16 > pPBO,W16 
where pBYL,W16 is the response rate on alpelisib at Week 16 and pPBO,W16 is the response rate on 
placebo at Week 16. The analysis to test these hypotheses will consist of a Fisher’s exact test at 
the appropriate α-level governed by the graphical gatekeeping procedure described below and 
in Figure 12-1. 
Response rates at Week 16 in Groups 1 and 2 will be summarized using descriptive statistics 
(N, %) along with 2-sided exact 95% confidence interval (CI) (Clopper-Pearson exact method). 
The difference between treatment arms (alpelisib - placebo) in response rates at Week 16 will 
be presented together with 2-sided 95% confidence interval (unadjusted for multiple testing), 
separately for Groups 1 and 2. 
Sequentially rejective graphical procedure for multiple testing 
The 4 null hypotheses (primary hypotheses H1 and H2 described in Section 12.4.2; key 
secondary hypotheses H3 and H4 described above) are tested using the graphical approach to 
sequentially rejective multiple test procedures proposed by Bretz et al 2009. Significance levels 
αi, i=1,…,4, are initially defined such that they sum up to α. The 2 primary hypotheses H1 and 
H2 are allocated with the levels αi = 1/2α, i=1 or 2, where α = 0.025 (one-sided), i.e., the two 
primary hypothesis are considered equally important. For the 2 key secondary hypotheses H3 
and H4, αi = 0, i=3 or 4, i.e., the key secondary hypothesis is not tested until its parent primary 
hypothesis is rejected. 
The procedure then is as follows: Test the hypotheses Hi, i=1,…,4, each at its local significance 
level αi. If a hypothesis Hi is rejected, remove Hi from the graph and propagate its level to other 
hypotheses according to a pre-specified rule represented by a directed, weighted graph. Update 
the reduced graph and repeat the testing step for the remaining, non-rejected hypotheses with 
the updated local significance levels. The procedure is repeated until no further hypothesis can 
be rejected. The procedure is fully determined by the initial graph given below and an updating 
algorithm, see Bretz et al 2009. 

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• The actual and percentage change from baseline in the sum of target lesion volumes, the 
sum of MRI-measurable non-target lesion volumes, the sum of all MRI-measurable lesion 
(target and non-target) volumes. 
Changes in other non-target lesions (via BIRC) will be reported in the following ways  
• The proportion of participants with changes in non-target lesions. 
• The proportion of participants with new lesions. 
Overall clinical response 
The proportion of participants with overall clinical response reported as improvement, stable or 
worsening of clinical condition, as assessed by the Investigator (see Section 8.3) will be 
summarized descriptively and/or graphically displayed. 
Duration of response 
This analysis only applies to participants who are on treatment with alpelisib and who achieve 
response. Duration of response (DOR) is defined as the time from first documented response 
until progression of PROS lesions by BIRC or death. The start date is the date of first 
documented response (Section 8.3), and the end date is defined as the date of first documented 
progression of PROS lesions by BIRC or death. Participants continuing without an event will 
be censored at the date of last adequate PROS lesion assessment prior to cut-off. 
Time to treatment failure 
This analysis only applies to participants who are on treatment with alpelisib. Time to treatment 
failure (TTF) is defined as the time from randomization/alpelisib treatment start date until the 
discontinuation of study treatment due to lack of efficacy (including unsatisfactory therapeutic 
effect, disease progression) or safety reasons (including adverse events, death). Participants 
who complete the study or discontinue study treatment for other reasons (e.g. discontinuation 
due to Participant/Guardian decision, technical problems) will be censored at the date of last 
study treatment received. 
Changes in symptoms and complications/comorbidities associated with PROS 
Changes in symptoms and complications/comorbidities (i.e., walking impairment, 
cardiac/pulmonary/renal function, pain, Karnofsky/Lansky performance status) will be 
summarized descriptively and/or graphically displayed as appropriate. For each 
complication/comorbidity, only participants who have this reported as being present at baseline 
will be included in the analysis. When new symptoms/complications/comorbidities appear at 
any time of study therapy, they will be assessed for clinical significance and reported as adverse 
events when applicable. 
Healthcare visits/hospitalization due to PROS, surgeries to manage PROS 
Healthcare visits/hospitalizations and surgeries related to PROS during on-treatment period, 
will be summarized in the following ways 

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• Proportion of participants with healthcare visit/hospitalized due to PROS, and the number 
and duration of hospitalizations required 
• Proportion of participants requiring surgery due to PROS, and the number of surgeries 
• The proportion of participants where an anticipated PROS surgery is avoided due to 
improvement. 
12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
age group and treatment arm. 
. 
The overall observation period will be divided into three mutually exclusive segments:  
1. Pre-treatment period: from day of participant’s informed consent to the day before first dose 
of study medication 
2. On-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
3. Post-treatment period: starting at day 31 after last dose of study medication. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g., change from 
baseline summaries). In particular, summary tables for adverse events (AEs) will summarize 
only on-treatment events, with a start date during the on-treatment period (treatment-emergent 
AEs). 
The on-treatment period will be further divided in order to separately present safety summaries 
according to study periods. For instance, safety summaries based on data from the period from 
randomization up to Week 16 in order to compare safety between alpelisib and placebo. 
Adverse events 
All information obtained on adverse events will be displayed by age group, treatment arm and 
participant. 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment. 
Serious adverse events, non-serious adverse events and adverse events of special interest 
(AESI) during the on-treatment period will be tabulated. 
All deaths (on-treatment) will be summarized. 
All AEs, deaths, and serious adverse events (including those from the pre- and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged. 

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Vital signs 
All vital signs data will be summarized by age group, treatment arm and visit/time. 
12-lead ECG 
PR, QRS, QT, QTcF and RR intervals will be obtained from triplicate 12-lead ECGs for each 
participant during the study. ECG data will be read and interpreted locally. 
Categorical analysis of QT/QTc interval data based on the number of participants meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline 
will be presented. In addition, a listing of these participants will be produced. 
All ECG data will be summarized by treatment and visit/time. 
Clinical laboratory evaluations 
Laboratory data will be summarized by age group and treatment arm. Shift tables using the 
low/normal/high/ (low and high) classification will be used to compare baseline to the worst 
on-treatment value. 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 
For laboratory tests where grades are not defined by CTCAE v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges. 
The following summaries will be generated separately for hematology, and biochemistry tests: 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE v4.03 
grades if applicable and the classifications relative to the laboratory normal ranges. 
For laboratory tests where grades are defined by CTCAE v4.03: 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each participant will 
be counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE v4.03 grades to compare baseline to the worst on-treatment value. 
For laboratory tests where grades are not defined by CTCAE v4.03: 
• Shift tables using the low/normal/high/ (low and high) classification to compare baseline to 
the worst on-treatment value. 
Change from baseline in selected laboratory tests will also be summarized by visit and/or 
displayed graphically.  
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in other laboratory tests over time or box plots 
might be specified in the analysis plan. 

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Specific analyses to assess the impact of renal (as part of efficacy) and liver function tests will 
be described in the analysis plan. 
Other safety evaluations 
Growth, bone/dental development and sexual maturation  
Data on growth, bone/dental development and sexual maturation (Tanner stage) will be 
summarized for children and adolescents.  
Height and Body Mass Index (BMI) will be summarized at 6-month intervals, using the 
standard deviation scores (SDS, also called z-score), velocity and velocity SDS. SDS will be 
calculated based on published referenced height and BMI information. 
Height/BMI SDS and height/weight velocity SDS will be summarized using descriptive 
statistics (mean, standard deviation, range) for each time window, as well as by presenting 
number of participants with SDS values lower/higher than 5th/95th percentiles respectively. All 
height/BMI SDS, velocity and velocity SDS data will be listed. 
Data on bone/dental development will be summarized descriptively. 
Sexual maturation will be monitored by Tanner staging. The age at which Tanner Stages 2-5 
are achieved by gender will be summarized descriptively. All Tanner stage data will be listed. 
Resource utilization 
Data relating to resource utilization will be used for the purpose of economic evaluation and 
will be carried out and reported as a separate activity.  
PROS-related hospitalizations and surgeries will be analyzed as part of efficacy objectives. 
12.5.3 
Pharmacokinetics 
PAS will be used in all PK data analysis and PK summary statistics. 
Alpelisib plasma concentration data will be listed by age group/dose, participant, and 
visit/sampling time point. Descriptive summary statistics will be provided by visit/sampling 
time point, including the frequency (n, %) of concentrations below the LLOQ and reported as 
zero. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum, and maximum. Concentrations below LLOQ will be treated as 
zero in summary statistics and for PK parameter calculations.  
The PK parameters (Table 12-1) will be calculated from individual plasma concentration versus 
time profiles using non-compartmental analysis (Phoenix WinNonlin). Cmax and Ctrough are 
primary PK parameters; AUClast, AUCinf, Tmax, T1/2, CL/F and Vz/F may be evaluated as 
secondary PK parameters if data permit. PK parameters will be listed by treatment and 
participant. Descriptive summary statistics will include mean (arithmetic and geometric), SD, 
and CV (arithmetic and geometric), median, minimum, and maximum. An exception to this is 
Tmax where median, minimum, and maximum will be presented. 

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Table 12-1 
Pharmacokinetic parameters 
AUClast 
The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x 
time x volume-1) 
AUCinf 
The AUC from time zero to infinity (mass x time x volume-1) 
Tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time) 
Cmax 
The observed maximum plasma (or serum or blood) concentration following drug 
administration (mass x volume-1) 
Ctrough 
The trough observed concentration is the concentration that is just prior to the beginning, or at 
the end, of a dosing interval (mass x volume-1) 
T1/2 
The elimination half-life associated with the terminal slope (λz) of a semi logarithmic 
concentration-time curve (time). 
CL/F 
The total body clearance of drug from the plasma (volume x time-1) 
Vz/F 
The apparent volume of distribution during terminal phase (associated with λz) (volume) 
12.5.4 
Patient reported outcomes 
The patient-reported global impression of symptom severity and BPI worst pain intensity item 
are identified as the primary PRO measures of interest. Change from baseline in scores at Week 
16 will be assessed on treatment with alpelisib as compared to placebo in pediatric (12 to 17 
year old) and adult (≥ 18 year old) populations. Full details of the derivation of the endpoints 
and corresponding analyses will be defined in the SAP. 
The FAS will be used for analyzing PRO data. No multiplicity adjustment will be applied. 
The change from baseline will be summarized and/or graphically displayed at scheduled 
assessments for the following PRO measures: 
• Patient Global impression of symptom severity item 
• Worst Pain intensity, item from the BPI, as collected with the PRO Diary 
• Pain interference with general activity in the past 24 hours, as collected with the PRO Diary 
• Location of pain, as collected with the PRO Diary 
• Type of pain, as collected with the PRO Diary 
• Dyspnea items, as collected with the PRO Diary 
• PROMIS Profile domains 
Age appropriate versions of the PRO tools will be used as described in Table 8-8 and  
Table 8-9. For the analysis, PRO scores based on adult self-reports (≥ 18 years old), child self-
report (12-17 years), child reports with parent/caregiver assistance (3-11 years old) and 
parent/caregiver reports (<12 years old) will be presented separately. 
Further details will be provided in the SAP.  

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13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines 
• Applicable ICH Good Clinical Practice (GCP) guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator’s Brochure, Investigational Directions 
for Use (IDFU), and other relevant documents (e.g. advertisements) must be submitted to an 
IRB/IEC by the Investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments/modifications to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
The Investigator will be responsible for the following: 

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• Signing a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Quality Assurance representatives, designated agents of Novartis, IRBs/IECs, 
and regulatory authorities as required 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), European Medical Device Regulation 2017/745 for clinical device 
research (if applicable), and all other applicable local regulations 
Inform Novartis immediately if an inspection of the clinical site is requested by a regulatory 
authority. 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC or European Clinical Trial 
Regulation 536/2014, US CFR 21), and with the ethical principles laid down in the Declaration 
of Helsinki. 
13.2 
Responsibilities of the Investigator and IRB/IEC 
Before initiating a study, the Investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the study 
protocol, written informed consent form, consent form updates, participant recruitment 
procedures (e.g., advertisements) and any other written information to be provided to 
participants. Prior to study start, the Investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all 
of the instructions and procedures found in this protocol and to give access to all relevant data 
and records to Novartis monitors, auditors, Novartis Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an 
inspection of the clinical site is requested by a regulatory authority, the Investigator must inform 
Novartis immediately that this request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as ClinicalTrials.gov and 
as required in CTIS public website. In addition, after study completion (defined as last 
participant last visit) and finalization of the study report the results of this study will be 
submitted for publication and posted in a publicly accessible database of clinical study results, 
such as the Novartis clinical study results website and all required Health Authority websites 
(e.g., ClinicalTrials.gov, CTIS public website etc.). 

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For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the study 
Investigator meetings. 
Any data analysis carried out independently by the Investigator should be submitted to Novartis 
before publication or presentation. 
Summary results or primary and secondary endpoints will be disclosed based upon the global 
Last Participant Last Visit (LPLV) date, since multinational studies are locked and reported 
based upon the global LPLV. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of Investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical study. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
13.5 
Data protection 
Participants will be assigned a unique identifier by Novartis. Any participant records or datasets 
that are transferred to Novartis will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 
The participant or their legally authorized representative must be informed that his/her personal 
study-related data will be used by Novartis in accordance with local data protection law. The 
level of disclosure must also be explained to the participant who will be required to give consent 
for their data to be used as described in the informed consent. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Novartis by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
Novartis has appropriate processes and policies in place to handle personal data breaches 
according to applicable privacy laws. 
13.6 
Participant Engagement 
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the timepoints indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modification to 
these requirements with Novartis. 
• Thank You Letter – at study start and End of study  
• Plain language trial summary – after CSR publication 
• Individual study results – after CSR publication 

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• Trial Feedback Questionnaire (TFQ) – at Week 1 Day 1, Week 48 and Week 264 (End of 
Study Treatment) 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances, including 
incidental collection, is an Investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the Investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 

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15 
References 
References are available upon request. 
Adams DM, Trenor CC, Hammill AM, et al (2016) Efficacy and Safety of Sirolimus in the 
Treatment of Complicated Vascular Anomalies. Pediatrics; 137(2):e20153257. 
Ader, Deborah N. (2007) Developing the Patient-Reported Outcomes Measurement 
Information System (PROMIS); 45(5):S1-S2. 
Bretz F, Maurer W, Brannath W, et al (2009) A graphical approach to sequentially rejective 
multiple test procedures. Stat Med p. 586-604. 
Busaidy NL, Farooki A, Dowlati A, et al (2012) Management of metabolic effects associated 
with anticancer agents targeting the PI3K-Akt-mTOR pathway. J. Clin. Oncol. p. 2919-28. 
Canaud C, Gutiérrez JCL, Irvine A, et al (2021) EPIK-P1: Retrospective chart review study of 
patients (pts) with PIK3CA-related Overgrowth Spectrum (PROS) who have received 
alpelisib (ALP) as part of a compassionate use programme [abstract]. Annals of Oncology; 32 
Suppl 5:S1297. 
Caron PJ, Bevan JS, Petersenn S, et al (2014) Tumor shrinkage with lanreotide Autogel 120 mg 
as primary therapy in acromegaly: results of a prospective multicenter clinical trial. J. Clin. 
Endocrinol. Metab. p. 1282-90. 
Cella D, Choi SW, Condon DM, et al (2019) PROMIS® Adult Health Profiles: Efficient Short-
Form Measures of Seven Health Domains. Value Health; 22(5):537–44. 
Cleeland C (2009) The Brief Pain Inventory, user Guide. 
De Santis MC, Sala V, Martini M, et al (2017) PI3K Signaling in Tissue Hyper-Proliferation: 
From Overgrowth Syndromes to Kidney Cysts. Cancers (Basel); 9(4):30. 
Fine KD, Schiller LR (1999) AGA technical review on the evaluation and management of 
chronic diarrhea. Gastroenterology p. 1464-86. 
Fritsch C, Huang A, Chatenay-Rivauday C, et al (2014) Characterization of the novel and 
specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy 
for clinical trials. Mol. Cancer Ther. p. 1117-29. 
Graham BL, Steenbruggen I, Miller MR, et al (2019) Standardization of Spirometry 2019 
Update. An Official American Thoracic Society and European Respiratory Society Technical 
Statement. Am. J. Respir. Crit. Care Med. p. e70-e88. 
Greulich, WW and Pyle SI (1959) Radiographic Atlas of Skeletal Development of the Hand 
and Wrist; 8(4):513. 
Hernán MA, Robins JM (2020) Causal Inference: What If. 1st edition. Boca Raton: Chapman 
& Hall/CRC, chapter 12 and 13. //.hsph.harvard.edu/miguel-hernan/causal-inference-book/. 

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Hojreh A, Gamper J, Schmook MT, et al (2018) Hand MRI and the Greulich-Pyle atlas in 
skeletal age estimation in adolescents. Skeletal Radiol. 47(7):963-71. 
Hoste G, Slembrouck L, Jongen L, et al (2019) Correction to: Unexpected Benefit from 
Alpelisib and Fulvestrant in a Woman with Highly Pre-treated ER-Positive, HER2-Negative 
PIK3CA Mutant Metastatic Breast Cancer. Clin Drug Investig. 39(1):113. 
Juric D, Rodon J, Tabernero J, et al (2018) Phosphatidylinositol 3-Kinase α-Selective Inhibition 
with Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human 
Study. J. Clin. Oncol. 36(13):1291-9. 
Keegan NM, Gleeson JP, Hennessy BT, et al (2018) PI3K inhibition to overcome endocrine 
resistance in breast cancer. Expert Opin Investig Drugs; 27(1):1-15. 
Keppler-Noreuil KM, Parker VE, Darling TN, et al (2016) Somatic overgrowth disorders of the 
PI3K/AKT/mTOR pathway & therapeutic strategies. Am J Med Genet C Semin Med 
Genet;172(4):402-21. 
Keppler-Noreuil KM, Rios JJ, Parker VE, et al (2015) PIK3CA-related overgrowth spectrum 
(PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am. J. 
Med. Genet. A; 167A(2):287-95. 
Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, et al (2014) Clinical delineation and natural 
history of the PIK3CA-related overgrowth spectrum. Am. J. Med. Genet. A p. 1713-33. 
Kornblau S, Benson AB, Catalano R, et al (2000) Management of cancer treatment-related 
diarrhea. Issues and therapeutic strategies. J Pain Symptom Manage; 19(2):118-29. 
Kuentz P, St-Onge J, Duffourd Y, et al (2017) Molecular diagnosis of PIK3CA-related 
overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing. Genet. 
Med; 19(9):989-97. 
Kurek KC, Luks VL, Ayturk UM, et al (2012) Somatic mosaic activating mutations in PIK3CA 
cause CLOVES syndrome. Am. J. Hum. Genet. 90(6):1108-15. 
Lee CA, O'Connor MA, Ritchie TK, et al (2015) Breast cancer resistance protein (ABCG2) in 
clinical pharmacokinetics and drug interactions: practical recommendations for clinical victim 
and perpetrator drug-drug interaction study design. Drug Metab. Dispos. p. 490-509. 
Leoni C, Gullo G, Resta N, et al (2019) First evidence of a therapeutic effect of miransertib in 
a teenager with Proteus syndrome and ovarian carcinoma. Am. J. Med. Genet. A 179(7):1319-
24. 
Lindhurst MJ, Parker VE, Payne F, et al (2012) Mosaic overgrowth with fibroadipose 
hyperplasia is caused by somatic activating mutations in PIK3CA. Nat. Genet; 44(8):928-33. 
Lindhurst MJ, Yourick MR, Yu Y, et al (2015) Repression of AKT signaling by ARQ 092 in 
cells and tissues from patients with Proteus syndrome. Sci Rep (5):17162. 
Maurer W, Glimm E, Bretz F (2011) Multiple and Repeated Testing of Primary, Coprimary, 
and Secondary Hypotheses. Statistics in Biopharmaceutical Research; 3(2):336-52.  

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16 
Appendices 
16.1 
Appendix 1: PROS diagnostic criteria 
Clinical Diagnostic Criteria for PROS 
Required: 
• Presence of somatic PIK3CA mutation* 
• Congenital or Early Childhood Onset 
• Overgrowth Sporadic and Mosaic (Other terms: Patchy, Irregular) 
• Features as described in either A or B 
A. Spectrum (two or more features)** 
1. Overgrowth: Adipose, Muscle, Nerve, Skeletal 
2. Vascular Malformations: Capillary, Venous, Arteriovenous Malformation, Lymphatic 
3. Epidermal Nevus 
B. Isolated features 
1. Large Isolated Lymphatic Malformation 
2. Isolated Macrodactyly*** OR Overgrown Splayed Feet/ Hands, Overgrown Limbs 
3. Truncal Adipose Overgrowth 
4. Hemimegalencephaly (bilateral)/ Dysplastic Megalencephaly/ Focal Cortical Dysplasia 2¹ 
5. Epidermal nevus² 
6. Seborrheic Keratoses² 
7. Benign Lichenoid Keratoses³ 
Abbreviations: + present; − absent; HC hydrocephalus; ID intellectual disability 
*If no mutation identified, then consider as presumptive PROS 
**Typically Progressive. Can manifest as: Scoliosis (Kyphosis), Limb overgrowth, CNS (HC, 
Cerebellar tonsillar ectopia, Chiari, Megalencephaly, Mega corpus callosum, Regional 
lipomatous undergrowth with overgrowth, Infiltrating lipomatosis, Wilms tumor/ovarian 
cystadenoma 
***Other terms: macrodystrophia lipomatosa, macrodactylia fibrolipomatosis and gigantism 
1. Dobyns WB, 2014 (unpublished data); 
2. Hafner et al. [2007]; 
3. Groesser et al. [2012] 
Adopted from: Kim M. Keppler-Noreuil et al., PIK3CA-Related Overgrowth Spectrum 
(PROS): Diagnostic and Testing Eligibility Criteria, Differential Diagnosis, and Evaluation. 
Am J Med Genet A. 2015 February ; 0(2): 287–295. Keppler-Noreuil et al 2015 

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16.2 
Appendix 2: Karnofsky performance scale index 
Percentage 
Characteristics 
100% 
Normal, no complaints, no signs of disease 
90% 
Capable of normal activity, few symptoms or signs of disease 
80% 
Normal activity with some difficulty, some symptoms or signs 
70% 
Caring for self, not capable of normal activity or work 
60% 
Requiring some help, can take care of most personal requirements 
50% 
Requires help often, requires frequent medical care 
40% 
Disabled, requires special care and help 
30% 
Severely disabled, hospital admission indicated but no risk of death 
20% 
Very ill, urgently requiring admission, requires supportive measures or treatment 
10% 
Moribund, rapidly progressive fatal disease processes 
0% 
Death. 
16.3 
Appendix 3: Lansky play performance scale 
Grade 
Characteristics 
100 
Fully active, normal. 
90 
Minor restrictions in physically strenuous activity. 
80 
Active, but tires more quickly 
70 
Both greater restriction of, and less time spent in, active play 
60 
Up and around, but minimal active play, keeps busy with quieter activities 
50 
Gets dressed, but lies around much of the day; no active play; able to participate in all quiet 
play and activities 
40 
Mostly in bed; participates in quiet activities 
30 
In bed; needs assistance even for quiet play 
20 
Often sleeping; play entirely limited to very passive activities 
10 
No play; does not get out of bed. Moribund 

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16.6.1 
Permitted medication to be used with caution and/or action 
As described in this list of CYP substrates was compiled from the University of Washington’s 
Drug Interaction Database (Updated April 2019). This list only meant to be used as a guide.  
Table 16-1 
List of CYP450 substrates to be used with caution 
Category 
Drug names 
CYP2C9 substrates 
Narrow Therapeutic index substrates of CYP2C9 
(S)-Warfarin and other coumarin-derivative 
anticoagulants 
Sensitive substrates of CYP2C9 
Benzbromarone, Celecoxib, Glimepiride, Glipizide, 
(R)/(S)-Ibuprofen, Lornoxicam, Meloxicam, Piroxicam, 
Tolbutamine, (S)-Warfarin 
CYP2B6 substrates 
Narrow Therapeutic index substrates of CYP2B6 
Meperidine 
Sensitive substrates of CYP2B6 
Bupropion, Efavirenz 
Selected CYP3A4 substrates 
Narrow Therapeutic index substrates of CYP3A 
Alfentanil, Diergotamine, Ergotamine, Fentanyl, 
Pimozide, Quinidine 
Sensitive substrates of CYP3A 
Alfentanil, Atazanavir, Atorvastatin, Darunavir, 
Lumefantrine, Midazolam, Simvastatin, Triazolam 
CYP3A4 substrates which are known or potential 
auto-perpetrators 
Clarithromycin, Conivaptan, Encorafenib, 
Erythromycin, Diltiazem, Mifepriston, Ribociclib, 
Telthromycin, Troleandomycin, Verapamil 
* Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increase in 
their exposure levels by the concomitant use of potent inhibitors may lead to serious concerns (e.g. Torsades 
de Pointes, QT prolongation). 
** Sensitive substrates: Drug that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-administered 
with a known potent inhibitor. 
CYP3A4 substrates which are auto-perpetrators: Based on Novartis internal assessment. 
16.6.2 
Prohibited Medication 
Strong inducers of CYP3A4 
This list of CYP inducers was compiled from the University of Washington’s Drug Interaction 
Database (Updated April 2019). This list only meant to be used as a guide.  
Table 16-2 
List of prohibited strong inducers of CYP3A 
Category 
Drug Name 
Strong CYP3A Inducers  
Apalutamide, Avasimibe1, Carbamazepine, 
Enzalutamide, Ivosidenib, Lumacaftor, Mitotane, 
Phenobarbital, Phenytoin, Rifabutin, Rifapentine, 
Rifampin (Rifampicin), St. John's wort (hypericum 
perforatum)1  
1 Herbal product 

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Inhibitors of BCRP 
The table encompasses only drugs and molecular entities for which inhibition of BCRP has 
been investigated and/or formally shown in vivo in a clinical DDI study. Please note that this is 
not an exhaustive list and only meant to be used as a guide. When in doubt, refer to the 
prescribing information of the drug to assess whether a potential for BCRP inhibition is 
described.  
Table 16-3 
List of prohibited BCRP inhibitors 
Category 
Drug Name 
BCRP inhibitors - 
Evidence for DDI potential shown in vivo 
Protease Inhibitors (e.g., Atazanavir/ritonavir1,2, , 
Lopinavir/ritonavir1,2, Tipranavir/ritonavir1,2, Tipranavir2 , 
Paritaprevir2), Elvitegravir/cobicistat1,2, Curcumin1,2, 
Cyclosporine1,2, Daclatasvir1,2, Ledipasvir2, Eltrombopag1,2, 
Gefitinib2, Lapatinib1, Pantoprazole1,2 
1 Lee et al 2015 
2 Novartis PK Sciences DDI List (January, 2018) 

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