A Phase III, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of Alpelisib (BYL719) in Combination With Nab-paclitaxel in Patients With Advanced Triple Negative Breast Cancer With Either Phosphoinositide-3-kinase Catalytic Subunit Alpha (PIK3CA) Mutation or Phosphatase and Tensin Homolog Protein (PTEN) Loss Without PIK3CA Mutation
Phase: PHASE3
Conditions: Triple Negative Breast Neoplasms
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
BYL719 / Alpelisib 
Clinical Trial Protocol CBYL719H12301 / NCT04251533
EPIK-B3: A Phase III, multicenter, randomized, double-
blind, placebo-controlled study to assess the efficacy and 
safety of alpelisib (BYL719) in combination with nab-
paclitaxel in patients with advanced triple negative breast 
cancer with either phosphoinositide-3-kinase catalytic 
subunit alpha (PIK3CA) mutation or phosphatase and 
tensin homolog protein (PTEN) loss without PIK3CA 
mutation 
Document type: 
Amended Protocol Version (Clean) 
EUDRACT number: 
2019-002637-11 
Version number: 
02  
Clinical Trial Phase: 
III 
Release date: 
14-Mar-2023
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 2.0 (01-Aug-2018) 

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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 14 
Amendment 02 (14-Mar-2023) ......................................................................................... 17 
Amendment 01 (25-May-2021) ......................................................................................... 23 
Amendment 00-CN.01 (16-Oct-2020) .............................................................................. 29 
Protocol summary .............................................................................................................. 30 
1 
Introduction ....................................................................................................................... 34 
1.1 
Background ............................................................................................................ 34 
1.1.1 
Triple Negative Breast Cancer .............................................................. 34 
1.1.2 
The PI3K pathway overview and the PI3K pathway in TNBC ............ 36 
1.1.3 
Overview of Alpelisib ........................................................................... 38 
1.2 
Purpose .................................................................................................................. 42 
2 
Objectives, endpoints and estimands ................................................................................. 43 
2.1 
Primary estimand ................................................................................................... 46 
2.2 
Key secondary estimand ........................................................................................ 48 
3 
Study design ...................................................................................................................... 48 
4 
Rationale ............................................................................................................................ 54 
4.1 
Rationale for study design ..................................................................................... 54 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 55 
4.2.1 
Alpelisib antitumor activity in TNBC ................................................... 55 
4.2.2 
Alpelisib Phase III dose ........................................................................ 58 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 59 
4.3.1 
Nab-Paclitaxel in TNBC ....................................................................... 59 
4.3.2 
Nab-Paclitaxel dose schedule 100 mg/m2 on Day 1, 8, and 15 of 28 
Day treatment cycle ............................................................................... 60 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 61 
4.5 
Risks and benefits .................................................................................................. 61 
4.5.1 
Potential benefits to clinical trial participants ....................................... 61 
4.5.2 
Potential risks to clinical trial participants ............................................ 61 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 62 
5 
Study Population ............................................................................................................... 62 
5.1 
Inclusion criteria .................................................................................................... 63 

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5.2 
Exclusion criteria ................................................................................................... 64 
6 
Treatment ........................................................................................................................... 67 
6.1 
Study treatment ...................................................................................................... 67 
6.1.1 
Investigational and control drugs .......................................................... 68 
6.1.2 
Additional study treatments .................................................................. 70 
6.1.3 
Treatment arms/group ........................................................................... 70 
6.1.4 
Guidelines for continuation of treatment .............................................. 70 
6.1.5 
Treatment duration ................................................................................ 70 
6.2 
Other treatment(s) .................................................................................................. 71 
6.2.1 
Concomitant therapy ............................................................................. 71 
6.2.2 
Prohibited medication ........................................................................... 74 
6.3 
Participant numbering, treatment assignment, randomization .............................. 75 
6.3.1 
Participant numbering ........................................................................... 75 
6.3.2 
Treatment assignment, randomization .................................................. 75 
6.4 
Treatment blinding ................................................................................................. 76 
6.5 
Dose escalation and dose modification .................................................................. 77 
6.5.1 
Dose modifications ................................................................................ 77 
6.5.2 
Follow-up for toxicities ......................................................................... 86 
6.6 
Additional treatment guidance ............................................................................... 92 
6.6.1 
Treatment compliance ........................................................................... 92 
6.6.2 
Emergency breaking of assigned treatment code .................................. 92 
6.7 
Preparation and dispensation ................................................................................. 92 
6.7.1 
Handling of study treatment and additional treatment .......................... 93 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 94 
7 
Informed consent procedures ............................................................................................ 95 
8 
Visit schedule and assessments ......................................................................................... 97 
8.1 
Screening ............................................................................................................. 119 
8.1.1 
Eligibility screening ............................................................................ 121 
8.1.2 
Information to be collected on screening failures ............................... 122 
8.2 
Participant demographics/other baseline characteristics ..................................... 122 
8.3 
Efficacy ................................................................................................................ 123 
8.3.1 
Imaging tumor assessments................................................................. 123 
8.3.2 
Blinded independent review committee (BIRC) assessment .............. 126 
8.3.3 
Appropriateness of efficacy assessments ............................................ 126 
8.4 
Safety ................................................................................................................... 126 
8.4.1 
Laboratory evaluations ........................................................................ 127 
8.4.2 
Electrocardiogram (ECG) ................................................................... 129 

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8.4.3 
Pregnancy and assessments of fertility ............................................... 131 
8.4.4 
Appropriateness of safety measurements ............................................ 132 
8.5 
Additional assessments ........................................................................................ 132 
 
 132 
8.5.2 
Pharmacokinetics ................................................................................ 135 
 
 139 
9 
Study discontinuation and completion ............................................................................ 143 
9.1 
Discontinuation .................................................................................................... 143 
9.1.1 
Discontinuation from study treatment ................................................. 143 
9.1.2 
Discontinuation from study ................................................................. 144 
9.1.3 
Withdrawal of informed consent and exercise of participants’ data 
privacy rights ....................................................................................... 144 
9.1.4 
Lost to follow-up ................................................................................. 145 
9.1.5 
Early study termination by the sponsor ............................................... 145 
9.2 
Study completion and post-study treatment ........................................................ 145 
9.2.1 
Follow-up for safety evaluations ......................................................... 146 
9.2.2 
Follow-up for efficacy evaluations ..................................................... 146 
9.2.3 
Follow-up after disease progression.................................................... 147 
9.2.4 
Survival follow-up .............................................................................. 147 
10 Safety monitoring, reporting and committees ................................................................. 147 
10.1 
Definition of adverse events and reporting requirements .................................... 147 
10.1.1 
Adverse events .................................................................................... 147 
10.1.2 
Serious adverse events ........................................................................ 149 
10.1.3 
SAE reporting...................................................................................... 150 
10.1.4 
Pregnancy reporting ............................................................................ 151 
10.1.5 
Reporting of study treatment errors including misuse/abuse .............. 152 
10.2 
Additional Safety Monitoring .............................................................................. 152 
10.2.1 
Liver safety monitoring ....................................................................... 152 
10.2.2 
Data Monitoring Committee ............................................................... 153 
10.2.3 
Steering Committee ............................................................................. 153 
11 Data Collection and Database management .................................................................... 154 
11.1 
Data collection ..................................................................................................... 154 
11.2 
Database management and quality control .......................................................... 154 
11.3 
Site monitoring .................................................................................................... 155 
12 Data analysis and statistical methods .............................................................................. 155 
12.1 
Analysis sets ........................................................................................................ 156 
12.2 
Participant demographics and other baseline characteristics ............................... 157 

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12.3 
Treatments ........................................................................................................... 157 
12.4 
Analysis supporting objectives ............................................................................ 158 
12.4.1 
Definition of primary endpoint(s) ....................................................... 158 
12.4.2 
Statistical model, hypothesis, and method of analysis ........................ 158 
12.4.3 
Handling of intercurrent events of primary estimand ......................... 160 
12.4.4 
Handling of missing values not related to intercurrent event ............. 161 
12.4.5 
Supplementary analyses ...................................................................... 161 
12.5 
Analysis supporting secondary objectives ........................................................... 161 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................. 162 
12.5.2 
Safety endpoints .................................................................................. 163 
 
 165 
12.7 
Interim analyses ................................................................................................... 168 
12.8 
Sample size calculation ........................................................................................ 168 
12.8.1 
Primary endpoint(s) ............................................................................. 169 
12.8.2 
Secondary endpoint(s) ......................................................................... 170 
13 Ethical considerations and administrative procedures .................................................... 171 
13.1 
Regulatory and ethical compliance ...................................................................... 171 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................ 172 
13.3 
Publication of study protocol and results............................................................. 172 
13.4 
Quality Control and Quality Assurance ............................................................... 173 
13.5 
Data protection ..................................................................................................... 173 
13.6 
Participant Engagement ....................................................................................... 173 
14 Protocol adherence .......................................................................................................... 174 
14.1 
Protocol amendments ........................................................................................... 174 
15 References ....................................................................................................................... 175 
16 Appendices ...................................................................................................................... 183 
16.1 
Appendix 1: Guidelines for Response, Duration of Overall Response, TTF, 
TTP, Progression-Free Survival, and Overall Survival (based on RECIST 1.1) 183 
16.1.1 
Introduction ......................................................................................... 184 
16.1.2 
Efficacy assessments ........................................................................... 184 
16.1.3 
Efficacy definitions ............................................................................. 193 
16.1.4 
Data handling and programming rules ................................................ 203 
16.1.5 
Reference (available upon request) ..................................................... 206 
16.2 
Appendix 2: List of concomitant medications ..................................................... 208 
16.2.1 
Permitted medication to be used with caution .................................... 208 
16.2.2 
Prohibited medication ......................................................................... 209 

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16.3 
Appendix 3: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements ....................................................................................................... 210 
16.4 
Appendix 4: Statistical considerations ................................................................. 212 
List of tables 
Table 1-1 
Recently approved targeted therapies ................................................... 35 
Table 2-1 
Objectives, and related endpoints for Part A (TNBC with PIK3CA 
mutation) ............................................................................................... 43 
Table 2-2 
Objectives and related endpoints for Part B1 (TNBC with PTEN 
loss) ....................................................................................................... 44 
Table 2-3 
Objectives and related endpoints for Part B2 (TNBC with PTEN 
loss without PIK3CA mutation) ............................................................ 45 
Table 4-1 
Adverse events reported for alpelisib in combination with nab-
paclitaxel in Study CBYL719XUS06T ................................................. 57 
Table 6-1 
Investigational and control drug - Parts A and B2 ................................ 68 
Table 6-2 
Investigational and control drug – Part B1 ........................................... 69 
Table 6-3 
Stepwise dose reduction for alpelisib/placebo ...................................... 78 
Table 6-4 
Criteria for dose reduction / interruption and re-initiation of 
alpelisib/placebo treatment for adverse drug reactions ......................... 78 
Table 6-5 
Stepwise Dose reduction for Nab-paclitaxel ......................................... 84 
Table 6-6 
Hematologic Toxicities requiring dose adjustments for Nab-
Paclitaxel ............................................................................................... 84 
Table 6-7 
Overlapping toxicities with alpelisib requiring dose adjustments for 
Nab-Paclitaxel ....................................................................................... 86 
Table 6-8 
Alternative causes of liver disease ........................................................ 87 
Table 8-1 
Allowable visit windows ....................................................................... 98 
Table 8-2 
Assessment Schedule, Parts A and B2 .................................................. 99 
Table 8-3 
Assessment Schedule, Part B1 ............................................................ 113 
Table 8-4 
Imaging Assessment Collection Plan .................................................. 124 
Table 8-5 
Assessments & Specifications ............................................................ 127 
Table 8-6 
ECOG performance status .................................................................. 127 
Table 8-7 
Clinical laboratory parameters collection plan ................................... 129 
Table 8-8 
ECG collection plan ............................................................................ 130 
Table 8-9 
Patient reported outcomes collection plan - Parts A and B2 ............... 133 
 
. 136 
 
 137 
Table 8-12 
Pharmacokinetic blood collection log- alpelisib/placebo - Part B2 .... 137 
 
 138 
 
 138 

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Table 12-1 
Part B1 PPE Operating characteristics ................................................ 170 
Table 16-1 
Response criteria for target lesions ..................................................... 189 
Table 16-2 
Response criteria for non-target lesions .............................................. 191 
Table 16-3 
Overall lesion response at each assessment ........................................ 192 
Table 16-4 
Overall lesion response at each assessment: participants with non-
target disease only ............................................................................... 200 
Table 16-5 
Options for event dates used in PFS, TTP, duration of response ........ 201 
Table 16-6 
List of CYP450 substrates to be used with caution ............................ 208 
Table 16-7 
List of inhibitors and inducers of CYP2C8 and strong inhibitors of 
CYP3A to be used with caution .......................................................... 208 
Table 16-8 
List of prohibited strong inducers of CYP3A ..................................... 209 
Table 16-9 
List of prohibited BCRP inhibitors ..................................................... 209 
Table 16-10 
Liver event and laboratory trigger definitions .................................... 210 
Table 16-11 
Follow up requirements for liver laboratory triggers – ALT, AST, 
TBL ..................................................................................................... 210 
Table 16-12 
Follow up requirements for liver laboratory triggers – Isolated 
Hyperbilirubinemia ............................................................................. 211 
Table 16-13 
Part B1 Operating characteristics for ORR with 32, 36 or 40 
participants in each arm ...................................................................... 213 
List of figures 
Figure 3-1 
Study design .......................................................................................... 50 
Figure 3-2 
Study flow ............................................................................................. 53 
Figure 4-1 
Kaplan-Meier plot of PFS by median dose intensity (first 4 weeks) 
in the PIK3CA mutant cohort - Study CBYL719C2301 (Full 
analysis set) ........................................................................................... 59 
Figure 6-1 
Study drug administration on scheduled visit days ............................... 95 
Figure 8-1 
Timing of study procedures ................................................................ 130 
 

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List of abbreviations 
aBC 
advanced Breast Cancer 
ADA 
American Diabetes Association 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANA 
Antinuclear antibody 
ANC 
Absolute Neutrophil Count 
ARA 
Acid Reducing Agents 
ASCO 
American Society of Clinical Oncology  
ASMA 
Antismooth muscle antibody 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the curve 
AV 
Atrioventricular 
b.i.d. 
twice a day 
BAL 
Broncho-alveolar lavage 
BC 
Breast Cancer 
BCRP 
Breast Cancer Resistant Protein 
BIRC 
Blinded Independent Review Committee 
BMA 
Bone Modifying Agents 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BP 
Blood Pressure 
BPI-SF 
Brief Pain Inventory-Short form questionnaire  
BSA 
Body Surface Area 
BSEP 
Bile Salt Export Pump 
BUN 
Blood Urea Nitrogen 
C 
Cycle 
CABG 
Coronary artery bypass graft 
CBR 
Clinical Benefit Rate 
CD 
Carbohydrate-deficient 
CD-ROM 
Compact disc – read only memory 
CD8 
Cluster of Differentiation 8 
CDx 
Companion Diagnostics  
CFR 
Code of Federal Regulation 
CHF 
Congestive heart failure 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
Maximal plasma concentration 
CMO&PS  
Chief Medical Office and Patient Safety 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
CO 
Country Organization 

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COA 
Clinical Outcome Assessment 
COVID-19 
Coronavirus disease 2019 
CR 
Complete Response 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CT 
Computerized Tomography 
CTA 
Clinical Trial Assay 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating Tumor Deoxyribonucleic Acid  
CTT 
Clinical Trial Team 
CV 
Coefficient of Variation 
CYP 
Cytochrome P450 
D 
Day 
DB 
Double-blind 
DBP 
Diastolic Blood Pressure  
DD 
Differential Discordance 
DDI 
Drug-drug interaction 
DI 
Dose Intensity 
DILI 
Drug-Induced Liver Injury 
DKA 
Diabetic Ketoacidosis  
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid  
DOR 
Duration Of Response 
DRESS 
Drug Reaction with Eosinophilia and Systemic Syndrome  
DTI 
Direct Thrombin inhibitors 
Dx 
Diagnostic 
EASD 
European Association for the study of Diabetes 
EBV 
Epstein-Barr virus 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic Case Report/Record Form  
EDC 
Electronic Data Capture 
EDR 
Early discrepancy rate 
EM 
Erythema multiforme 
EMA 
European Medicines Agency 
EORTC-QLQ-C30 
European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire 
EOT 
End of Treatment 
EQ-5D-5L 
EuroQoL 5-level instrument  
ER 
Estrogen Receptor 
ERCP 
Endoscopic retrograde cholangiopancreatography 
EU 
Europe 

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FAS 
Full Analysis Set  
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FDG PET  
Fluorodeoxyglucose positron emission tomography  
FFPE 
Formalin fixed paraffin embedded 
FG 
Fasting Glucose 
FPFV 
First Patient First Visit 
FPG 
Fasting Plasma Glucose 
FSH 
Follicle-stimulating hormone 
G 
Grade 
GABA 
gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT/gammaGT/G-
GT 
Gamma-glutamyltranspeptidase 
GI 
Gastrointestinal 
GLDH 
Glutamate dehydrogenase 
h 
Hour 
HAV 
Hepatitis A 
HbA1c 
Glycosylated Hemoglobin 
HBV 
Hepatitis B virus 
hCG 
Human chorionic gonadotropin  
HCV 
Hepatits C virus 
HDL 
High Density Lipoprotein 
HER 
Human Epidermal growth factor Receptor 
HEV 
Hepatitis E virus 
HR 
Hormone Receptor 
HHNKS 
Hyperglycemic hyperosmolar non-ketotic syndrome  
HR' 
Hazard Ratio 
HSV 
Herpes Simplex Virus 
i.v. / IV 
intravenous 
IB 
Investigator's Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IHC 
immunohistochemistry 
IIT 
Investigator initiated trial 
IL-6 
Interleukin-6  
IMP 
Investigational Medicinal Product 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IR 
Immediate Release 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent To Treat 

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IUD 
Intrauterine device 
IUS 
Intrauterine system 
LC 
Liquid chromatography 
LDH 
Lactate dehydrogenase 
LDL 
Low Density Lipoprotein 
LDR 
Late discrepancy rate 
LFT 
Liver function test 
LLN 
Lower limit of normal 
LLOQ 
Lower limits of quantitation 
LPLV 
Last Patient Last Visit 
LVEF 
Left Ventricular Ejection Fraction 
MATE 
Multidrug and toxin extrusion 
mBC 
metastatic Breast Cancer 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
mL 
milliliter(s) 
MRI 
Magnetic Resonance Imaging 
MRP2 
Multidrug resistance-associated protein 2 
MS 
Mass spectrometry 
MTD 
Maximum tolerated dose 
mTOR 
mammalian Target Of Rapamycin 
MUGA 
Multiple Gated Acquisition  
NaF 
Sodium fluoride 
NCI 
National Cancer Institute 
NGS 
Next Generation Sequencing  
NTI 
Narrow therapeutic index 
o.d. 
once a day 
OATP 
Organic Anion-transporting Polypeptide 
OCT 
Organic Cation Transporter 
OL 
Open-label 
ONJ 
Osteonecrosis of the jaw 
ORR 
Overall Response Rate 
OS 
Overall Survival 
P-gp 
P-glycoprotein 
p.o. 
oral 
PARP 
Poly ADP Ribose Polymerase  
PAS 
Pharmacokinetic Analysis Set  
pCR 
Pathological complete response 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamic(s) 
PD' 
Progressive Disease 
PD-L1 
Programmed cell death ligand  
PET 
Positron emission tomography 
PFS 
Progression Free Survival 
PhRMA 
Pharmaceutical Research and Manufacturers in America 

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PI3K 
Phosphatidylinositol-3-kinase 
PIK3CA 
Phosphoinositide-3-kinase catalytic subunit alpha 
PK 
Pharmacokinetic(s) 
PLT 
Platelets 
PoC 
Proof of Concept 
PPE 
Proof of preliminary efficacy 
PR 
Progesterone Receptor 
PR' 
Partial Response 
PRO 
Patient Reported Outcome 
PS 
Performance status 
PSDS 
Post-study drug supply 
PTA 
Post-Trial Access 
PTEN 
Phosphatase and tensin homolog protein 
QOL 
Quality of Life 
QTc 
corrected QT interval 
QTcF 
Fridericia QT correction formula 
R Value 
ALT/ALP in x ULN 
RANK 
Receptor Activator of Nuclear Factor Kappa-B 
RAS 
Randomized Analysis Set 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RGQ 
Rotor-Gene Q 
RNA 
Ribonucleic acid  
RoW 
Rest of World 
RPTD 
Recommended Phase II Dose 
RTK 
Receptor tyrosine kinase 
s.c. 
subcutaneous 
SAE 
Serious Adverse Event 
sAG 
surface antigen 
SBP 
Systolic Blood Pressure  
SC 
Steering Committee  
SD 
standard deviation 
SD' 
Stable Disease 
SGLT2 
Sodium-glucose cotransporter 2 
SJS 
Steven-Johnson Syndrome 
SMQ 
Standardized MedDRA Query 
SMT 
Safety Management Team 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TBL 
Total bilirubin 
TCGA 
Translation Cancer Genome Atlas 
TEN 
Toxic Epidermal Necrolysis 
TNBC/mTNBC 
Triple-Negative Breast Cancer / metastatic Triple-Negative Breast Cancer 
TTR 
Time To Response 
ULN 
Upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
WBC 
White blood cell(s) 

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WHO 
World Health Organization 

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Glossary of terms 
Additional treatment 
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. any background 
therapy) 
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 
A 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 
characteristics, or a group of individuals followed-up or traced over time 
Control drug 
A study drug (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. 
Cycles 
Number and timing or recommended repetitions of therapy are usually expressed 
as number of days (e.g., q28 days) 
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. No 
specific request is made to stop the use of their samples or data. 
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 drug administration, if 
any). Participant agrees to the other protocol required assessments including 
follow-up. No specific request is made to stop the use of their samples or data. 
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 participant 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. 
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 
patients 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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Investigational treatment 
All investigational drug(s) whose properties are being tested in the study as well 
as their associated treatment controls. This includes any placebos, any active 
controls, as well as approved drugs used outside of their indication/approved 
dosage or tested in a fixed combination. Investigational treatment generally does 
not include other treatments administered as concomitant background therapy 
required or allowed by the protocol when used within approved indication/dosage. 
Medication number 
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system. 
Medication pack number 
A unique identifier on the label of medication kits.  
Mis-randomized 
participants 
Mis-randomized participants are those who were not qualified for randomization 
and who did not take study treatment, but have been inadvertently randomized 
into the study or the participant allocated to an invalid stratification factor 
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. 
Non-investigational 
medicinal Product (NIMP) 
Products which are not the object of investigation (e.g. any background therapy 
administered to each of the clinical trial participants, regardless of randomization 
group, rescue medication, active drug run-ins etc.) 
Part 
A sub-division of a study used to evaluate specific objectives or contain different 
populations. For example, one study could contain a single dose part and a 
multiple dose part, or a part in participants with established disease and in those 
with newly-diagnosed disease 
Participant 
A trial participant (can be a healthy volunteer or a patient). "Participant" 
terminology is used in the protocol whereas term "Subject" is used in data 
collection 
Participant 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. 
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. 
Perpetrator drug 
A drug which affects the pharmacokinetics of the other drug 
Personal data 
Participant information collected by the Investigator that is coded and transferred 
to Novartis 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. 
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 
Remote 
Describes any trial activities performed at a location that is not the investigative 
site  
Screen Failure 
A participant who did not meet one or more criteria that were required for 
participation in the study. The participant is screened but is not treated or 
randomized 
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 

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Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has spread 
from the original site to other parts of the body 
Stage 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 
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 completion 
Point/time at which the participant came in for a final evaluation visit or when study 
drug was discontinued whichever is later. 
Study drug 
discontinuation 
Point/time when participant permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature participant withdrawal. 
Study treatment 
Any drug or combination of drugs or intervention administered to the study 
participants as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy.  
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. 
Treatment arm/group  
A treatment arm/group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. 
Treatment of interest 
The treatment of interest and, as appropriate, the alternative treatment to which 
comparison will be made. These might be individual interventions, combinations of 
interventions administered concurrently, e.g. as add-on to standard of care, or 
might consist of an overall regimen involving a complex sequence of interventions. 
This is the treatment of interest used in describing the related clinical question of 
interest, which might or might not be the same as the study treatment 
Treatment number 
A unique identifier assigned in non-randomized studies to each dosed participant, 
corresponding to a specific treatment arm  
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 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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Amendment 02 (14-Mar-2023) 
Amendment rationale  
Study CBYL719H12301 was initiated in June 2020. 
The recruitment for Part A was halted on 11-Nov-2022 due to slow recruitment. This decision 
was not triggered by any new or unexpected safety findings. In total, 102 participants were 
randomized in Part A.  
Part B1 recruitment was completed in February 2022 with 35 participants enrolled. Part B1 did 
not meet its primary objective for confirmed overall response rate. Therefore, Part B2 will not 
be initiated. 
Thus, recruitment was halted for the entire study, and the primary analysis for Part A will now 
be descriptive only. 
Ongoing participants were allowed to continue study treatment if they were deriving benefit as 
assessed by the investigator.  
At the time of protocol amendment version 02 release, 29 participants were on study treatment 
in Part A and 3 participants in Part B1. 
Participants in Part A will be unblinded when all participants have completed 6 months of study 
treatment or have been discontinued from the study treatment, whichever occurs earlier.  
Treatment crossover from the control arm to the experimental arm will not be permitted. 
Participants in the experimental arm will be allowed to continue on the combination of alpelisib 
and nab-paclitaxel, based on the investigator’s judgement and individualized benefit/risk 
assessment, after discussion with the participant and documentation in the medical record.  
Participants in the control arm will be allowed to continue on nab-paclitaxel only, based on the 
investigator’s judgement and individualized benefit/risk assessment and after discussion with 
the participant and documentation in the medical record. Placebo tablets will no longer be 
administered.  
The main purposes of this amendment are to revise the protocol following the decision of 
recruitment halt: 
• To adjust the study objectives and endpoints due to the limited sample size in Part A 
• The primary analysis will be descriptive only  
• The overall survival (OS) will be a secondary rather than a key secondary endpoint, 
 
 
 
 
 
 
• To allow unblinding of all participants in Part A for investigators to know participant’s 
current treatment allocation 
• To streamline the safety and efficacy assessments once all participants have completed 6 
months of study treatment or have been discontinued from study treatment 
• The imaging assessments will be performed locally as clinically indicated, 

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• The laboratory assessments will be performed locally, 
 
 
   
• The collection of biopsies in case of skin toxicity is at Investigator’s discretion and 
will not be centrally collected, 
• The collection of survival, and antineoplastic therapies since discontinuation of study 
treatment will stop. 
• To clarify that the imaging data will not be centrally collected and no BIRC 
assessment will be performed 
• To update the protocol based on the Investigator’s Brochure (IB) Edition 17: 
• Recommendation to consider metformin extended release (XR) as a suitable 
alternative to metformin immediate release (IR). Metformin XR is associated with 
less gastrointestinal toxicities, and once daily dosing, both of which may lead to better 
participant compliance and improved glucose management compared to the 
immediate release formulation (Jabbour and Ziring 2011). 
• Updated guidance regarding diarrhea; addition of colitis and its management 
• Updated definition of hypersensitivity to include angioedema 
• Removal of the requirement to monitor effectiveness when co-administering oral 
antidiabetics predominantly metabolized by CYP2C9 and CYP2C8, based on results 
from a post-marketing study (Cocktail Study CBYL719A2111) concluding that no 
dose adjustment is required when co-administering alpelisib with sensitive substrates 
for CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A4. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through font for deletions and underline for insertions. The following 
sections have been changed in the amended protocol: 
• Editorial revisions, clarifications and corrections are made throughout the protocol to 
improve consistency. 
• In Section 5 and the following ones, the term “subject” is replaced with the term 
“participant”, the section titles have been updated in line with the latest protocol template 
v5.0 (dated 14-Jan-2022, wherever applicable) 
• List of abbreviations updated 
• Glossary of terms: aligned with protocol template v 5.0 
• Protocol summary: aligned with changes applicable in protocol amendment 2 and to 
correct the release date of protocol amendment 01 
• Section 1.1.3.2 has been updated with the latest Investigator’s Brochure information on 
the number of clinical studies in which alpelisib has been investigated as of 23-May-2022 
• Table 2-1, Table 2-2 and Table 2-3 objectives and endpoints have been updated post study 
revision after recruitment halt 
• Section 2.2 is no longer applicable following implementation of protocol amendment 02 

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• Section 3 has been updated with the the changes based on the study revision after 
recruitment halt  
• Figure 3-1: updated to reflect changes applicable in protocol amendment 2 
• Figure 3-2: updated to reflect changes applicable in protocol amendment 2 
• Section 4.4 not applicable anymore: header was kept to preserve the section numbering 
• Section 4.5.2 was updated with potential fetal harm results in animal studies and the 
update that the assessment of Benefit/Risk assessment did not reveal any additional risks 
related to coronaviurs disease 2019 (COVID-19) 
• Section 5 has been updated with the recruitment halt for the study and the new protocol 
amendment 02 study workflow 
• Section 6 was updated to specify that participants will be unblinded and options post 
unblinding were presented 
• Table 6-1 updated with footnotes to clarify that post unblinding participants in the 
experimental arm will continue with alpelisib and participants in the control arm will stop 
receiving placebo supplies 
• Section 6.2.1 was updated with the latest language for the guidelines for the treatment of 
alpelisib-induced hyperglycemia 
• Section 6.4 was updated to mention that Part A patients will be unblinded and options post 
unblinding were presented 
• Table 6-4 has been updated with the latest language for the management of fasting 
Glucose, gastro-intestinal and skin related adverse events 
• Section 6.5.2.3 was updated to clarify that with protocol amendment 02, skin biopsy 
sample collection will no longer need to be submitted to Novartis for central assessment 
and for Grade 4 or any grade of suspected severe cutaneous reaction, skin toxicity it is no 
longer a must to perform skin photographs and skin biopsy 
• Section 6.5.2.4 has been updated for guidelines for the treatment of alpelisib-induced 
hyperglycemia 
• Section 6.5.2.6 was updated to add “angiodema” as a hypersensitivitiy reaction to alpelisib 
and nab-paclitaxel  
• Section 6.6.2 was updated to remove “name (if applicable)” and to clarify that with 
protocol amendment 02 this section is no longer applicable as all participants in Part A are 
to be unblinded 
• Figure 6.1 updated to clarify that PROs are to be performed until all participants have 
completed 6 months of study treatment or have been discontinued from study treatment 
• Table 8-1 was updated with the changes based on protocol amendment 2 
• Table 8-2 assessment schedule was updated for Part A participants based on changes 
following protocol amendment 02 
• Table 8-3 assessment schedule was updated for Part B1 participants based on changes 
following protocol amendment 02 
• Section 8.1 was updated to no longer keep a small amount of any remaining tissue for the 
development of future companion diagnostic   

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• Section 8.1.2 was updated to include local PIK3CA mutational status for screening 
failures 
• Section 8.3.1 was updated to remove central collection and review of the scans, to clarify 
that tumor assessment will be collected locally as clinically indicated and survival 
assessment will continue until all participants have completed 6 months of study treatment 
or have been discontinued from study treatment 
• Table 8-4 was updated to clarify that imaging assessments will continue as clinically 
indicated until all participants have completed 6 months of study treatment or have been 
discontinued from study treatment 
• Section 8.3.3 renumbered further to the removal of previous Section 8.3.2 (no longer 
applicable following protocol amendment 02) and  updated to reflect that BIRC 
assessments will not be performed for any participants  
• Section 8.4.1 was updated to reflect safety assessments will be collected and analysed only 
by local laboratory once all participants have completed 6 months of study treatment or 
have been discontinued from the study 
• Section 8.5.1.1 was updated to reflect that PRO assessments will no longer performed 
once all participants have completed 6 months of study treatment or have been 
discontinued from the study 
• Table 8-9: Footnote was added to reflect that PRO assessments will no longer performed 
once all participants have completed 6 months of study treatment or have been 
discontinued from the study treatment 
• Section 8.5.2 the sentence “Following implementation of protocol amendment 02, PK 
samples collection will stop was added  
• Section 8.5.2.1 the sentence “Following implementation of protocol amendment 02, PK 
samples collection will stop was added 
• Section 8.5.3.1.3 removed since no longer applicable with protocol amendment 02 
• Table 8-10, Table 8-11, Table 8-13 Pharmacokinetic blood collection log - nab-paclitaxel 
- Part A and Table 8-14 were updated each with a footnote reflecting that collection of 
unscheduled samples will stop after all participants have completed 6 months of study 
treatment or have been discontinued from the study treatment 
• Table 8-12 was updated with the sentence “Not applicable following protocol amendment 
02.” 
 
 
 
 
 
• Section 9.1.1 was updated with “if applicable” for New antineoplastic therapy 
• Section 9.1.3 was updated with clarification of the conditions meeting withdrawal of 
infomred consent and clarifications on procedures for withdrawal of consent 
• Section 9.1.4 was updated with clarifications on lost to follow-up as per protocol template 
v 5.0  
• Section 9.2 was updated to match protocol amendment 02 updates regarding study 
completion and post study treatment  

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• Section 9.2.2 was updated with the changes regarding efficacy evaluations following 
protocol amendment 02  
• Section 9.2.3 was updated with the changes regarding disease progression following 
protocol amendment 02 
• Section 9.2.4 was updated with the changes regarding survival follow-up following 
protocol amendment 02 
• Section 10.1.1 Clarifications on adverse events have been added 
• Section 10.1.3  Reporting of SAE was clarified regarding disease progression as per 
protocol template v 5.0  
• Section 10.1.4 Clarifications on procedures and reporting in case of pregnancy as per 
protocol template v 5.0 
• Section 10.1.5 Study treatment misuses have been clarified and Table 10-1 has been 
removed 
• Section 10.2.1 Update of liver safety monitoring as per protocol template v 5.0 
• Section 11.1 Updated to clarify which data will be captured on CRF and on external 
originating source  
• Section 11.2 was updated to match protocol amendment 02 
• Section 12 was updated to match protocol amendment 02 
• Section 12.1 the following sentence was added “Part B2 was never initiated” 
• Section 12.4 the primary objective was updated accordingly to Section 2 updates and 
sentence added that Part B2 was never initiated 
• Section 12.4.1 the primary endpoints updated for Part A and sentence added that Part B2 
was never initiated 
• Section 12.4.2 updated for Part A primary efficacy analysis and sentence added that Part 
B2 was never initiated 
• Section 12.4.3 was updated to reflect that Part B2 was never initiated 
• Section 12.4.4 was updated to reflect that Part B2 was never initiated 
• Section 12.4.5 Sensitivity analysis is not applicable anymore 
• Section 12.5 was updated according to changes with protocol amendment 02 
• Section 12.5.1.1 is not applicable anymore 
• Section 12.5.3 and Section 12.5.4 removed from secondary endpoints 
 
 
 
• Section 12.7 Interim analysis updated for Part A and Part B2 removed as no longer 
applicable 
• Section 12.8 Clarification added on the sample size calculation after recruitment halt 
• Section 12.8.1 Audit size for BIRC assessment removed as no longer applicable 
• Section 12.8.2 was updated to clarify that it referred to the original design 
• Section 13.1 Section clarified with additional details added as per protocol template v 5.0 

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Protocol No. CBYL719H12301 
 
• Section 13.2 Clarification on Investigator’s responsibilities have been added as per 
protocol template v 5.0 
• Section 13.3 Clarifications added on CTIS public website. Addition that any data analyses 
carried out independently by the Investigator should be submitted to Novartis before 
publication or presentation  
• Section 13.4 Clarifications added as per protocol template v 5.0 
• Section 13.5 Addition of data protection section as per protocol template v 5.0 
• Section 15 Addition of new reference 
• Table 16-11 was updated according to the protocol template v 5.0 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (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 No. CBYL719H12301 
 
Amendment 01 (25-May-2021)  
As of the release of this amendment, 21 participants have received study treatment in the 
randomized study Part A, and 10 participants have received study treatment in the non-
randomized study Part B1 of this clinical trial. 
Amendment rationale  
The main purposes of this amendment are: 
• To incorporate guidance related to the use of sodium-glucose cotransporter 2 (SGLT2) 
inhibitors for the management of hyperglycemia, an on-target side effect of the PI3K 
inhibitor alpelisib. It is recommended to start treatment with metformin, however SGLT2 
inhibitors may be a suitable alternative or add-on therapy to metformin based on available 
data from the SOLAR-1 study (see Section 6.2.1).  
• To incorporate further guidance on alpelisib associated rash and its optimal management. 
 
 
 
  
• To allow TNBC patients with tumor harboring PTEN loss and unknown PIK3CA status to 
enroll into study Part B1. PIK3CA status is defined as ‘unknown’ if the PIK3CA results 
from the PIK3CA mutation assay are reported as invalid based on specified assay control 
parameters. The incidence of a PIK3CA unknown tumor to be PIK3CA mutant is 
estimated to be low (2%) based on the prevalence of PIK3CA mutation and PTEN loss 
overlap in TNBC (Cossu-Rocca et al 2015).  
In addition, the following changes are implemented: 
• Addition of language related to a Public Health emergency (when it limits or prevents on-
site study visits during the Public Health emergency, such as a pandemic).  
• Wording changes to align with new Novartis guidance on the estimand framework and 
protocol template v4.0 language 
• Clarifications and updates in response to Health Authority feedback:  
• exclusion criteria # 2 modified to add examples intolerance to glucose due to the 
presence of lactose in the placebo formulation;  
• inclusion criteria #7 modified to align with nab-paclitaxel label (USPI Abraxane®) 
and alpelisib program language;  
• correction of discrepancies in several sections of the protocol;  
• assessment of the Benefit/Risk identified no additional risks related to COVID-19 and 
no changes were made as a result 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through font for deletions and underline for insertions. The following 
sections have been changed in the amended protocol: 

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• Editorial revisions, clarifications and corrections are made throughout the protocol to 
improve consistency. 
• Throughout the protocol, the term “subject” is replaced with the term “participant”, the 
section titles have been updated in line with the latest protocol template v4.0 (dated 15-
Feb-2021, wherever applicable) 
• List of abbreviations: new abbreviations added 
• Glossary of terms: aligned with protocol template v 4.0 
• Protocol summary: aligned with changes applicable in Amendment 1 
• Section 1.1.3.2: updated the number of clinical studies in which alpelisib has been 
investigated as of 13-May-2020 
• Table 2-1, Table 2-2 and Table 2-3: Clarification of the Endpoints to corresponding to 
specific Objectives; update of title of Table 2-2  
• Section 2.1:  For Part A/B2, start of new anti-neoplastic therapy was removed from 
intercurrent events since it has been incorporated in the treatment attribute; clarification on 
justification for targeting the treatment effect was added for Part A, B1 and B2 ; scientific 
question of interest, primary estimand and summary measure corrected for part B1 to 
reflect open-label design 
• Section 2.2: Secondary estimand updated 
• Section 3:  Stratification factor definition clarified; Clarification that endocrine-based 
therapy for HR+ advanced/metastatic BC should not be counted as a line of treatment; 
modification to allow TNBC patients with tumor harboring PTEN loss and unknown 
PIK3CA status to enroll into study Part B1; addition of  ‘unknown’ PIK3CA status 
definition; Modification of Screening period into Pre-screening and Screening period; 
Clarification that local testing for PIK3CA mutation status is not limited to tumor tissue 
• Figure 3-1:  Correction to reflect changes applicable in Amendment 1 
• Figure 3-2:  Correction that Parts A & B2 are double-blind, randomized, placebo-
controlled, update to reflect revision of eligibility criteria and to add the molecular pre-
screening period 
• Section 4.1:  Modification to allow TNBC patients with tumor harboring PTEN loss and 
unknown PIK3CA status to enroll into study Part B1; clarification on “Line of therapy” 
wording. 
• Section 4.5.2: Update regarding risk benefit assessment related to COVID-19 
• Section 4.6:  Addition of section on the rationale for mitigation procedures in case of 
public health emergency 
• Consistent with this rationale, mitigation procedures in case of public health emergency 
have been added to the following sections:   
• Section 6.7 – Preparation and dispensation (applicable for alpelisib/placebo) 
• Section 7 – Informed consent procedures 
• Section 8 – Visit schedule and assessments 
• Section 8.4 – Safety 
• Section 8.4.1 – Laboratory evaluations 
• Section 8.4.3 – Pregnancy and assessments of fertility 

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• Section 5.1 Inclusion criteria: 
• #4: Renumbered from 4 to 4a. Change to allow patients with PTEN loss and unknown 
PIK3CA status to enrol into study Part B1; Clarification that local testing for PIK3CA 
mutation status is not limited to tumor tissue  
• #6: Clarification that endocrine-based therapy for HR+ advanced/metastatic BC 
should not be counted as a line of treatment 
• #7: Renumbered from 7 to 7a. Modification laboratory criteria (for AST/ALT and 
Total bilirubin values) that defines adequate bone marrow and organ function to align 
with nab-paclitaxel label (USPI Abraxane®) and alpelisib program language 
• Section 5.2 Exclusion criteria 
• # 2: Clarification of possible intolerance due to excipients present in the placebo 
tablet  
• #3, #9, #10, #11, #13, #15, #16, #24:  Clarification of criteria, respectively, related to 
inflammatory breast cancer, prior malignancy, CNS involvement, diabetes mellitus, 
pancreatitis, pneumonitis/interstitial lung disease, cardiac events, male participants 
• #23:  Addition of the provision for locally regulated methods of contraception 
• Section 6.1:  Clarification of criteria for nab-paclitaxel brands that need to be met for use 
in the study 
• Table 6-1 & Section 6.1.1.2:  Addition of powder for infusion dispersion as another nab-
paclitaxel pharmaceutical dosage form 
• Table 6-1: Clarification that nab-paclitaxel can be supplied by study site 
• Section 6.1.1.1 and Section 6.1.1.2: Recommendation for prophylactic antihistamine use 
added to decrease frequency and severity of alpelisib associated rash; clarification on nab-
paclitaxel administration after alpelisib/placebo dosing 
• Section 6.1.5: Addition of post-trial access information 
• Section 6.1.5.1: Clarification that disease progression is assessed locally by investigator as 
per RECIST 1.1 
• Section 6.2.1:  Recommendations for use of sodium-glucose cotransporter 2 (SGLT2) 
inhibitors as additional oral anti-diabetics to manage alpelisib associated hyperglycemia 
• Section 6.2.1.2:  Update of drug classification of denosumab as a RANK-ligand inhibitor  
• Section 6.3.1: Clarification that participant number is assigned by the clinical database and 
that a new patient number is assigned in case of re-screening 
• Section 6.3.2:  Clarification on disclosure of Randomization codes to PK Bioanalysts 
• Section 6.4:  Clarification that unblinding at site for safety reasons results in 
discontinuation from the study treatment  
• Section 6.5.1.1: Addition of cross-references for specific events requiring permanent 
treatment discontinuation; dose changes must be recoreded in the appropriate eCRF 
• Table 6-4:  Update of table title and dose modification recommendation for 
alpelisib/placebo for specified adverse drug reactions 
• Section 6.5.2.1 Update of follow-up on potential drug-induced liver injury (DILI) cases 
• Section 6.5.2.3:  Update of guidelines for treatment of alpelisib-induced skin toxicity 

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• Section 6.5.2.4: Update of guidelines for the treatment of alpelisib-induced hyperglycemia 
• Section 6.5.2.5: Addition of of CTCAE version number  
• Section 6.7: Clarification added that participants will receive alpelisib/placebo on an 
outpatient basis) 
• Section 6.7.1.1: Possibility of on-site destruction of study treatment added 
• Figure 6-1:  Correction of diagram depicting blood draw order to be consistent with blood 
draw order as described in the Central Laboratory manual and Flow chart 
• Section 7: Addition of a list indicating informed consents used in the study 
• Section 8: Update to clarify assessments to be recorded in the clinical database and visits 
to be performed in case of study treatment and study discontinuation or Withdrawal of 
consent/Opposition to use data/biological samples 
• Table 8-1: Addition of molecular pre-screening visit and update of screening visit 
window. Clarification of C1D1 visit and dosing; extension of allowed time window for 
follow-up after disease progression 
• Table 8-2 and Table 8-3 
• Modification of study period, time window for tumor tissue collection, information on 
prior local PIK3CA mutation testing and IRT registration consistent with addition of 
Pre-screening to determine participant’s molecular status 
• IRT Randomization and IRT Study Drug Dispensation corrected to be recorded in the 
clinical database or received from a vendor 
• Physical examination frequency modified and visits requiring a short or full physical 
examination updated, footnotes added in these tables to reflect those changes 
• Clarification on the collection of skin photography in case of Grade 3/4 skin toxicity 
• Applicable only to Table 8-3:  Removal of ECOG assessments at visits after 
Screening to align with Part B1 objectives 
 
 
 
 
• Section 8.1.1: Update to align with the addition of Pre-screening 
• Section 8.1.2:  Clarification of information collected on screen failures 
• Section 8.2:  Addition of rationale on the collection of demography information 
• Section 8.3.1: Clarification that imaging data will be centrally collected for Parts A and 
B2 participants and that no central imaging collection/BIRC assessment will be made for 
Part B1 participants 
• Table 8-4:  Clarification on the timeframe within which imaging assessments is 
considered as baseline images 
• Table 8-5:  Modification of the frequency for short physical examinations 
• Section 8.4.1: Clarification that clinically significant abnormalities must be recorded as 
either medical history/current medical conditions or adverse events 
• Section 8.4.2:  Clarification on use of Fridericia QTcF for clinical decisions 
• Section 8.5.1.1:  Clarification on self-administration of PROs by study participants 

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• Section 8.5.2.1:  Correction of order of PK sample collection to be consistent with blood 
collection order as specified in the Central laboratory manual and Flow Chart  
 
 
 
• Section 9.1.1: Removal of six treatment cycles as target for nab-paclitaxel administration 
in absence of disease progression or unaccepted toxicities; Clarification provided on visits 
to be completed upon discontinuation from study treatment 
• Section 9.1.2:  Addition of section on discontinuation from study 
• Section 9.1.3, Section 9.1.4, Section 9.2.2: Modification to include Opposition to use 
data/biological samples with Withdrawal of informed consent; Modification of the 
conditions meeting withdrawal of informed consent and clarification on procedures for 
withdrawal of consent/opposition to use data/biological samples 
• Following the grouping of Opposition to use data/biological samples with Withdrawal 
of informed consent, the mention of “opposition to use data/biological samples” have 
been added in other protocol sections where previously only withdrawal of informed 
consent is mentioned 
• Section 10.1.1:  Clarification of AE collection during the Molecular Pre-screening period; 
Inclusion of CTCAE 4.03 Grade 5 (AEs leading to deaths) in AE assessment and grading; 
Clarification of AE reporting in case of progression of malignancy 
• Section 10.1.3:  Clarification on SAE reporting 
• Section 10.1.4:  Clarification on procedures and reporting in case of pregnancy  
• Section 10.2.1: Update of liver safety monitoring 
• Section 11.2:  Clarification of data tracked in the IRT system 
• Section 12.4.3:  Deletion of start of new anti-neoplastic therapy as an intercurrent event 
attribute that characterizes the primary estimand for Parts A and B2 
• Section 12.5:  For Parts A and B2, summary statistics of plasma alpelisib (Parts A & B2) 
and paclitaxel (Part A only) concentrations by time point were added; For Part B1, the 
removal of time to deterioration in ECOG performance status and the addition of summary 
statistics of plasma alpelisib and paclitaxel concentrations by time point 
• Section 12.5.1.1: removal of start of new antineoplastic therapy’ from the intercurrent 
events) 
• Section 12.5.1.2:  Clarification of summary statistics that will be presented for ORR and 
CBR 
• Section 12.5.2:  Clarification of safety summaries that will presented in data analyses 
• Section 12.5.4:  Clarification of PRO assessments that will be included in the data analysis 
• Section 13.5:  Addition of materials provided to patient as part of patient engagement 
initiatives  
• Section 15: Addition of new references 
• Table 16-9: Protease inhibitors term has been deleted from the List of prohibited BCRP 
inhibitors to keep only drug name 
• Section 16.3:  Update of laboratory trigger definitions and follow-up requirements in case 
of Liver events 

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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (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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Amendment 00-CN.01 (16-Oct-2020)  
Amendment rationale 
As of the release of this amendment, no site has been initiated and no subject has been screened 
or has received study treatment in China. 
The main objective of this local amendment 00-CN.01 is to implement the Human Genetic 
Resources Administration of China (HGRAC) request to reduce the number of tumor slides 
requested for central PIK3CA mutation and PTEN expression testing in China. A total of 7 
slides from a resection tissue or 11 slides from a core needle biopsy are considered adequate for 
prospective patient selection to determine a subject’s biomarker eligibility of either having a 
PIK3CA mutation or PTEN loss. 
Changes to the protocol 
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. 
• Section 5.1 Inclusion criteria 4: The number of slides required for screening is removed 
and instead reference to 
 
  
• Section 8.1 Screening:  The number of slides required for screening is removed and 
instead references 
  
 
 
  
 
 
   
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
 

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Protocol summary 
Protocol number 
CBYL719H12301 
Full Title 
EPIK-B3: A Phase III, multicenter, randomized, double-blind, placebo-controlled study 
to assess the efficacy and safety of alpelisib (BYL719) in combination with nab-
paclitaxel in patients with advanced triple negative breast cancer with either 
phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) mutation or phosphatase 
and tensin homolog protein (PTEN) loss without PIK3CA mutation 
Brief title 
Study assessing the efficacy and safety of alpelisib plus nab-paclitaxel in participants 
with advanced triple negative breast cancer who carry either a PIK3CA mutation or 
have PTEN loss without PIK3CA mutation 
Sponsor and 
Clinical Phase 
Novartis; Phase III 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this study is to determine whether treatment with alpelisib in 
combination with nab-paclitaxel is safe and effective in participants with advanced triple 
negative breast cancer (aTNBC) who carry either a PIK3CA mutation (Study Part A) or 
have PTEN loss (Study Parts B1 and B2). 
An investigator-initiated study in HER2-negative metastatic breast cancer patients who 
were treated with alpelisib combined with nab-paclitaxel included 12 participants with 
aTNBC. These TNBC participants had an Overall Response Rate (ORR) of 58%. Five 
of the 12 TNBC participants carried a Phosphatidylinositol-3-kinase (PI3K) pathway 
alteration in their tumor samples: 3 had a PIK3CA mutation, 1 had a PTEN loss without 
a PIK3CA mutation and 1 had both a PIK3CA mutation and PTEN loss. Clinical benefit 
was observed in all these participants. 
Primary 
Objective(s)  
Part A  
• 
to assess whether treatment with alpelisib in combination with nab-paclitaxel 
prolongs Progression Free Survival (PFS) compared to placebo in combination with 
nab-paclitaxel 
Part B2*  
• 
to determine whether treatment with alpelisib in combination with nab-paclitaxel 
prolongs Progression Free Survival (PFS) compared to placebo in combination with 
nab-paclitaxel 
Part B1 
• 
to assess the antitumor activity of alpelisib in combination with nab-paclitaxel based 
on the Overall Response Rate (ORR) with confirmed response at 6 months via 
local radiology assessments 
*Part B2 was not initiated 
Secondary 
Objectives 
Part A and Part B2* secondary objectives: 
• 
To assess whether treatment with alpelisib in combination with nab-paclitaxel 
prolongs Overall Survival (OS) compared to placebo in combination with nab-
paclitaxel 
• 
To evaluate safety and tolerability 
• 
To evaluate the efficacy of alpelisib in combination with nab-paclitaxel measuring 
the ORR with confirmed response, Clinical Benefit Rate (CBR) with confirmed 
response, Duration of response (DOR) with confirmed response and Time To 
Response (TTR) based on local radiological assessments 
• 
To evaluate the association between PIK3CA mutation status as measured in 
Circulating Tumor Deoxyribonucleic Acid (ctDNA) at baseline with PFS upon 
treatment with alpelisib 
*Part B2 was not initiated 
Part B1 secondary objectives: 
• 
To evaluate safety and tolerability 

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• 
To evaluate the efficacy measuring the CBR with confirmed response, DOR with 
confirmed response and TTR based on local radiological assessments 
Study design 
This is a phase III, multicenter, international, randomized, double-blind, placebo-
controlled study in participants with aTNBC with either PIK3CA mutation or PTEN loss. 
Upon confirming either PIK3CA mutation and/or PTEN loss status, advanced TNBC 
participants meeting all other eligibility criteria will be assigned to either Part A (PIK3CA 
mutation regardless of PTEN loss), Part B1 (PTEN loss with PIK3CA unknown or non 
mutant) or B2 (PTEN loss without PIK3CA mutation). Part B1 is single-arm and open-
label with approximately 32 participants receiving alpelisib combined with nab-
paclitaxel. ORR and safety data after 6 months of follow-up will be used to make the 
decision on whether or not to initiate part B2. 
If the results of part B1 warrant further development in this patient population, additional 
participants with PTEN loss and without PIK3CA mutation and meeting all other 
eligibility criteria will be enrolled into Part B2. 
For both Part A and Part B2, participants will be randomized in a 1:1 ratio to receive 
alpelisib or placebo, combined with nab-paclitaxel. Randomization will be stratified by 
the line of therapy in the advanced/metastatic setting (1st line versus 2nd line); 
Hormone Receptor (HR) status of primary tumour (HR+ versus HR-); and prior 
treatment with checkpoint inhibitors (Yes versus No). 
In all Part A, Part B1 and Part B2, participants will continue to receive the study 
treatment until discontinuation due to disease progression, death, unacceptable toxicity, 
lost to follow-up or withdrawal of consent/opposition to use data/biological samples. 
Part B1, in participants with PTEN loss and without PIK3CA mutation, didn’t meet its 
primary endpoint of ORR. Hence, Part B2 will not be initiated. Inaddition, Novartis 
decided to halt enrollment of Part A due to slow recruitment.  
Study Population 
The study was initially planned to include approximately 566 male or female adult 
participants with aTNBC who carry either a PIK3CA mutation (approximately 252 
participants in Part A) or have PTEN loss (approximately 32 participants in Part B1 and 
282 participants in Part B2*) and who have received no more than one prior line of 
therapy for metastatic disease. 
When recruitment was permanently halted, a total of 137 participants were 
randomized/enrolled (102 participants in Part A and 35 participants in Part B1).  
*Part B2 was not initiated 
Key Inclusion 
criteria 
No changes were made to the eligibility criteria since all participants were randomized 
prior to the permanent recruitment halt and the release of the protocol amendment 02. 
• 
Participant is ≥ 18 years old at the time of informed consent  
• 
Participant has histologically confirmed diagnosis of advanced (loco-regionally 
recurrent and not amenable to curative therapy, or metastatic (stage IV)) TNBC 
• 
Participant has either a measurable disease per RECIST 1.1 criteria or, if no 
measurable disease is present, then at least one predominantly lytic bone lesion or 
mixed lytic-blastic bone lesion with identifiable soft tissue component (that can be 
evaluated by CT/MRI) must be presentParticipant has adequate tumor tissue to 
identify the PIK3CA mutation status (either carrying a mutation or without a 
mutation) and the PTEN loss status; both of which will determine whether the 
Participant can be allocated to Part A - PIK3CA mutation regardless of PTEN 
status; or to Part B - PTEN loss  
• 
Participant has an Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1 
• 
Participant has received no more than one line of therapy for metastatic disease. 
• 
Participant has adequate bone marrow and organ function 
Key Exclusion 
criteria 
• 
Participant has received prior treatment with any PI3K, mTOR or AKT inhibitor  
• 
Participant has a known hypersensitivity to alpelisib, nab-paclitaxel or to any of their 
excipients 
• 
Participant has not recovered from all toxicities related to prior anticancer therapies 
to NCI CTCAE version 4.03 Grade ≤1; with the exception of alopecia 
• 
Participant has central nervous system (CNS) involvement 

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• 
Participant with an established diagnosis of diabetes mellitus type I or uncontrolled 
type II based on Fasting Plasma Glucose and HbA1c 
• 
Participant has impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of the study drugs (e.g., ulcerative diseases, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel 
resection) based on investigator discretion 
• 
Participant has a history of acute pancreatitis within 1 year prior to screening or 
past medical history of chronic pancreatitis 
• 
Participant has currently documented pneumonitis/interstitial lung disease  
• 
Participant has a history of  severe cutaneous reactions, such as Steven-Johnson 
Syndrome (SJS), erythema multiforme (EM),Toxic Epidermal Necrolysis (TEN) or 
Drug Reaction with Eosinophilia and Systemic Syndrome (DRESS) 
• 
Participant with unresolved osteonecrosis of the jaw 
Study treatment 
For Study Part A and B2*, participants will be randomized 1:1 to receive either: 
• 
Experimental arm: alpelisib (at 300 mg orally, once daily) + nab-paclitaxel (at 100 
mg/m2 intravenously at Days 1, 8 and 15 of a 28-day cycle); or 
• 
Control arm: placebo (orally, once daily) + nab-paclitaxel (at 100mg/m2 
intravenously at Days 1, 8 and 15 of a 28-day cycle) 
For Study Part B1, all participants will receive alpelisib (at 300 mg orally, once daily) + 
nab-paclitaxel (at 100 mg/m2 intravenously at Days 1, 8 and 15 of a 28-day cycle) 
*Part B2 was not initiated 
Efficacy 
assessments 
• 
Chest, abdomen, and pelvis, CT/MRI at screening and every 8 weeks (+/- 7 days) 
during the first 18 months and every 12 weeks thereafter until disease progression, 
end of treatment, death, withdrawal of consent/opposition to use data/biological 
samples, or lost to follow-up. Once all participants have completed 6 months of 
study treatment or have been discontinued from the study treatment, efficacy 
assessments will be performed locally as clinically indicated. 
• 
Survival status every 12 weeks (or earlier if required) until all participants have 
completed 6 months of study treatment or have been discontinued from study 
treatment 
Pharmacokinetic 
assessments 
• 
Blood samples to calculate PK parameters for alpelisib for participants enrolled in in 
Part 
 B2* 
• 
Blood samples to calculate PK parameters for paclitaxel for participants enrolled in 
Part 
 B1 
*Part B2 was not initiated 
Following implementation of protocol Amendment 02, PK samples collection will stop 
Key safety 
assessments 
• 
Physical examination 
• 
Body weight and vital signs 
• 
ECOG performance status 
• 
Laboratory assessment including hematology, biochemistry, urinalysis and 
coagulation 
• 
Serum pregnancy test for women of child-bearing potential 
• 
Electrocardiogram (ECG) 
• 
Cardiac imaging 
• 
Monitoring of adverse events (AEs) and serious adverse events (SAE) 
Once all participants have completed 6 months of study treatment or have been 
discontinued from the study treatment, laboratory assessments will be performed 
locally. 
Other 
assessments  

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Data analysis 
Part A: 
The primary efficacy analysis for Part A is to compare and summarize PFS between the 
two treatment groups descriptively. The primary analysis will be performed when all 
participants in Part A have completed 6 months of study treatment or have discontinued 
from study treatment, whichever occurs earlier. PFS will be analyzed based on the FAS 
according to the randomized treatment group and strata at randomization. The 
stratification factors include (i) line of therapy in advanced/metastatic setting (1st line 
versus 2nd line), ii) hormone receptor status at initial breast cancer diagnosis (HR+ 
versus HR-), and iii) prior therapy with checkpoint inhibitors (Yes/No). 
The PFS distribution will be estimated using the Kaplan-Meier method, and Kaplan-
Meier curves, medians and 95% confidence intervals of the medians will be presented 
for each treatment group. The hazard ratio for PFS will be calculated, along with its 95% 
confidence interval, from a stratified Cox model using the stratification factors at 
randomization.  
Part B1: 
The primary efficacy variable is ORR with confirmed response at 6 months. Proof of 
preliminary efficacy of alpelisib in combination with nab-paclitaxel will be declared if both 
of the following conditions are met: (1) the mean of the posterior distribution of ORR is 
at least 35%; and (2) the posterior probability that the ORR is ≥ 25% is at least 0.9. The 
posterior distribution of ORR will be derived from the prior distribution and all available 
data from the participants included in the FAS. A minimally informative unimodal Beta 
prior will be used for ORR (see Section 16.4 for further details). Additionally, ORR will 
be summarized by a two-sided exact binomial 95% confidence interval.   
OS as one of the secondary variables will be analyzed in the FAS. The OS distribution 
will be estimated using the Kaplan-Meier method, and the Kaplan-Meier curves, 
medians and 95% confidence intervals of the medians will be presented for each 
treatment group. The hazard ratio for OS will be calculated, along with its 95% 
confidence interval, using a stratified Cox model as PFS. 
Other secondary variables ORR with confirmed response and CBR with confirmed 
response will be calculated based on the FAS and according to the ITT principle. ORR 
and its 95% confidence interval will be presented by treatment group. TTR and DOR will 
be listed and summarized by treatment group. 
Time to definitive deterioration of ECOG performance status and EORTC QLQ-C30 
global health status will be estimated using the Kaplan-Meier method. The median time 
along with 95% confidence intervals will be presented by treatment group. A stratified 
Cox regression model will be used to estimate the hazard ratio (HR) of time to definitive 
deterioration, along with 95% confidence interval.  
Safety assessment will be based on the frequency of adverse events and on the 
number of laboratory values that fall outside of pre-determined ranges. 
Part B2: 
Never initiated based on Part B1 results. 
Key words 
advanced triple negative breast cancer (aTNBC), alpelisib, nab-paclitaxel, PIK3CA, 
PTEN, PI3K pathway, PI3K inhibitor 

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1 
Introduction 
1.1 
Background 
1.1.1 
Triple Negative Breast Cancer 
Breast cancer (BC) is the most common cancer in women and the second leading cause of 
cancer-related death (National Breast Cancer Foundation 2018, Goetz et al 2019). In men, 
breast cancer is a rare condition constituting < 1% of all breast cancer diagnoses 
(Siegel et al 2019). Breast cancer can be categorized into different histopathologic subtypes 
based on the expression of the estrogen receptor (ER), the progesterone receptor (PR), and 
human epidermal growths factor receptor (HER2) overexpression or gene amplification. Triple-
negative breast cancer (TNBC) is an aggressive clinical subset of BC defined by the lack of 
estrogen receptors (ERs) and progesterone receptors (PRs) and by human epidermal growth 
factor receptor 2 (HER2)-negative status and accounts for 15% to 20% of newly diagnosed 
breast cancer cases (Kohler et al 2015). TNBCs are sub-classified into multiple different 
subtypes based on their gene expression profiles (Lehmann et al 2011, Millis et al 2015, 
Burstein et al 2015, Bareche et al 2018, Shi et al 2018) making it challenging to treat. 
Without hormone receptors to target, no specific recommendations or treatment standards 
existed 
for 
advanced 
TNBC 
until 
recently 
(Gradishar et al 2017, 
NCCN Breast Cancer 4.2017, Cardoso et al 2017). Cytotoxic chemotherapy was and is still the 
foundation of treatment for advanced TNBC. Sequential use of single-agent chemotherapy is 
the most widely practiced treatment strategy for metastatic TNBC (mTNBC) and is typically 
continued until disease progression or significant/unacceptable toxicity (Zeichner et al 2016, 
O'Dea AP 2017). Commonly used single chemotherapy agents include taxanes, platinum based 
agents, anthracyclines, antimetabolites, gemcitabine, vinca alkaloids, and nontaxane tubulin 
polymerizing agents, such as ixabepilone and eribulin (O'Dea AP 2017). The chemotherapy 
agent and sequence is individualized for each patient based on prior chemotherapy treatments, 
previous/ persisting toxicities, and patient preference. Although less common, combination 
chemotherapy may also be utilized in cases of visceral involvement or an aggressive clinical 
course (Zeichner et al 2016, Lebert et al 2018). Despite a high initial sensitivity to 
chemotherapy (Murray et al 2012, Zeichner et al 2016), patients with TNBC suffer high relapse 
rates, more aggressive visceral disease, a higher likelihood of distant disease progression, and 
a 
higher 
frequency 
of 
brain 
metastases 
than 
other 
breast 
cancer 
subtypes 
(Lebert et al 2018, Pascual and Turner 2019). Consequently, patients with TNBC have a 
shorter median survival, only 9-18 months (Liedtke et al 2008, Yardley et al 2018), 
representing a population with a high unmet medical need for targeted therapies to delay disease 
progression. 
Recent approvals of the poly ADP ribose polymerase (PARP) inhibitors, olaparib and 
talazoparib, in HER2-negative advanced BC, as well as the approval of atezolizumab in 
combination with nab-paclitaxel in programmed cell death 1 ligand 1 (PD-L1) positive 
metastatic TNBC (Table 1-1), signal the beginning of targeted therapies for molecularly defined 
mTNBC subtypes. These therapies have been adapted into the most recent treatment guidelines 
(Lebert et al 2018, 
Cardoso et al 2018, 
NCCN Breast Cancer 1.2019, 
Goetz et al 2019). 
Various other therapeutic targets are also being investigated in mTNBC, both as single agent 
therapy and in combination with chemotherapy (Denkert et al 2017, Gerratana et al 2018, 

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Kim et al 2017, 
Kok et al 2017, 
Marra et al 2019, 
Miles et al 2016, 
Nanda et al 2016, 
Schmid et al 2019, Stover et al 2018, Traina et al 2017). 
Table 1-1 
Recently approved targeted therapies 
Indication 
Registration study summary 
Olaparib(LYNPARZA®) monotherapy 
Lynparza is indicated as monotherapy for the 
treatment of adult patients with germline BRCA1/2-
mutations, who have HER2 negative locally advanced 
or metastatic breast cancer. Patients should have 
previously been treated with an anthracycline and a 
taxane in the (neo)adjuvant or metastatic setting 
unless patients were not suitable for these treatments. 
The OlympiAD, open-label, phase III, registration trial 
randomized 302 patients (205 olaparib, 97 placebo) to 
either olaparib or standard single agent 
chemotherapy. Median PFS was significantly longer 
in the olaparib group than in the standard-therapy 
group (7.0 months vs. 4.2 months; HR for disease 
progression or death = 0.58; 95% CI, 0.43 - 0.80; 
P<0.001). The response rate was 59.9% in the 
olaparib group and 28.8% in the standard-therapy 
group (Robson et al 2017).At the final OS analysis, 
median OS was 19.3 months with olaparib versus 
17.1 months with standard single agent 
chemotherapy (HR = 0.90, 95% CI: 0.66, 1.23; 
P=0.513) (Robson et al 2019). 
Talazoparib (Talzenna®) monotherapy 
Talzenna is indicated as monotherapy for the 
treatment of adult patients with germline BRCA1/2-
mutations, who have HER2-negative locally advanced 
or metastatic breast cancer. Patients should have 
been previously treated with an anthracycline and/or a 
taxane in the (neo)adjuvant, locally advanced or 
metastatic setting unless patients were not suitable 
for these treatments 
The EMBRACA, open-label, phase III, registration trial 
randomized 287 patients to talazoparib and 144 to 
standard single agent chemotherapy. Median PFS 
was significantly longer in the talazoparib group than 
in the standard-therapy group (8.6 months vs. 5.6 
months; HR for disease progression or death = 0.54; 
95% CI: 0.41, 0.71; P<0.001). The OS hazard ratio at 
the time of the PFS analysis was 0.76 (95% CI: 
0.55,1.06; P=0.11; median of 22.3 vs 19.5 months) 
[57% of projected events]). The objective response 
rate was higher in the talazoparib group than in the 
standard-therapy group (62.6% vs. 27.2%; P<0.001); 
(Litton et al 2018). 
Atezolizumab (Tecentriq®), in combination with nab-paclitaxel 
TECENTRIQ is a programmed death-ligand 1 (PD-L1) 
blocking antibody indicated in combination with 
paclitaxel protein-bound for the treatment of adult 
patients with unresectable locally advanced or 
metastatic TNBC whose tumors express PD-L1. 
Impassion130, a double-blind, phase III study, 
randomized 451 untreated metastatic TNBC patients 
to atezolizumab plus nab-paclitaxel and 451 patients 
to placebo plus nab-paclitaxel. Median PFS, 
irrespective of PD-L1 status, was 7.2 months with 
atezolizumab plus nab-paclitaxel, as compared to 5.5 
months with placebo plus nab-paclitaxel (HR=0.80; 
95% CI: 0.69, 0.92; P=0.002). Among patients with 
PD-L1 positive tumors, the median PFS was 7.5 
months and 5.0 months, respectively (HR=0.62; 95% 
CI: 0.49, 0.78; P<0.001). The median OS was 21.3 
months with atezolizumab plus nab-paclitaxel versus 
17.6 months with placebo plus nab-paclitaxel 
(HR=0.84; 95% CI: 0.69, 1.02; P = 0.08; [59% of 
projected events]); among patients with PD-L1 
positive tumors, the median OS was 25.0 months and 
15.5 months, respectively (HR=0.62; 95% CI: 0.45, 
0.86) (Schmid et al 2018). 

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Indication 
Registration study summary 
At the second interim OS analysis [80% of projected 
events], median OS for all subjects was 21.0 months 
versus 18.7 months, respectively (HR=0.86, 95% CI: 
0.72, 1.02; P=0.0777); among patients with PD-L1 
positive tumors, the median OS was 25.0 months and 
18.0 months, respectively (HR=0.71; 95% CI: 0.54, 
0.93 (Schmid et al 2019)).Recently, the CHMP also 
adopted a positive opinion for this combination in 
adult, chemotherapy-naive patients with unresectable 
locally advanced or metastatic triple-negative PD-L1-
positive TNBC. 
While a few targeted treatment options have been approved, overall, the treatment of TNBC 
remains challenging and new therapeutic options are needed to improve efficacy in patients 
with biomarker targets.  
1.1.2 
The PI3K pathway overview and the PI3K pathway in TNBC 
PI3K Pathway 
The phosphatidylinositol-3-kinase (PI3K) pathway is a central oncogenic pathway that 
regulates cell proliferation, cell metabolism, growth, survival and apoptosis. Constitutive 
activation of PI3K signaling is a critical step in mediating the transforming potential of 
oncogenes and tumor suppressors in many tumor types, with PI3K as the oncogenic driver of 
the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway (Liu et al 2009). 
Aberrant PI3K pathway activation can occur through several events including alterations in 
receptor tyrosine kinases (RTKs) (Chan et al 2002), mutations in Phosphoinositide-3-kinase 
catalytic subunit alpha (PIK3CA) gene, the gene encoding the p110α catalytic subunit of the 
class IA phosphatidylinositol 3-kinases (PI3Ks) PI3Kα (Burke et al 2012, Rodon et al 2013), 
and loss-of-function mutations, gene deletions, or transcriptional down-regulation in the tumor 
suppressor genes such as the phosphatase and tensin homolog (PTEN) (Lin et al 2012, 
Cossu-Rocca et al 2015, Bareche et al 2018). In TNBC, the majority of activating mutations 
occur in the alpha subunit (p110α) encoded by the PIK3CA gene, which are detected in 
approximately 9% of primary TNBC tumors and this may be enhanced in advanced TNBC 
(Lin et al 2012, TCGA 2012, Weisman et al 2016, Pascual and Turner 2019). The prevalence 
of PIK3CA mutations was higher in Chinese TNBC populations at 18% (Jiang et al 2019) and 
28% (Chen et al 2018), compared to the prevalence of 9% reported in the global Translation 
Cancer Genome Atlas (TCGA) database (TCGA 2012). 
Role of PTEN in PI3K pathway activation 
Phosphatase and tensin homolog (PTEN) is a protein (phosphatidylinositol-3,4,5-trisphosphate 
3-phosphatase) that is encoded by the PTEN gene, a tumor suppressor gene. Inactivation of the 
PTEN gene can result in abnormal PI3K pathway activation via loss-of-function mutations, 
gene deletions, or transcriptional down-regulation. PTEN loss and PIK3CA hotspot mutations 
appear to be generally mutually exclusive in TNBC. The TCGA analysis showed an overlap of 
approximately 3% between PTEN loss hetero/homozygosity and PIK3CA mutations, an 
overlap of approximately 15% with PTEN loss hetero/homozygosity and PD-L1 upregulation, 
an overlap of approximately 10% with PTEN loss and PIK3CA amplification, and an overlap 
of approximately 9% between PIK3CA amplification and PIK3CA mutation (TCGA 2012). 

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PTEN loss is typically determined by reduction in PTEN protein expression based on 
immunohistochemistry 
(IHC) 
because 
PTEN 
is 
regulated 
post-transcriptionally 
(Zhang and Yu 2010). PTEN loss has been reported in approximately 11-66% of TNBC 
patients, as determined by different IHC assays and thresholds, with an average of 
approximately 
36% 
between 
these 
studies 
(Gonzalez-Angulo et al 2011, 
Lin et al 2012,TCGA 2012 , Millis et al 2015, Cossu-Rocca et al 2015). 
In the SAFIR02 trial (NCT02299999), 649 patients with metastatic BC (mBC), available 
mutational profile and clinical data were selected for outcome analyses with PIK3CA 
mutations, which were prospectively determined by next-generation sequencing (NGS) on 
metastatic samples. Ten percent (n=27) of TNBC tumors presented with a PIK3CA mutation. 
PIK3CA mutations were noted at a higher frequency in patients whose primary tumor was HR-
positive and then changed to HR-negative (39% (14/36) of patients) as compared to those that 
were HR-negative at primary and metastatic tumor assessment (7% (9/138)). The median OS 
in the TNBC patients with a PIK3CA mutation was 24.2 months vs. 14.0 months for patients 
with TNBC PIK3CA wild type tumors (p=0.028) This improvement in median OS could be 
explained by an enrichment of PIK3CA mutations in luminal breast cancer tumors who lost HR 
positivity in the metastatic setting (Mosele et al 2019). 
PI3K pathway and therapy resistance 
Activation of the PI3K pathway plays a role in endocrine resistance in HR-positive BC 
(Campbell et al 2001, Mills et al 2018). Additionally it has been linked to intrinsic and acquired 
resistance to paclitaxel (McCubrey et al 2006). While the exact mechanisms underlying the 
development of treatment resistance towards taxanes are not well elucidated, it has been shown 
that inhibition of the PI3K/AKT pathway increased sensitivity of taxane resistant breast cancer 
cell lines to paclitaxel (Zhang et al 2015, Zhang et al 2017, Zhou et al 2019). In addition, 
concomitant inhibition of the PI3K pathway enhanced the efficacy of taxanes in both human 
breast cancer cell lines and xenograft breast cancer mouse models (Wallin et al 2012). 
Clinical data on PI3K pathway activation in TNBC 
Recent clinical studies have demonstrated that inhibition of the PI3K pathway improved 
efficacy in advanced TNBC. In a double-blind, placebo-controlled Phase II study (LOTUS) in 
first-line, advanced TNBC subjects with a PIK3CA/AKT1/PTEN alteration (by NGS) or PTEN 
low status (by IHC), 62 subjects were randomized to ipatasertib (an AKT inhibitor) plus 
paclitaxel and 62 subjects were randomized to placebo plus paclitaxel. For the intent-to-treat 
(ITT) population, median Progression Free Survival (PFS) was 6.2 months for ipatasertib plus 
paclitaxel compared to 4.9 months for placebo plus paclitaxel (HR=0.60, 95% CI: 0.37, 0.98, 
p=0.037). For subjects with PTEN low status, median PFS was 6.2 months with ipatasertib plus 
paclitaxel (n=25) vs 3.6 months with paclitaxel (n=23), stratified HR=0.59, 95% CI: 0.26, 1.32, 
p=0.18). For subjects with PIK3CA/AKT1/PTEN alterations, median PFS was 9.0 months with 
ipatasertib plus paclitaxel (n=26) vs 4.9 months with paclitaxel (n=16), HR=0.44, 95% CI: 0.20, 
0.99). Of the 42 subjects with PIK3CA/AKT1/PTEN alterations, 18 (43%) had PIK3CA 
alterations, 8 (19%) had AKT1 alterations, and 16 (38%) had PTEN alterations. Overall 
Response Rate (ORR) was 40% vs 32% for all subjects, 48% vs 26% for subjects with PTEN 
low status, and 50% vs 44% for subjects with PIK3CA/AKT1/PTEN alterations. Duration of 
response was 7.9 vs 7.4 months for all subjects, 6.5 vs 7.5 months for subjects with PTEN low 

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status, and 11.2 vs 6.1 months for subjects with PIK3CA/AKT1/PTEN alterations 
(Kim et al 2017). 
In the double-blind, placebo-controlled Phase II PAKT study in previously untreated metastatic 
TNBC, 70 subjects were randomized to capivasertib (another AKT inhibitor) in combination 
with paclitaxel and 70 subjects were randomized to placebo in combination with paclitaxel. For 
the intent-to-treat population, median PFS was 5.9 months for capivasertib plus paclitaxel 
compared to 4.2 months for placebo plus paclitaxel (HR=0.74, 95% CI: 0.50, 1.08, P=0.06). 
For subjects with PIK3CA/AKT1/PTEN alterations, median PFS was 9.3 months in 17 subjects 
in the capivasertib arm versus 3.7 months in 11 subjects in the placebo arm, HR=0.30, 95% CI: 
0.11, 0.79, p=0.01)(Schmid et al 2018). Therefore, the PI3K pathway is an important target in 
advanced TNBC. 
1.1.3 
Overview of Alpelisib 
Alpelisib is an oral, alpha-specific class IA PI3K inhibitor belonging to the 2-aminothiazole 
class of compounds. Alpelisib potently inhibits p110α, in its wild-type form as well as when 
constitutively activated by somatic mutations, and inhibits less strongly the β, δ, and γ isoforms 
of PI3K. 
1.1.3.1 
Non-clinical experience 
Gain-of-function mutations in the gene encoding the catalytic α-subunit of PI3K (PIK3CA) lead 
to activation of PI3Kα and Akt-signaling, cellular transformation and the generation of tumors 
in in vitro and in vivo models. 
In breast cancer cell lines, alpelisib inhibited the phosphorylation of PI3K downstream targets, 
including Akt and showed activity in cell lines harboring a PIK3CA mutation. In vivo, alpelisib 
inhibited the PI3K/Akt signaling pathway and reduced tumor growth in xenograft models, 
including models of breast cancer. 
More detailed information on the pharmacology of alpelisib, single and multiple dose 
pharmacokinetic (PK) studies conducted in multiple species and nonclinical safety evaluations 
can be found in the Investigator's Brochure (IB). 
1.1.3.2 
Clinical experience 
Clinical Study CBYL719C2301 leading to alpelisib approval: 
Alpelisib (Piqray®) was first approved in May 2019 in the United States and is indicated in 
combination with fulvestrant for the treatment of postmenopausal women, and men, with 
hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative PIK3CA 
mutated, advanced or metastatic breast cancer following progression on or after an endocrine-
based regimen.   
Alpelisib has been investigated both as a single agent and as combination therapy in 42 clinical 
studies and as of 23-May 2022, 25 studies have been completed and 17 studies are ongoing. In 
general, the data suggest that the safety profile of alpelisib is acceptable with manageable, and 
reversible AEs. The IB provides a more detailed review of the preclinical and clinical 
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Approval of alpelisib was primarily based on efficacy and safety data from Study 
CBYL719C2301 (SOLAR-1, Study CBYL719C2301, André et al 2019), which met its primary 
endpoint in subjects with a PIK3CA mutation. A statistically significant and clinically 
meaningful improvement in median PFS in favor of the alpelisib plus fulvestrant arm (HR = 
0.65; 95% CI: 0.50, 0.85; p=0.00065, one-sided) was observed. Median PFS was prolonged by 
5.3 months, from 5.7 months (95% CI: 3.7, 7.4) in the placebo plus fulvestrant arm to 11.0 
months (95% CI: 7.5, 14.5) in the alpelisib plus fulvestrant arm.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Clinical trials with alpelisib data in TNBC: 
Alpelisib has been explored, and demonstrated activity, in two studies including patients with 
advanced TNBC.  
Study CBYL719X2101 
Study CBYL719X2101 was a Phase I dose escalation study in patients with advanced solid 
tumors. Five subjects with TNBC were included in this study and treated with alpelisib 
monotherapy. Of these, 3 had tumors harboring a PIK3CA amplification or mutation and were 
treated with once daily alpelisib. Encouraging early activity of alpelisib was observed in 2 of 
these three heavily pre-treated subjects with TNBC: 
• One subject (alpelisib starting dose of 300 mg per day) was on study treatment for 442 
days and had a best response of Stable Disease (SD) with 23.5% tumor shrinkage 
• A second subject (alpelisib starting of dose 400 mg per day) was on study treatment for 
168 days and had an unconfirmed Partial Response (PR) with 37.5% tumor shrinkage 

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The third subject (alpelisib starting dose of 300 mg per day) was on study for 3 days. 
Study CBYL719XUS06T 
Alpelisib in combination with nab-paclitaxel was explored in a Phase I/II investigator initiated 
study, Study CBYL719XUS06T (NCT02379247), in 43 subjects with HER2-negative, 
advanced breast cancer (regardless of PI3K pathway activation or PTEN status) who had 
received ≥ 1 prior line of chemotherapy (prior taxane treatment, except nab-paclitaxel, was 
permitted) in either advanced or adjuvant setting (Sharma et al 2018, Sharma et al 2021). 
The primary objectives were to determine the recommended phase II dose (RPTD) of alpelisib 
+ nab-paclitaxel and to assess the overall response rate (ORR). Phase I was a 3+3 dose-
escalation design with 3 dose levels of alpelisib (250 mg, 300 mg, and 350 mg) administered 
PO once daily (Days 1-28) with nab-paclitaxel at 100 mg/m2 i.v. on Days 1, 8, and 15 of a 28 
day cycle. Phase II was a Simon’s two stage minimax design targeting an ORR of 40% 
(NCT02379247). 
In the Phase I portion of the study, there were no DLTs and no PK interactions reported for the 
9 evaluable subjects (n=10; 1 patient stopped treatment within 10 days). The recommended 
Phase II dose (RP2D) for alpelisib was 350 mg with nab-paclitaxel at 100 mg/m2 i.v. on Days 
1, 8, and 15 of a 28 day cycle. In the Phase II portion of the study, 33 subjects were treated at 
the RP2D. PI3K pathway-activation, defined as the presence of PIK3CA-activating or PTEN-
inactivating mutations, was tested in either tumor tissue or ctDNA and was observed in 44% 
(19/43) of patients. 
In the overall study population, 23%, 69%, and 8% of subjects had been treated with 0, 1, or ≥ 
2 lines of prior chemotherapy for metastatic breast cancer, respectively. Nine subjects continued 
on treatment for > 12 months; 5 of these had a PIK3CA mutation. For the 42 evaluable subjects 
(1 subject did not have response data), the ORR was 60% and CBR was 79%. For subjects with 
a PIK3CA mutation, the ORR was 74% and CBR was 100%. Median PFS was 13 months for 
subjects with a PIK3CA mutation (n=19) compared to 7 months for those without a PIK3CA 
mutation (n=23) (HR=0.40; 95% CI: 0.18, 0.90, p=0.017). 
Twelve of the 43 subjects had advanced TNBC. The majority of these subjects were treated 
with an alpelisib dose of 350 mg (250 mg (n=2), 300 mg (n=1), and 350 mg (n=9)), in 
combination with nab-paclitaxel. The ORR and CBR for these 12 TNBC subjects was 58%. 
Five of the 12 TNBC subjects’ tumors harbored a PI3K pathway alteration: 3 had a PIK3CA 
mutation, 1 had PTEN loss without a PIK3CA mutation, and 1 had both a PIK3CA mutation 
and PTEN loss. Clinical benefit was observed in all TNBC patients with a PI3K pathway 
activated tumor. 
The following best overall responses were observed among the 12 subjects with TNBC: 
• Two (17%) subjects had a CR (one with a PIK3CA mutation without PTEN loss, one with 
PIK3CA mutation with PTEN loss). 
• Five (42%) subjects had a PR (one with a PIK3CA mutation without PTEN loss, one with 
PTEN loss without a PIK3CA mutation). 
• Two (17%) subjects had SD (one with a PIK3CA mutation without PTEN loss). 
• Three (25%) subjects had PD (none had a PIK3CA mutation or PTEN loss). 

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Clinical benefit was observed in all TNBC patients with a PI3K pathway activated tumor. 
In study CBYL719XUS06T, the safety profile for alpelisib in combination with nab-paclitaxel 
was consistent with the known adverse event profiles of each medication. The following is a 
summary of the safety observations among the 43 patients: 
• Hyperglycemia was noted in 76% of subjects (grade 3 = 27%, no grade 4 events) with 
32% of patients requiring metformin for hyperglycemia management. 
• Rash was noted in 63% of subjects (grade 3 = 7%, no grade 4 events). All subjects 
received second or third generation H1-anti-histaminic for rash prophylaxis. 
• Alpelisib dose reductions occurred in 26% (11/43) of subjects (n=1 at 250 mg dose, n=10 
at 350 mg dose). The reasons for alpelisib dose reductions were: fatigue/anorexia (n=3), 
diarrhea (n=3), rash (n=2), hyperglycemia (n=1), hypokalemia (n=1), and investigator’s 
choice (n=1). 
• Two subjects discontinued therapy (after two cycles) due to grade 2 pneumonitis. 
• Nab-Paclitaxel dose reductions occurred in 28% (10/43) of subjects. The reasons for nab-
paclitaxel dose reductions were: peripheral neuropathy (n=3), fatigue (n=1), rash (n=1), 
diarrhea (n=1), thrombocytopenia (n=1), neutropenia (n=1), and investigator’s choice 
(n=2). 
• Two subjects stopped nab-paclitaxel and continued on single agent alpelisib. Both of these 
subjects stopped alpelisib at 12 weeks due to progressive disease (one subject’s tumor had 
a PIK3CA mutation, the other did not.) 
The incidence of AEs reported, by severity are presented in protocol Section 4.2, Table 4-1. 
Overall, the combination of alpelisib and nab-paclitaxel was well tolerated with manageable 
toxicities. No unexpected toxicity signals were observed. 
In summary, these data demonstrate promising early anti-tumor activity of alpelisib in advanced 
Breast Cancer (aBC) where the PI3K pathway is activated by the presence of a PIK3CA 
mutation or PTEN loss and warrant the investigation of the combination of alpelisib with nab-
paclitaxel in advanced TNBC. 
Clinical Pharmacology 
The pharmacokinetics of alpelisib has been studied in healthy subjects and adult patients with 
solid tumors. Steady-state alpelisib maximum plasma concentration (Cmax) and Area under the 
curve (AUC) increased proportionally over the dose range of 30 mg to 450 mg (0.1 to 1.5 times 
the approved recommended dosage) under fed conditions. The mean accumulation of alpelisib 
is 1.3 to 1.5 and steady-state plasma concentrations are reached within 3 days following daily 
dosage. In adult patients who received alpelisib 300 mg once daily in the Study 
CBYL719C2301, mean steady-state alpelisib [coefficient of variation (CV%)] Cmax was 2480 
(23%) ng/mL and AUC0-24hr was 33224 (21%) ng*h/mL based on a population approach 
analysis. The median time to reach peak plasma concentration (Tmax) ranged between 2.0 to 
4.0 hours. The half-life of alpelisib is predicted to be 8 to 9 hours. The mean (%CV) clearance 
of alpelisib is predicted to be 9.2 L/hr (21%) under fed conditions.   
A high-fat high-calorie meal (985 calories with 58.1 g of fat) increased alpelisib AUC by 73% 
and Cmax by 84%, and a low-fat low-calorie meal (334 calories with 8.7 g of fat) increased 
alpelisib AUC by 77% and Cmax by 145% following a single dose of alpelisib. No clinically 

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significant differences in alpelisib AUC were observed between low-fat low-calorie and high-
fat high-calorie meals. Alpelisib can be co-administered with acid reducing agents, as long as 
it is taken following food, since food exhibited a more pronounced effect on the solubility of 
alpelisib than the effect of gastric pH. 
Alpelisib is primarily metabolized by chemical and enzymatic hydrolysis to form its metabolite 
BZG791 and to a lesser extent by Cytochrome P450 (CYP)3A4 in vitro. Following a single oral 
dose of 400 mg radiolabeled alpelisib under fasted condition, 81% of the administered dose was 
recovered in feces (36% unchanged, 32% BZG791) and 14% (2% unchanged, 7.1% BZG791) 
in urine. CYP3A4-mediated metabolites (12%) and glucuronides amounted to approximately 
15% of the dose. Excretion of unchanged alpelisib occurs primarily via hepatobiliary export 
and/or intestinal secretion of alpelisib. As Alpelisib is a substrate of Breast Cancer Resistance 
Protein (BCRP), its elimination may be affected when co-administered with BCRP inhibitors. 
Alpelisib inhibits CYP3A4 in a time-dependent manner and induces CYP2B6, CYP2C9 and 
CYP3A4 in vitro. Alpelisib is an inhibitor of P-gp. No clinically significant differences in 
pharmacokinetics of everolimus (a substrate of CYP3A4 and P-gp), however, were observed 
when co-administered with alpelisib. Alpelisib has a low potential to inhibit BCRP, MRP2, 
BSEP, OATP1B1, OATP1B3, OCT1, OAT1, OAT3, OCT2, MATE1, and MATE2K at 
clinically relevant concentrations. 
For further details on non-clinical experience, please refer to the latest version of [Alpelisib 
(BYL719) IB]. 
1.2 
Purpose 
Advanced TNBC is a heterogeneous disease and effective treatments are lacking (see 
Section 1.1.1). There is a high, unmet need for novel therapies or the combination of new 
therapies with established chemotherapy agents. Although taxanes are effective early on in 
advanced stage breast cancer, resistance often develops (O'Reilly et al 2015). While the exact 
mechanism(s) underlying the development of treatment resistance towards taxanes remain 
largely unknown, it has been demonstrated that activation of the PI3K/AKT pathway confers 
resistance to paclitaxel (Hu et al 2002, Zhang et al 2017, Zhou et al 2019) and that increased 
AKT activity may be an early compensatory mechanism of chemotherapy resistance 
(Clark et al 2002). Additionally, in preclinical models, concomitant inhibition of the PI3K 
pathway enhances the efficacy of taxanes as compared to each agent given separately 
(Hu et al 2002). PI3K/AKT/mTOR represents the main signaling pathway responsible for cell 
proliferation, survival, metabolism and motility regulation and is often activated in breast 
cancer. Targeting the PI3K/AKT/mTOR pathway is of increasing interest in patients which 
harbor genetic alterations in this pathway and provides the rationale for studying the 
combination of nab-paclitaxel with the alpha-specific PI3K inhibitor alpelisib in advanced 
TNBC. 
In the Study CBYL719C2301, alpelisib plus fulvestrant significantly improved PFS and ORR 
in patients with hormone receptor positive, HER2-negative advanced breast cancer with 
PIK3CA mutation, which progressed on or after aromatase inhibitor treatment, compared to 
fulvestrant alone (André et al 2019). Approximately 40% of HR+ advanced breast cancer 
patients harbor a PIK3CA mutation, which is associated with poor prognosis. Since 
approximately 9% of TNBC patients also harbor PIK3CA mutations, and it is believed that 

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these mutations are both a driver of tumor development as well as therapy resistance 
(Massihnia et al 2016, Zhang et al 2017) alpelisib given in combination with nab-paclitaxel 
may provide additional clinical benefit. 
Given promising efficacy signals from a phase I/II investigator initiated trial in HER2-negative 
mBC patients, including 12 patients with metastatic TNBC (PIK3CA mutant, PIK3CA wild 
type, and PTEN loss) (CBYL719XUS06T; Sharma et al 2018, Sharma et al 2021), the goal of 
this study is to determine if targeted therapy with the alpha-specific PIK3CA inhibitor, alpelisib, 
in combination with nab-paclitaxel, is safe and effective in patients with advanced TNBC 
harboring a PIK3CA mutation, or PTEN loss.  
2 
Objectives, endpoints and estimands 
Table 2-1 
Objectives, and related endpoints for Part A (TNBC with PIK3CA 
mutation) 
  
Objective 
Endpoint (s) 
Primary 
 
To assess  whether treatment with 
alpelisib in combination with nab-paclitaxel 
prolongs PFS compared to placebo in 
combination with nab-paclitaxel 
Progression Free Survival (PFS) based on 
investigator assessment using RECIST 1.1 
criteria (refer to Section 2.1 for the primary 
estimand) 
Secondary 
  
To assess whether treatment with alpelisib 
in combination with nab-paclitaxel 
prolongs OS compared to placebo in 
combination with nab-paclitaxel 
Overall Survival (OS)  
To assess safety and tolerability of 
alpelisib in combination with nab-paclitaxel 
Safety: Incidence, type, and severity of 
adverse events per CTCAE v4.03 criteria 
including changes in laboratory values, 
vital signs, liver assessments, renal and 
cardiac assessments 
Tolerability: dose interruptions, 
reductions, dose intensity, and duration of 
exposure for all drug components 
To assess additional efficacy parameters 
ORR with confirmed response, CBR with 
confirmed response, Duration Of 
Response (DOR) with confirmed 
response, TTR based on local radiology 
assessments and using Response 
Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 criteria 
Refer to Section 2.2  for the ORR endpoint 
definition (the summary measure attribute 
of the secondary estimand). 
To evaluate the association between 
PIK3CA mutation status as measured in 
ctDNA at baseline with PFS upon 
treatment with alpelisib 
PFS based on local radiology 
assessments using RECIST 1.1 criteria for 
participants by PIK3CA mutation status 
measured in baseline ctDNA 

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Table 2-2 
Objectives and related endpoints for Part B1 (TNBC with PTEN loss) 
  
Objective 
Endpoint (s) 
Primary 
To assess the antitumor activity of alpelisib 
in combination with nab-paclitaxel   
Overall response rate (ORR) 
with confirmed response using RECIST 
1.1 criteria (refer to Section 2.1 for the 
primary estimand) 
Secondary 
To determine the safety and tolerability of 
alpelisib in combination with nab-paclitaxel 
Safety: Incidence, type, and severity of 
adverse events per CTCAE v4.03 criteria 
including changes in laboratory values, 
vital signs, liver assessments, renal and 
cardiac assessments 
Tolerability: dose interruptions, 
reductions, dose intensity, and duration of 
exposure for all drug components  
To evaluate additional efficacy parameters 
of alpelisib in combination with nab-
paclitaxel 
CBR with confirmed response, DOR with 
confirmed response, TTR, and PFS 
(based on local radiology assessments 
and using RECIST 1.1 criteria), OS  

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Table 2-3 
Objectives and related endpoints for Part B2 (TNBC with PTEN loss 
without PIK3CA mutation) 
The enrollment in Part B1 was completed in February 2022. In November 2022, Novartis 
decided to halt enrollment to Part A due to slow recruitment. Part B2 was not initiated since 
Part B1 results didn’t meet the primary endpoint of ORR. 
 
  
Objective 
Endpoint (s) 
Primary 
To determine whether treatment with 
alpelisib in combination with nab-paclitaxel 
prolongs PFS compared to placebo in 
combination with nab-paclitaxel 
Progression Free Survival (PFS) based on 
investigator assessment using RECIST 1.1 
criteria (refer to Section 2.1 for the primary 
estimand) 
Key Secondary 
To determine whether treatment with 
alpelisib in combination with nab-paclitaxel 
prolongs OS compared to placebo in 
combination with nab-paclitaxel 
Overall Survival (OS) (refer to Section 2.2 
for the key secondary estimand) 
Secondary 
To assess safety and tolerability of 
alpelisib in combination with nab-paclitaxel 
Safety: Incidence, type, and severity of 
adverse events per CTCAE v4.03 criteria 
including changes in laboratory values, 
vital signs, liver assessments, renal and 
cardiac assessments 
Tolerability: dose interruptions, 
reductions, dose intensity, and duration of 
exposure for all drug components 
To assess additional efficacy parameters 
ORR with confirmed response, CBR with 
confirmed response, DOR with confirmed 
response, TTR based on local radiology 
assessments and using RECIST 1.1 
criteria 
Refer to Section 2.2 for the ORR endpoint 
definition (the variable attribute of the 
secondary estimand). 
To characterize exposure of alpelisib when 
administered in combination with nab-
paclitaxel  
Summary statistics of plasma alpelisib 
concentrations by time point 
To evaluate patient-reported outcomes of 
alpelisib in combination with nab-paclitaxel 
versus placebo with nab-paclitaxel 
1) Change from baseline in the global 
health status/QoL scale score of the 
EORTC QLQ-C30 
2) Time to 10% definitive deterioration in 
the global health status/QOL scale score 
of the EORTC QLQ-C30 
To evaluate the association between 
PIK3CA mutation status as measured in 
ctDNA at baseline with PFS upon 
treatment with alpelisib 
PFS based on local radiology 
assessments using RECIST 1.1 criteria for 
participants by PIK3CA mutation status 
measured in baseline ctDNA 
To evaluate alpelisib in combination with 
nab-paclitaxel versus placebo with nab-
paclitaxel with respect to time to 
deterioration of ECOG performance status 
Time to definitive deterioration of the 
ECOG performance status from baseline 

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2.1 
Primary estimand 
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 section below describes the primary estimand 
for all Study Parts.  Supplementary estimands to the primary estimand are defined in Section 12. 
Part A: 
The primary scientific question of interest is: what is the treatment effect based on PFS for 
alpelisib in combination with nab-paclitaxel versus placebo in combination with nab-paclitaxel 
in men and women with advanced (locally recurrent or metastatic) TNBC with a PIK3CA 
mutation (with or without concurrent PTEN loss), regardless of study treatment discontinuation 
or start of new anti-neoplastic therapy? 
The justification for targeting this treatment effect is that we wish to estimate the treatment 
effect during the whole course of the study including after study treatment discontinuation; and 
compare not just alpelisib+nab-paclitaxel versus placebo+nab-paclitaxel, but alpelisib+nab-
paclitaxel followed by any new anti-neoplastic therapy versus placebo+nab-paclitaxel followed 
by any new anti-neoplastic therapy, i.e. any subsequent anti-neoplastic therapy is part of the 
treatment attribute. 
The primary estimand is characterized by the following attributes: 
1. Population: all participants randomized with advanced (locally recurrent or metastatic) 
TNBC with a PIK3CA mutation. Further details on the population are provided in Section 5. 
2. Treatment: the investigational treatment is alpelisib in combination with nab-paclitaxel plus 
any subsequent anti-neoplastic therapy as needed. The control treatment is placebo in 
combination with nab-paclitaxel plus any subsequent anti-neoplastic therapy as needed. Further 
details about the investigational treatment and control treatment are provided in Section 6. 

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3. Variable: PFS based on local investigator assessment and using RECIST 1.1 criteria. Further 
details on PFS are provided in Section 12.4.1. 
4. Intercurrent events: 
discontinuation of study treatment for any reason (treatment policy strategy). 
Details on how to handle intercurrent events are provided in Section 12.4.3. 
5. Summary measure: PFS hazard ratio (alpelisib versus placebo) and its 95% confidence 
interval, estimated using a Cox proportional hazard model stratified by the randomization 
stratification factors. Further details on how the summary measure will be tested are provided 
in Section 12.4.2. 
Part B1 
The scientific question of interest is: what is the treatment effect based on ORR for alpelisib in 
combination with nab-paclitaxel in men and women with advanced (locally recurrent or 
metastatic) TNBC with PTEN loss prior to treatment discontinuation date+30 days or prior to 
start of new anti-neoplastic therapy, whichever occurs first. 
The justification for targeting this treatment effect is the intent to assess the treatment effect 
during the on-treatment period and up to 30 days after the discontinuation of treatment. 
The primary estimand is characterized by the following attributes: 
1. Population: all participants enrolled with advanced (locally recurrent or metastatic) TNBC 
with PTEN loss. Further details on the population are provided in Section 5. 
2. Treatment: the investigational treatment is alpelisib in combination with nab-
paclitaxel. Further details about the investigational treatment are provided in Section 6. 
3. Variable: Best overall response with confirmed response after 6 months of treatment based 
on local investigator assessment and using RECIST 1.1 criteria. Further details on ORR are 
provided in Section 12.4.1. 
4. Intercurrent events: 
· discontinuation of study treatment for any reason (while on-treatment strategy). 
· start of new anti-neoplastic therapy (while on-treatment strategy) 
Details on how to handle intercurrent events are provided in Section 12.4.3. 
5. Summary measure: ORR with confirmed response and its 95% confidence interval . Further 
details on how the summary measure will be tested are provided in Section 12.4.2. 
Part B2: 
The primary scientific question of interest is: what is the treatment effect based on PFS for 
alpelisib in combination with nab-paclitaxel versus placebo in combination with nab-paclitaxel 
in participants with advanced (locally recurrent or metastatic) TNBC with PTEN loss (without 
PIK3CA mutation), regardless of study treatment discontinuation or start of new anti-neoplastic 
therapy? 

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The justification for targeting this treatment effect is that we wish to estimate the treatment 
effect during the whole course of the study including after study treatment discontinuation; and 
compare not just alpelisib+nab-paclitaxel versus placebo+nab-paclitaxel, but alpelisib+nab-
paclitaxel followed by any new anti-neoplastic therapy versus placebo+nab-paclitaxel followed 
by any new anti-neoplastic therapy, i.e. any subsequent anti-neoplastic therapy is part of the 
treatment attribute. 
The primary estimand is characterized by the following attributes: 
1. Population: all participants randomized with advanced (locally recurrent or metastatic) 
TNBC with PTEN loss (without PIK3CA mutation). Further details on the population are 
provided in Section 5. 
2. Treatment: the investigational treatment is alpelisib in combination with nab-paclitaxel plus 
any subsequent anti-neoplastic therapy as needed. The control treatment is placebo in 
combination with nab-paclitaxel plus any subsequent anti-neoplastic therapy as needed. Further 
details about the investigational treatment and control treatment are provided in Section 6. 
3. Variable: PFS based on local investigator assessment and using RECIST 1.1 criteria. Further 
details on PFS are provided in Section 12.4.1. 
4. Intercurrent events: 
· discontinuation of study treatment for any reason (treatment policy strategy). 
Details on how to handle intercurrent events are provided in Section 12.4.3. 
5. Summary measure: PFS hazard ratio (alpelisib versus placebo) and its 95% confidence 
interval, estimated using a Cox proportional hazard model stratified by the randomization 
stratification factors. Further details on how the summary measure will be tested are provided 
in Section 12.4.2. 
2.2 
Key secondary estimand 
Part A: 
Not applicable following protocol amendment 02. 
Part B2: 
Not applicable following protocol amendment 02. 
3 
Study design 
Study CBYL719H12301 has been designed as a three part, Phase III, multicenter, international 
trial evaluating the efficacy and safety of alpelisib in combination with nab-paclitaxel in 1st or 
2nd line therapy of advanced (loco-regionally recurrent or metastatic) TNBC with a PIK3CA 
mutation or PTEN loss. 
• Part A: randomized, double-blind (DB) and placebo-controlled. 
• Part B1: single-arm, open-label (OL). 
• Part B2: randomized, double-blind and placebo-controlled. 

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Enrollment in Part B1 was completed in February 2022. In November 2022, Novartis took the 
decision to halt the enrollment to the Part A due to slow recruitment. Additionally, Part B2 was 
not initiated since Part B1 didn’t meet its primary endpoint of ORR.  
The reference to Part B2 remains in the protocol to reflect the initial study design and avoid 
confusion. Part B2 will not be conducted. 
Part A: Advanced TNBC with PIK3CA mutation 
The purpose of study Part A is to assess PFS in participants treated with alpelisib in combination 
with nab-paclitaxel vs.  participants treated with placebo in combination with nab-paclitaxel in 
advanced TNBC participants with a PIK3CA mutation (with or without concurrent PTEN loss). 
Approximately 252 participants were intially planned to be randomly assigned to receive either 
alpelisib plus nab-paclitaxel or placebo plus nab-paclitaxel. With the halt of recruitment in Part 
A, a total of 102 participants were randomized in this part of the study.Randomization to 
treatment will follow a 1:1 ratio and will be stratified by three factors of prognostic value: i) 
line of therapy in advanced/metastatic setting (1st line versus 2nd line), ii) hormone receptor 
status at initial breast cancer diagnosis (HR+ versus HR-), and iii) prior therapy with a 
checkpoint inhibitor (Yes versus No). 
For stratification factor i) line of therapy in advanced/metastatic setting the following applies: 
• A patient will be stratified as 1st line if he/she has NOT received any prior treatment for 
advanced/metastatic BC.  
• A patient will be stratified as 2nd line if he/she has received one prior line of treatment for 
advanced/metastatic BC and subsequently progressed. 
Note: Endocrine-based therapy for HR+ advanced/metastatic BC should not be counted as a 
line of treatment. If a treatment regimen was stopped for toxicity without documentation of 
disease progression and another treatment regimen started subsequently, this should be 
considered as the same “line of therapy”.  
Part B1: Advanced TNBC with PTEN loss  
The purpose of study part B1 is to determine whether alpelisib in combination with nab-
paclitaxel in 32 participants with advanced TNBC and PTEN loss (with PIK3CA unknown or 
non-mutant) warrants further development. PIK3CA status is defined as ‘unknown’ if the 
PIK3CA results from the PIK3CA mutation assay are reported as invalid based on specified 
assay control parameters.  ORR and safety data after 6 months of follow-up will be used to 
make the decision on whether or not to initiate part B2. 
Enrollment was completed for Part B1; a total of 35 participants were enrolled. 
Note: Participants with a PIK3CA mutation and concurrent PTEN loss are only eligible to be 
randomized into Part A of this study. 
Part B2: Advanced TNBC with PTEN loss (without PIK3CA mutation) 
If review of Part B1 results leads to the decision to open Part B2, (refer to Section 12.4.1), the 
purpose of Part B2 is to determine whether treatment with alpelisib in combination with nab-
paclitaxel prolongs PFS compared to placebo in combination with nab-paclitaxel in advanced 
TNBC participants with PTEN loss (without a concurrent PIK3CA mutation). 

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Approximately 282 participants will be randomly assigned to receive either alpelisib plus nab-
paclitaxel or placebo plus nab-paclitaxel. 
Randomization to treatment will follow a 1:1 ratio and will be stratified by three factors of 
prognostic value: i) line of therapy in advanced/metastatic setting (1st line versus 2nd line), ii) 
hormone receptor status at initial breast cancer diagnosis (HR+ versus HR-), and iii) prior 
therapy with a checkpoint inhibitor (Yes versus No). The stratification factors and definition of 
line of therapy for Parts A and B2 are identical. 
Part B2 was not initiated since Part B1 did not meet its primary endpoint of ORR. 
Figure 3-1 
Study design 
 
  
*Not applicable after protocol amendment 02. 
Pre-Screening period 
Pre-Screening starts upon signature of the molecular pre-screening Informed Consent Form 
(ICF) by the study participant.  
PIK3CA mutation status (refer to Section 8.1) and PTEN expression status will be assessed 
centrally using fresh or archival tumor samples (locally advanced or metastatic tumor tissue) 
by a Novartis designated laboratory. If a participant's PIK3CA mutation status is already 
available and was assessed by a local laboratory using either a Food and Drug Administration 
(FDA)-approved PIK3CA Companion Diagnostic (CDx) test for alpelisib or the CE-IVD 
QIAGEN therascreen® PIK3CA RGQ Polymerase Chain Reaction (PCR) test (Refer to 
Section 8.1), the mutation status may be used for enrollment into this study and must be 
documented in the source documents. In such cases central confirmation of PIK3CA mutation 

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status by a Novartis designated laboratory is not required prior to randomization. 
 
 
 
PIK3CA mutation results generated by “research use only” version of the Qiagen test, or other 
laboratory-developed tests, are not acceptable. 
• Participants with a PIK3CA mutation (regardless of PTEN loss) will be eligible only for 
Part A of the study. 
• Participants with PTEN loss without a PIK3CA mutation will be eligible for part B1 or 
part B2 of the study. 
• Participant with PTEN loss and unknown PIK3CA mutation status will be eligible for part 
B1 only 
• Participants with unknown or unconfirmed PIK3CA mutation status and with unknown or 
unconfirmed PTEN status will not be eligible for this study. 
Screening period 
Screening starts upon signature of the main study ICF by any study participant who meets the 
molecular pre-screening criteria. 
Treatment period 
This period begins when the first dose of study treatment is administered to a participant and 
ends with documentation of progressive disease per RECIST 1.1, unacceptable toxicity or until 
discontinuation of study treatment due to any other reason.  
Once all participants have completed 6 months of study treatment or have been discontinued 
from the study treatment, participants and investigators will be unblinded and participants will 
have the option to continue with their assigned treatment.  
Participants in the control arm receiving placebo in combination with nab-paclitaxel will not 
have the option to transition to the experimental arm (alpelisib in combination with nab-
paclitaxel). 
End of treatment 
Participants will be scheduled for an End of Treatment (EOT) visit within 14 days after 
discontinuation of study treatment due to any reason (except death). 
Safety follow-up 
Participants will be followed for safety evaluations 30 days after last administration of study 
treatment dose as outlined in Section 10. 
Efficacy follow-up* 
Participants who discontinued study treatment for reasons other than disease progression by 
RECIST 1.1, death, lost to follow up, or withdrawal of consent/opposition to use data/biological 
samples will continue tumor assessments as outlined in Section 8.3.1 until documented disease 
progression. PRO data will also be collected using the same schedule as tumor assessments, for 
participants enrolled in Parts A and B2. 

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Follow-up after disease progression* 
PRO data will be collected 8 weeks after documentation of disease progression for participants 
enrolled in Parts A and B2. 
Survival follow-up* 
Participants will be followed for survival as outlined in Section 8. 
* Once all participants have completed 6 months of study treatment or have been discontinued 
from the study treatment, the tumor assessments in the efficacy follow-up, the collection of 
PRO data in the efficacy follow-up and 8 weeks after disease progression, and the collection of 
survival data will stop.  

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Figure 3-2 
Study flow 
 
 
 

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4 
Rationale 
4.1 
Rationale for study design 
Part A 
To assess the treatment effect of alpelisib in combination with nab-paclitaxel specifically in 
participants with advanced TNBC and PIK3CA mutations, approximately 252 participants will 
be randomized into Part A. The majority of the mutations increasing the kinase activity of 
PIK3α, referred to as “hotspot mutations”, occur in exons 9 and 20, and to a lesser extent in 
exon 7 (Zhao and Vogt 2008). Part A will therefore limit the inclusion of participants with 
PIK3CA mutation meeting these “hotspot” criteria based on the tumor biomarker status from 
the Novartis designated laboratory using the Qiagen Therascreen PIK3CA RGQ PCR kit or by 
a local laboratory using either a FDA-approved PIK3CA CDx test for alpelisib or the CE-IVD 
QIAGEN therascreen® PIK3CA RGQ PCR test. PIK3CA mutation results generated by 
research use only version of the Qiagen test, or other laboratory-developed tests, are not 
acceptable. 
Part B1 
To assess if alpelisib in combination with nab-paclitaxel provides a benefit for participants with 
advanced TNBC with PTEN loss (with PIK3CA unknown or non-mutant), a single-arm, open-
label part B1 will assess ORR data after 6 months of follow-up in approximately 32 participants. 
These ORR results, in combination with safety data, will be used to determine if part B2 of this 
study will be opened. PTEN loss status will be assessed centrally on fresh or archival tumor 
samples (locally advanced or metastatic tumor tissue preferred) from the Novartis designated 
laboratory using the PTEN immunohistochemistry (IHC) Clinical Trial Assay (CTA). 
Part B2 
To assess the treatment effect of alpelisib in combination with nab-paclitaxel specifically in 
participants with advanced TNBC with PTEN loss (without PIK3CA mutation), approximately 
282 participants will be randomized into part B2 of this study. PTEN loss status will be assessed 
centrally on fresh or archival tumor samples (locally advanced or metastatic tumor tissue 
preferred) from the Novartis designated laboratory using the PTEN IHC CTA. 
Stratification factors for Parts A and B2 
In order to control for critical prognostic factors and to avoid imbalances between the two arms 
(Kernan et al 1999), randomization of participants in Part A and B2 will be stratified by: 
a. line of therapy in advanced/metastatic setting (1st line versus 2nd line) 
b. hormone receptor status at initial breast cancer diagnosis (HR+ versus HR-), and 
c. prior therapy with a checkpoint inhibitor (yes versus no). 
Line of therapy in the metastatic setting is a prognostic indicator. Participants in later lines of 
therapy generally fare worse with faster progression, shorter treatment duration, and shorter 
survival (Kassam et al 2009, Bajaj et al 2017, Fietz et al 2017). 
Furthermore, participants with HR+ BC at initial breast cancer diagnosis, which became TNBC 
in the advanced setting, likely constitute a different tumor entity compared to those that were 
TNBC since initial breast cancer diagnosis. Those participants, who were originally diagnosed 

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with HR-positive BC, received different treatment modalities in the primary setting (including 
hormonal therapy), and may have a different prognosis and possibly a different response to 
targeted therapy with alpelisib. In the SAFIR02 trial (NCT02299999), 649 patients with 
metastatic breast cancer with available mutational profile and clinical data were selected for 
outcome analyses with PIK3CA mutations prospectively determined by NGS on metastatic 
samples. Ten percent (n=27) of these TNBC tumors had a PIK3CA mutation. PIK3CA 
mutations were noted at a higher frequency in patients whose primary tumor was HR-positive 
at initial breast cancer diagnosis and then changed to HR-negative (39% (14/36) of patients) as 
compared to those that were HR-negative at primary and metastatic tumor assessments (7% 
(9/138), Mosele et al 2019). These data form the rationale for the first two stratification factors. 
With regard to the third stratification factor, the therapeutic landscape for TNBC is rapidly 
changing. Atezolizumab in combination with nab-paclitaxel was recently approved in the first 
line metastatic TNBC (Schmid et al 2018). Additionally, according to ClinicalTrials.gov there 
are 32 ongoing clinical studies which evaluate combinations with targeted therapies and 
immuno-oncology (IO) investigational drugs. Currently, no data are available to show if and 
how dual presence of PD-L1 positivity and a PIK3CA mutation, or pretreatment with a 
checkpoint inhibitor, may impact the outcome of any subsequent treatment with nab-paclitaxel 
and/or PI3K inhibitors, or if it may have any prognostic value. Therefore, it is important to 
assess the impact of prior IO treatment (immunomodulatory effect) on the safety and efficacy 
of alpelisib in combination with nab-paclitaxel. Stratification of randomization based on 
previous checkpoint inhibitor treatment in Study H12301 will prevent imbalance between the 
two treatment arms given that the published data currently predicts a small number of tumors 
with PD-L1 positivity and a PIK3CA mutation. Any possible influence of prior therapy can be 
better assessed by stratifying participants as to whether or not they received prior IO treatment 
(Emens and Middleton 2015). 
4.2 
Rationale for dose/regimen and duration of treatment 
4.2.1 
Alpelisib antitumor activity in TNBC 
Alpelisib has demonstrated preliminary anti-tumor activity, in two studies including patients 
with advanced TNBC. 
Study CBYL719X2101 
In the Phase Ia dose escalation study CBYL719X2101 in patients with advanced solid 
tumors alpelisib doses of 30 mg - 450 mg were explored; the maximum tolerated dose (MTD) 
for single-agent treatment was declared at 400 mg alpelisib under fed conditions. Clinical 
responses for alpelisib monotherapy were observed at doses of ≥ 270 mg once daily, though 
signs of tumor growth suppression were observed at doses ≥ 180 mg based on 
pharmacodynamic markers (Juric et al 2018). Five subjects with TNBC were included in this 
study and treated with alpelisib monotherapy. Of these, 3 had tumors harboring a PIK3CA 
amplification or mutation and were treated with once daily alpelisib. Encouraging early activity 
of alpelisib was observed in 2 of these three highly pre-treated subjects with TNBC: 
• One subject (alpelisib starting dose of 300 mg per day) was on study treatment for 442 
days and had a best response of SD with 23.5% tumor shrinkage. 

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• A second subject (alpelisib starting dose of 400 mg per day) was on study treatment for 
168 days and had an unconfirmed PR with 37.5% tumor shrinkage. 
• The third subject (alpelisib starting dose of 300 mg per day) was on study for 3 days. 
Study CBYL719XUS06T 
Alpelisib in combination with nab-paclitaxel was explored in a Phase I/II investigator initiated 
study, Study CBYL719XUS06T (NCT02379247), in 43 subjects with HER2-negative, 
advanced breast cancer (regardless of PI3K pathway activation or PTEN status) who had 
received ≥ 1 prior line of chemotherapy (prior taxane treatment, except nab-paclitaxel, was 
permitted) in either the advanced or adjuvant setting. 
The primary objectives were to determine the recommended phase II dose (RPTD) of alpelisib 
+ nab-paclitaxel and to assess the overall response rate (ORR). Phase I was a 3+3 dose-
escalation design with 3 dose levels of alpelisib (250 mg, 300 mg, and 350 mg) administered 
PO once daily (Days 1-28) with nab-paclitaxel at 100 mg/m2 i.v. on Days 1, 8, and 15 of a 28 
day cycle. Phase II was a Simon’s two stage minimax design targeting an ORR of 40% 
(NCT02379247). 
In the Phase I portion of the study, there were no DLTs and no PK interactions reported for the 
9 evaluable subjects (n=10; 1 patient stopped treatment within 10 days). The recommended 
Phase II dose (RP2D) for alpelisib was 350 mg with nab-paclitaxel at 100 mg/m2 i.v. on Days 
1, 8, and 15 of a 28 day cycle. In the Phase II portion of the study, 33 subjects were treated at 
the RP2D (Sharma et al 2018, Sharma et al 2021). PI3K pathway-activation, defined as the 
presence of PIK3CA-activating or PTEN-inactivating mutations, was tested in either tumor 
tissue or ctDNA and was observed in 44% (19/43) of patients.). PI3K pathway-activation, 
defined as the presence of PIK3CA-activating or PTEN-inactivating mutations, was tested in 
either tumor tissue or ctDNA and was observed in 44% (19/43) of patients. 
In the overall study population, 23%, 69%, and 8% of subjects had been treated with 0, 1, or ≥ 
2 lines of prior chemotherapy for metastatic breast cancer, respectively. Nine subjects continued 
on treatment for > 12 months; 5 of these had a PIK3CA mutation. For the 42 evaluable subjects 
(1 subject did not have response data), the ORR was 60% and CBR was 79%. For subjects with 
a PIK3CA mutation, the ORR was 74% and CBR was 100%. Median PFS was 13 months for 
subjects with a PIK3CA mutation (n=19) compared to 7 months for those without a PIK3CA 
mutation (n=23) (HR=0.40; 95% CI: 0.18, 0.90, p=0.017). 
TNBC Subjects in Study CBYL719XUS06T 
Twelve of the 43 subjects had advanced TNBC. The majority of these subjects were treated 
with an alpelisib dose of 350 mg (250 mg (n=2), 300 mg (n=1), and 350 mg (n=9)), in 
combination with nab-paclitaxel. The ORR and CBR for these 12 TNBC subjects was 58%. 
Five of the 12 TNBC subjects’ tumors harbored a PI3K pathway alteration: 3 had a PIK3CA 
mutation, 1 had PTEN loss without a PIK3CA mutation, and 1 had both a PIK3CA mutation 
and PTEN loss. Clinical benefit was observed in all TNBC patients with a PI3K pathway 
activated tumor. 
The following best overall responses were observed among the 12 subjects with TNBC: 
• Two (17%) subjects had a CR (one with a PIK3CA mutation without PTEN loss, one with 
PIK3CA mutation with PTEN loss). 

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• Five (42%) subjects had a PR (one with a PIK3CA mutation without PTEN loss, one with 
PTEN loss without a PIK3CA mutation). 
• Two (17%) subjects had SD (one with a PIK3CA mutation without PTEN loss). 
• Three (25%) subjects had PD (none had a PIK3CA mutation or PTEN loss). 
In study CBYL719XUS06T, the safety profile for alpelisib in combination with nab-paclitaxel 
is consistent with the known adverse event profiles of each medication (see Section 1.1.3.2). 
The following is a summary of the safety observations among the 43 patients: 
• Hyperglycemia was noted in 76% of subjects (grade 3 = 27%, no grade 4 events) with 
32% of patients requiring metformin for hyperglycemia management. 
• Rash was noted in 63% of subjects (grade 3 = 7%, no grade 4 events). All subjects 
received second or third generation H1-anti-histaminic for rash prophylaxis. 
• Alpelisib dose reductions occurred in 26% (11/43) of subjects (n=1 at 250 mg dose, n=10 
at 350 mg dose). The reasons for alpelisib dose reductions were: fatigue/anorexia (n=3), 
diarrhea (n=3), rash (n=2), hyperglycemia (n=1), hypokalemia (n=1), and investigator’s 
choice (n=1). 
• Two subjects discontinued therapy (after two cycles) due to grade 2 pneumonitis. 
• Nab-Paclitaxel dose reductions occurred in 28% (10/43) of subjects. The reasons for nab-
paclitaxel dose reductions were: peripheral neuropathy (n=3), fatigue (n=1), rash (n=1), 
diarrhea (n=1), thrombocytopenia (n=1), neutropenia (n=1), and investigator’s choice 
(n=2). 
• Two subjects stopped nab-paclitaxel and continued on single agent alpelisib. Both of these 
subjects stopped alpelisib at 12 weeks due to progressive disease (one subject’s tumor had 
a PIK3CA mutation, the other did not.) 
The incidence of AEs reported, by severity, are displayed in Table 4-1:  
Table 4-1 
Adverse events reported for alpelisib in combination with nab-
paclitaxel in Study CBYL719XUS06T 
N = 43 
CTCAE Grade 
  
  
Grade 1 
Grade 2 
Grade 3 
Grade 4 
All Grades (%) 
Musculoskeletal 
26 (63%) 
10 (24%) 
2 (5%) 
0 (0%) 
38 (93%) 
Diarrhea 
23 (56%) 
11 (27%) 
2 (5%) 
0 (0%) 
36 (88%) 
Hyperglycemia 
9 (22%) 
11 (27%) 
11(27%) 
0 (0%) 
31 (76%) 
Fatigue 
12 (29%) 
14 (34%) 
2 (5%) 
0 (0%) 
28 (68%) 
Nausea 
21 (51%) 
7 (17%) 
0 (0%) 
0 (0%) 
28 (68%) 
Peripheral neuropathy 
16 (39%) 
9 (22%) 
1 (2%) 
0 (0%) 
26 (63%) 
Rash 
21 (51%) 
2 (5%) 
3 (7%) 
0 (0%) 
26 (63%) 
Infections 
 7 (17%) 
15 (37%) 
2 (5%) 
0 (0%) 
24 (59%) 
Anorexia 
17 (41%) 
5 (12%) 
0 (0%) 
0 (0%) 
22 (54%) 
Anemia 
12 (29%) 
4 (10%) 
5 (12%) 
0 (0%) 
21 (51%) 
Neutropenia 
3 (7%) 
5 (12%) 
10 (24%) 
3 (7%) 
21 (51%) 
Mucositis/Oral Pain 
15 (37%) 
4 (10%) 
1 (2%) 
0 (0%) 
20 (49%) 
Electrolyte imbalance 
16 (39%) 
2 (5%) 
1 (2%) 
1 (2%) 
20 (49%) 
GI Other 
15 (37%) 
5 (12%) 
0 (0%) 
0 (0%) 
20 (49%) 
Dysgeusia 
17 (41%) 
2 (5%) 
0 (0%) 
0 (0%) 
19 (46%) 

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N = 43 
CTCAE Grade 
  
  
Grade 1 
Grade 2 
Grade 3 
Grade 4 
All Grades (%) 
Pulmonary Other 
11 (27%) 
6 (15%) 
1 (2%) 
0 (0%) 
18 (44%) 
Others 
10 (24%) 
8 (20%) 
0 (0%) 
0 (0%) 
18 (44%) 
Liver enzyme increase 
14 (34%) 
1 (2%) 
0 (0%) 
0 (0%) 
15 (37%) 
Eye Disorders 
11 (27%) 
3 (7%) 
0 (0%) 
0 (0%) 
14 (34%) 
Nail Changes 
11 (27%) 
2 (5%) 
0 (0%) 
0 (0%) 
13 (32%) 
Vomiting 
6 (15%) 
5 (12%) 
0 (0%) 
0 (0%) 
11 (27%) 
Myalgia 
8 (20%) 
2 (5%) 
0 (0%) 
0 (0%) 
10 (24%) 
Neurological 
8 (20%) 
0 (0%) 
0 (0%) 
0 (0%) 
8 (20%) 
Dry Mouth/Skin 
7 (17%) 
1 (2%) 
0 (0%) 
0 (0%) 
8 (20%) 
Weight loss 
2 (5%) 
5 (12%) 
0 (0%) 
0 (0%) 
7 (17%) 
Renal 
2 (5%) 
2 (5%) 
1 (2%) 
0 (0%) 
5 (12%) 
Edema 
2 (5%) 
1 (2%) 
0 (0%) 
0 (0%) 
3 (7%) 
Pneumonitis 
1 (2%) 
2 (5%) 
0 (0%) 
0 (0%) 
3 (7%) 
Thrombocytopenia 
1 (2%) 
1 (2%) 
0 (0%) 
0 (0%) 
2 (5%) 
In summary, these data demonstrate a tolerable safety profile and promising early anti-tumor 
activity of alpelisib in combination with nab-paclitaxel in advanced TNBC aBC where the PI3K 
pathway is activated by the presence of a PIK3CA mutation or PTEN loss and warrant the 
investigation of the combination of alpelisib with nab-paclitaxel in advanced TNBC. 
4.2.2 
Alpelisib Phase III dose 
Phase III dose selection of 300 mg of alpelisib in combination with nab-paclitaxel was based 
on an integrated assessment of the results of Study CBYL719XUS06T and analyses conducted 
by Novartis with data from the Phase III study of alpelisib plus fulvestrant in HR-positive, 
HER2-negative aBC (Study CBYL719C2301), and earlier Phase I studies, showing a 
relationship between plasma exposure and risk of hyperglycemia and rash in subjects with 
metastatic breast cancer. Overall, the alpelisib dose of 300 mg administered once daily provides 
the best benefit-risk profile. 
In Study CBYL719XUS06T, the recommended Phase II alpelisib dose was 350 mg in 
combination with nab-paclitaxel. However, dose reductions for subjects receiving 350 mg 
occurred in 30% of subjects (10 of the 33 treated at this dose level), primarily due to adverse 
events. Assuming a similar exposure-safety relationship in metastatic TNBC subjects as HR-
positive, HER2-negative aBC subjects, where the safety of the 300 mg dose is well 
characterized, the 300 mg alpelisib dose is considered more tolerable. 
Study CBYL719C2301 investigated both PIK3CA mutant and non-mutant cohorts. Since the 
PIK3CA non-mutant cohort did not meet the Proof of Concept (PoC) criteria, exposure-efficacy 
analysis using PFS data was only conducted for the PIK3CA mutant cohort. To investigate the 
benefit of starting alpelisib treatment at or close to the planned initial dose (300 mg) compared 
to a reduced level, dose intensity (DI) over the first 4 weeks of treatment (before the majority 
of subjects experienced dose reductions) was calculated. The PFS analysis by median DI at 4 
weeks demonstrated a clearer benefit for subjects with a DI greater than or equal to the median 
DI of 289 mg/day compared to a lower DI (<289 mg/day), with a median PFS of 14.5 months 
vs. 8.3 months, respectively (Figure 4-1). In summary, there is a greater treatment benefit of 
alpelisib plus fulvestrant for subjects with a starting dose of 300 mg compared to lower dose 

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levels. As clinical responses were observed in combination with nab-paclitaxel at the 300 mg 
dose level in CBYL719XUS06T (with 3 subjects enrolled at 300 mg, 1 PR and 2 SD) and 
assuming a similar exposure-efficacy relationship, 300 mg is more likely to optimize a sufficient 
dose intensity to provide clinical benefit with a better safety profile.  
Figure 4-1 
Kaplan-Meier plot of PFS by median dose intensity (first 4 weeks) in 
the PIK3CA mutant cohort - Study CBYL719C2301 (Full analysis set) 
 
 Alpelisib 300 mg orally daily and nab-paclitaxel 100 mg/m2 i.v. on Days 1, 8 and 15 of a 28-day cycle 
was selected for further evaluation in this Phase III study to maximize treatment benefit while retaining 
an acceptable and manageable safety profile.  
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
4.3.1 
Nab-Paclitaxel in TNBC 
Taxanes (paclitaxel, docetaxel, nab-paclitaxel) are microtubule inhibitors and have significant 
antitumor activity in breast cancer. They are recommended in TNBC in both the adjuvant and 
metastatic setting (Senkus et al 2015, Mustacchi and De Laurentiis 2015, Schettini et al 2016, 
Park et al 2018, 
NCCN Breast Cancer 1.2019). 
Nab-paclitaxel 
is 
an 
albumin-bound 
formulation of paclitaxel. It was developed to take advantage of the antitumor activity of 
paclitaxel while decreasing or eliminating toxicities typically associated with the solvent 
(Cremophor) used to administer the most common formulation of paclitaxel (Martín 2015). 
Nab-paclitaxel has an advantageous PK profile compared to solvent-based paclitaxel with 33% 
higher tumor uptake in preclinical models (Yardley 2013) and allows the infusion of higher 

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doses of paclitaxel compared with standard paclitaxel therapy, in a shorter infusion time, 
without premedication. Nab-paclitaxel is approved in the EU, US, and many other countries 
worldwide for metastatic breast cancer, after failure of combination chemotherapy for 
metastatic disease or relapse within 6 months of adjuvant chemotherapy. 
Nab-paclitaxel demonstrated higher response rates compared with standard paclitaxel (33% vs 
19%, respectively; p=0.001) and longer time to tumor progression (23.0 vs 16.9 weeks, 
respectively; HR = 0.75; p=0.006) in a Phase III trial of patients with mBC 
(Gradishar et al 2005). Various studies demonstrated high pathological complete response rates 
(pCR) in early-stage breast cancer, particularly in TNBC and encouraging overall survival 
in metastatic breast cancer across different doses and schedules (Brufsky 2017).  
Therefore, because of the proven efficacy in metastatic TNBC and its more advantageous 
administration method (including absence of steroid pre-medication), nab-paclitaxel is an 
appropriate combination partner for alpelisib.  
4.3.2 
Nab-Paclitaxel dose schedule 100 mg/m2 on Day 1, 8, and 15 of 28 Day 
treatment cycle 
Nab-paclitaxel at a dose of 260 mg/m2 as a once every 3-week (q3w) dose schedule is approved 
for the treatment of mBC (Gradishar et al 2005). Neither the 260 mg/m2 dose nor the once 
every 
3-week 
schedule 
are 
commonly 
used 
in 
clinical 
practice 
(Mustacchi and De Laurentiis 2015). Furthermore, Nab-paclitaxel is frequently used in TNBC 
patients that do not precisely fall into the defined category specified in the nab-paclitaxel 
label (Mustacchi and De Laurentiis 2015). Both the NCCN and ESMO clinical practice 
guidelines include nab-paclitaxel as a standard of care that may be administered as a single 
agent to patients with newly diagnosed recurrent or metastatic breast cancer 
(Cardoso et al 2018, NCCN Breast Cancer 1.2019). 
Findings from a later phase II study by Gradishar (2009) which examined the antitumor activity 
and safety of weekly and every 3-week nab-paclitaxel compared with docetaxel in first-line 
mBC suggested that nab-paclitaxel at 150 mg/m² given weekly for 3 weeks followed by a week 
break was more effective in terms of progression-free survival than 100 mg/m² nab-paclitaxel 
given weekly or 100 mg/m² docetaxel given once every 3 weeks followed by a week break 
(Gradishar et al 2009). In the four arms of this study, the ORRs were: 
• 37% with  nab-paclitaxel 300 mg/m2 every 3-week, 
• 45% with nab-paclitaxel 100 mg/m2  weekly (3-weeks-on/1-week-off schedule), 
• 49% with nab-paclitaxel 150 mg/m2 weekly  (3-weeks-on/1-week-off) weeks, and 
• 35% with q3w docetaxel 100 mg/m2.  
PFS were 11.0 months, 12.8 months, 12.9 months and 7.5 months for each of the four arms, 
respectively. These results illustrate the advantages of the nab-paclitaxel weekly dosing 
schedule over the every-3-week dosing schedule. Of note, improvement in ORR and PFS of 
nab-paclitaxel 150 mg/m2 weekly over 100 mg/m2 was not statistically significant. 
Additionally, patients receiving the higher nab-paclitaxel dose experienced higher incidences 
of Grade 3 or 4 neutropenia (44% vs. 25%) and Grade 3 sensory neuropathy (14% vs. 8%). 
Subsequent clinical studies have not clearly demonstrated that weekly doses of nab-paclitaxel 
above 100 mg/m2 are more efficacious. Furthermore, higher doses of nab-paclitaxel are 

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associated with greater toxicities (Gradishar et al 2009, Untch et al 2016). The CALGB 40502 
Phase III trial randomized patients with chemotherapy-naïve, HER2-negative mBC to receive 
weekly paclitaxel, weekly nab-paclitaxel at a higher dose of 150 mg/m2, or ixabepilone, with 
all agents given in combination with bevacizumab, and on a 3-week-on/1-week-off schedule 
(Rugo et al 2015). Nab-paclitaxel was not tolerable at this higher weekly dose and did not 
improve PFS in any aBC subtype over the standard dose of paclitaxel, leading to the conclusion 
that nab-paclitaxel 150 mg/m2 should not be utilized. 
The Impassion130 Phase III study in first-line mTNBC also administered nab-paclitaxel at 100 
mg/m2 weekly on a 3-week-on/1-week-off schedule. This trial led to the FDA approval of 
atezolizumab plus nab-paclitaxel in PDL1-positive advanced TNBC (Schmid et al 2018). The 
Phase I/II investigator initiated trial (IIT) in 43 subjects with HER2-negative, aBC demonstrated 
promising efficacy results, including 12 subjects with TNBC (Sharma et al 2018, 
Sharma et al 2021) with this nab-paclitaxel regimen. Subjects, regardless of PIK3CA mutation 
status, received nab-paclitaxel 100 mg/m2 on days 1, 8 and 15 of a 28-day cycle (3 weeks on/ 1 
week off) with alpelisib 250 mg, 300 mg, or 350 mg orally daily; this dosing schedule of nab-
paclitaxel was tolerable and efficacious. 
In summary, nab-paclitaxel at a dosing schedule of 100 mg/m2 i.v. on days 1, 8, and 15 of a 28 
day cycle is a well-studied and tolerated dose regimen with suggestions of improved efficacy 
and decreased toxicities in mBC and mTNBC compared with both higher weekly doses and the 
every 3-week nab-paclitaxel dosing schedule (Gradishar et al 2009, Brufsky 2017). As a result, 
subjects on this study will receive nab-paclitaxel 100 mg/m2 i.v. on Days 1, 8 and 15 of a 28-
day cycle. 
4.4 
Purpose and timing of interim analyses/design adaptations 
 With protocol amendment 02, no interim efficacy analyses will be performed. 
4.5 
Risks and benefits 
4.5.1 
Potential benefits to clinical trial participants 
Treatment with alpelisib in combination with nab-paclitaxel may provide a clinical benefit 
compared to nab-paclitaxel alone in men and women with advanced TNBC with either a 
PIK3CA mutation and/or PTEN loss in first or second line metastatic setting. All participants 
enrolled in this trial will receive nab-paclitaxel as active treatment for their disease (see 
Section 6.1), with either the addition of alpelisib or placebo. Based on preliminary clinical data 
(see Section 1.1.3.2), treatment with alpelisib in combination with nab-paclitaxel is expected to 
be tolerated with a manageable side effect profile. 
For further details on clinical safety, please refer to Section 1.1.3 and the latest version of 
[Alpelisib (BYL719) Investigator's Brochure] as well as local prescribing information for nab-
paclitaxel. 
4.5.2 
Potential risks to clinical trial participants 
Participants in this study will be carefully monitored using periodic laboratory, renal and liver 
function parameters and Electrocardiogram (ECG) for key toxicities that have been observed 

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with alpelisib (see Section 1.1.3), nab-paclitaxel (see Section 4.3) or the combination of both 
treatments (see Section 4.2). 
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 and Section 6.5.2), adherence to dose adjustment guidelines (see Section 6.5.1), and 
training of site personnel. An independent data monitoring committee (DMC) (see 
Section 10.2.2) will monitor safety, efficacy and available PK data as outlined in the protocol. 
A Steering Committee (SC) (see Section 10.2.3) comprising investigators and Novartis 
personnel participating in the trial will ensure transparent management of the trial according to 
the protocol. A Novartis Safety Management Team (SMT) periodically reviews and evaluates 
all emerging data across the alpelisib program for potential safety signal assessment in a timely 
manner. 
Male and female rat fertility studies revealed effects on fertility-associated parameters 
confirming previously obtained evidence of toxic effects of alpelisib on female fertility and on 
male reproductive organs, without affecting the fertility of male rats. In summary those data 
confirm that alpelisib can have effects on both male and female fertility in humans. 
Women 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 
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 question that the 
participant will not reliably comply, they should not be entered or continue in the study. 
The assessment of the Benefit/Risk did not reveal any additional risks related to coronavirus 
disease 2019 (COVID-19) and no changes were made as a result. 
4.6 
Rationale for 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 are listed in relevant sections. Notification of the Public health emergency should be 
discussed with Novartis prior to implementation of mitigation procedures, and 
permitted/approved by Local or Regional Health Authorities and Ethics Committees as 
appropriate. 
5 
Study Population 
This study will include approximately 566 men and women with advanced (locally recurrent or 
metastatic) TNBC with a PIK3CA mutation (Part A) or with PTEN loss (Parts B1 and B2), who 
have received no prior therapy, or only one prior therapy for their advanced disease. Participants 
will therefore be enrolled either in 1st line or 2nd line advanced/metastatic setting. Participants 
enrolled in this study are not permitted to participate in additional parallel investigational 
studies. The investigator or designee must ensure that only participants who meet all the 
following inclusion and none of the following exclusion criteria are offered treatment in this 
study. 

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The recruitment in Part B1 was completed; 35 participants were enrolled. The decision to stop 
the enrollment in Part A was due to slow recruitment; a total of 102 participants were 
randomized in Part A. Part B2 wasn’t initiated based on Part B1 results.  
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Participant is ≥ 18 years old at the time of informed consent and has signed informed 
consent before any trial related activities and according to local guidelines. 
2. Participant has histologically confirmed diagnosis of advanced (loco-regionally recurrent 
and not amenable to curative therapy, or metastatic (stage IV)) TNBC. This diagnosis 
should be established from the most recently analyzed biopsy from a metastatic or locally 
recurrent site (local lab) and meet the following criteria: 
a. HER2 negative in situ hybridization (ISH) test or an immunohistochemistry (IHC) 
status of 0 or 1+, and 
b. ER and PR expression is <1 percent as determined by IHC (Hammond et al 2010). 
Note: Participants that were previously identified with ER-positive, or PR-positive or 
HER2-positive early disease are allowed into the study if they have confirmed TNBC 
(meeting criteria 2a and 2b) by tumor biopsy in the locally advanced or metastatic setting 
at the time of screening. 
Note: TNBC status confirmation from a primary tumor biopsy can be accepted if it is 
unsafe or not clinically feasible to obtain a metastatic biopsy. 
3. Participant has either: 
a. Measurable disease, i.e., at least one measurable lesion per RECIST 1.1 criteria (a 
lesion at a previously irradiated site may only be counted as a target lesion if there is 
clear sign of progression since the irradiation) OR 
b. If no measurable disease is present, then at least one predominantly lytic bone lesion 
or mixed lytic-blastic bone lesion with identifiable soft tissue component (that can be 
evaluated by Computerized Tomography (CT) /Magnetic Resonance Imaging (MRI)) 
must be present. Participants with no measurable disease and only one predominantly 
lytic bone lesion that has been previously irradiated are eligible if there is documented 
evidence of disease progression of the bone lesion after irradiation. 
Note: Only participants with measurable disease are eligible for Part B1. 
4a. Participant has adequate tumor tissue for analysis of PIK3CA mutation and PTEN loss 
status by a Novartis designated laboratory (refer to Section 8.1). A formalin fixed paraffin 
embedded (FFPE) tumor block from a new or archival biopsy or unstained FFPE glass 
slides as described on Table 8-15 in Section 8.5.3 must be provided. If an archival tumor 
sample (preferably within 3 years prior to screening) is not available, a new or recent 
biopsy (collected at screening if feasible) is required. 
a. If a PIK3CA mutation is detected, then the participant may be eligible for Part A, if 
all other criteria are met 
b. If PTEN loss without a PIK3CA mutation is detected, then the participant may be 
eligible for Part B1 or B2, if all other criteria are met 
c. If PTEN loss is detected and PIK3CA status is unknown, then the participant may be 
eligible for Part B1, if all other criteria are met 

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Note: If a PIK3CA mutation was already confirmed by a local laboratory with either a 
FDA-approved PIK3CA CDx test for alpelisib or the CE-IVD QIAGEN therascreen® 
PIK3CA RGQ PCR test, this can serve as confirmation of the PIK3CA mutation status. 
Note: Analysis of PIK3CA mutation and PTEN loss from a primary tumor biopsy can be 
accepted if it is unsafe or not clinically feasible to obtain a metastatic biopsy. 
5. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 
or 1. 
6. Participant has received no more than one line of therapy for metastatic disease. 
Participant with de novo metastatic disease are eligible. 
a. Participant may have received prior taxane-based chemotherapy in the neoadjuvant or 
adjuvant setting, provided it has been completed ≥ 12  months prior to Day 1 of Cycle 
1. 
b. Participant may have received prior taxane-based chemotherapy for metastatic 
disease, provided the best response was not progressive and it has been completed ≥ 
12 months prior to Day 1 of Cycle 1. 
Note: Endocrine-based therapy for HR+ advanced/metastatic BC should not be counted as 
a line of treatment. 
7a. Participant has adequate bone marrow and organ function as defined by the following 
laboratory values (assessed by central laboratory for eligibility): 
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
b. Platelets (PLT) ≥ 100 × 109/L 
c. Hemoglobin ≥ 9.0 g/dL 
d. Calcium (corrected for serum albumin) and magnesium within normal limits or ≤ 
grade 1 according to National Cancer Institute (NCI)-CTCAE version 4.03 if judged 
clinically not significant by the investigator 
e. Potassium within normal limits, or corrected with supplements 
f. International Normalized Ratio (INR) ≤1.5 
g. Creatinine Clearance ≥ 35 mL/min using Cockcroft-Gault formula 
h. In absence of liver metastases, alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) < 3 × Upper limit of normal (ULN). If the patient has liver 
metastases, ALT and AST ≤ 5 × ULN he/she will be eligible for the study  
i. Total bilirubin < 1.5 x ULN (any elevated bilirubin should be asymptomatic at 
enrollment) except for participants with Gilbert’s syndrome who may only be 
included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN 
j. Fasting plasma glucose (FPG) ≤ 140 mg/dL (7.7 mmol/L) and Glycosylated 
Hemoglobin (HbA1c) ≤ 6.4% (both criteria have to be met)  
k. Fasting Serum amylase ≤ 2 × ULN 
l. Fasting Serum lipase ≤ ULN 
m. Albumin ≥ 2.5 g/dL 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Participant has received prior treatment with any PI3K, mTOR or AKT inhibitor. 

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2. Participant has a known hypersensitivity to alpelisib, nab-paclitaxel or to any of their 
excipients (e.g. rare hereditary problems of galactose intolerance, Lapp lactase deficiency, 
or glucose-galactose malabsorption, due to the excipient in the placebo tablet). 
3. Participant with inflammatory breast cancer at screening. 
4. Participant is concurrently using other anti-cancer therapy. 
5. Participant has had surgery within 14 days prior to starting study drug or has not recovered 
from major side effects. 
6. Participant has not recovered from all toxicities related to prior anticancer therapies to 
NCI CTCAE version 4.03 Grade ≤1. Exception to this criterion: participants with any 
grade of alopecia are allowed to enter the study. 
7. Participant with Child Pugh score B or C. 
8. Participant has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 
weeks prior to randomization, and who has not recovered to grade 1 or better from related 
side effects of such therapy (with the exception of alopecia). 
9. Participant has a concurrent malignancy or malignancy within 3 years prior to start of 
study treatment, with the exception of adequately treated, basal or squamous cell 
carcinoma, non-melanomatous skin cancer, or curatively resected cervical cancer. 
10. Participant has central nervous system (CNS) involvement which was not previously 
treated and/or was newly detected at screening. Previously treated CNS involvement must 
fulfill the following criteria to be eligible for the trial: 
a. Completed prior therapy (including radiation and/or surgery) for CNS metastases ≥ 
28 days prior to the start of study and 
b. CNS tumor is clinically stable at the time of screening, and 
c. Participant is not receiving steroids and/or enzyme inducing anti-epileptic 
medications for brain metastases 
11. Participant with an established diagnosis of diabetes mellitus type I or uncontrolled type II 
based on Fasting Plasma Glucose and HbA1c as per inclusion criterion 7. 
12. Participant has impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) based on 
investigator discretion. 
13. Participant has a history of acute pancreatitis within 1 year prior to screening or past 
medical history of chronic pancreatitis. 
14. Participant has any other concurrent severe and/or uncontrolled medical condition that 
would, in the investigator’s judgment, contraindicate patient participation in the clinical 
study (e.g., chronic active hepatitis [testing not mandatory unless required by local 
regulations or requirements], severe hepatic impairment). 
15. Participant has currently documented pneumonitis/interstitial lung disease (the chest CT 
scan performed before start of study treatment for the purpose of tumor assessment should 
be reviewed to confirm that there are no relevant pulmonary complications present). 
16. Participant has clinically significant, uncontrolled heart disease and/or recent cardiac 
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a. History of angina pectoris, coronary artery bypass graft (CABG), symptomatic 
pericarditis, or myocardial infarction within 6 months prior to the start of study 
treatment 
b. History of documented congestive heart failure (CHF) (New York Heart Association 
functional classification III-IV) 
c. Left Ventricular Ejection Fraction (LVEF) <50% at screening as determined by 
MRI/Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) 
d. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), high-grade 
AV block (e.g., bifascicular block, Mobitz type II; third degree AV block without 
pacemaker in place) 
e. Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome, or Fridericia QT correction formula (QTcF) >470 msec at screening. 
f. Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mmHg 
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without anti-
hypertensive medication. Initiation or adjustment of antihypertensive medication(s) is 
allowed prior to screening 
17. Participant has a history of severe cutaneous reactions, such as Steven-Johnson Syndrome 
(SJS), erythema multiforme (EM), Toxic Epidermal Necrolysis (TEN), or Drug Reaction 
with Eosinophilia and Systemic Syndrome (DRESS). 
18. Participant with unresolved osteonecrosis of the jaw 
19. Participant is currently receiving any of the following medications and cannot be 
discontinued 7 days prior to the start of the treatment: 
a. Strong inducers of CYP3A4 
b. Inhibitors of BCRP 
20. Participant is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior 
to starting study drug, or who have not fully recovered from side effects of such treatment. 
Note: The following uses of corticosteroids are permitted: single doses, topical 
applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye 
drops or local injections (e.g., intra-articular). 
21. Participation in a prior investigational study within 30 days prior to the start of study 
treatment or within 5 half-lives of the investigational product, whichever is longer. 
22. Participant is not able to understand and to comply with study instructions and 
requirements. 
23. Participant is a woman of child-bearing potential defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective methods of 
contraception during study treatment and for 6 months after the last dose of any study 
treatment. Highly effective contraception methods include: 
• 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 had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least 6 weeks before 

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taking study treatment. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). For female participants on the 
study the vasectomized male partner should be the sole partner for that patient 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS) without 
hormonal components. 
Note: Women are considered postmenopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (i.e., age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or bilateral 
tubal ligation at least 6 weeks before taking study treatment. In the case of oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment is she considered not of child bearing potential. 
If local regulations deviate from the contraception methods listed above, local regulations 
apply and will be described in the ICF. 
24. Participant is a sexually active male unwilling to use a condom during intercourse while 
taking study treatment, and up to 6 months after the last dose of study treatment. A 
condom 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. In 
addition, male participants must not donate sperm during the study and up to the time 
period specified above. 
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF. 
25. Participant is a nursing (lactating) or pregnant woman as confirmed by a positive serum 
(hCG) test prior to initiating study treatment. 
6 
Treatment 
6.1 
Study treatment 
In this study, the “study treatment” refers to the combination of alpelisib or placebo with nab-
paclitaxel in Parts A and B2, and alpelisib in combination with nab-paclitaxel in part B1. The 
term “investigational drug” refers to the Novartis study drug, alpelisib. 
Novartis Global Clinical Supply (GCS) will provide study drug for Part A and part B2 as global 
clinical double-blind labeled supplies (alpelisib/BYL719 and placebo as 200 mg or 50 mg 
tablets as individual participant supply packed in bottle). Study drug for part B1 will be provided 
as global clinical open-label supplies (alpelisib/BYL719 as 200 mg or 50 mg tablets as 
individual participant supply packed in bottle.). They will be packed and labeled under the 
responsibility of Novartis GCS.  
Once all participants have completed 6 months of study treatment or have been discontinued 
from the study treatment, Part A participants will be unblinded.  
Part A participants on the experimental arm will continue to receive alpelisib supplies while 
Part A participants on control arm will no longer be administered placebo supplies.Nab-
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subsidiary or designee as commercially available or centrally by Novartis, according to local 
practices and local regulations. The generic or brand name used in the study must conform to 
the definition of albumin-bound paclitaxel. Storage conditions are described in the medication 
label. Medication labels will comply with the legal requirements of each country and be printed 
in the local language. Generic nab-paclitaxel that was rejected by or withdrawn from regulatory 
agencies (e.g. FDA and/or European Medicines Agency (EMA)) should not be used. 
All dosages prescribed and dispensed to the participant and all dose changes during the study 
must be recorded on the appropriate electronic Case Report Form (eCRF). 
6.1.1 
Investigational and control drugs 
6.1.1.1 
Dosing regimen for Parts A and B2 
Table 6-1 
Investigational and control drug - Parts A and B2 
Investigational/ 
Control Drug 
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
Double-blind (DB) 
alpelisib/BYL719 
200 mg* 
Tablet 
Oral use 
Double-Blind label 
participant packs; 
bottles  
Sponsor (global) 
DB placebo 
200 mg*  
Tablet 
Oral use 
Double-Blind label 
participant packs; 
bottles  
Sponsor (global) 
DB 
alpelisib/BYL719 
50 mg* 
Tablet 
Oral use 
Double-Blind label 
participant packs; 
bottles  
Sponsor (global) 
DB placebo 50 mg* 
Tablet 
Oral use 
Double-Blind label 
participant packs; 
bottles  
Sponsor (global) 
Nab-paclitaxel 5 
mg/mL 
Powder for 
suspension for 
Injection or Powder 
for infusion 
dispersion 
Intravenous 
Vial 
Sponsor 
(local/global), study 
site 
* Once all participants have completed 6 months of study treatment or have been discontinued from study 
treatment and after participant’s unblinding, participants in the experimental arm will receive alpelisib and 
participants in the control arm will no longer be dispensed placebo supplies. The reference to “placebo” and 
double-blind remains in the protocol text to avoid confusion.  
In the double-blind, randomized, placebo-controlled parts (Parts A and B2), participants will be 
randomized in a 1:1 ratio to receive either: 
• Experimental arm (Arm 1) - alpelisib + nab-paclitaxel, or 
• Control arm (Arm 2) - placebo + nab-paclitaxel. 
Alpelisib or placebo will be administered at 300 mg orally once daily on a continuous basis 
immediately after food starting on Cycle 1 Day 1 in a 28-day cycle. 
A non-sedating antihistamine, such as cetirizine once daily on a continuous basis, is 
recommended to start on Cycle 1 Day 1 for approximately 8 weeks for the prevention of rash 
associated with PI3K inhibition. For participants benefiting from the antihistamine, treatment 

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can be continued beyond the first 8 weeks, if clinically indicated at the investigator’s discretion 
(Wang et al 2020). Refer to Section 6.5.2.3 for additional information on antihistamine 
treatment and incidence/severity of rash based on alpelisib clinical trial experience.Nab-
paclitaxel at 100 mg/m2 will be administered approximately 1 hour after alpelisib or 
alpelisib/placebo on Days 1, 8 and 15 of a 28-day cycle as a 30-minute i.v. infusion according 
to local standard practice. For instructions to reconstitute vials prior to administration please 
refer to the local prescribing information for nab-paclitaxel. 
A complete cycle of treatment is defined as 28 days (+/- 3 days) of once daily continuous 
treatment of alpelisib or placebo in combination with nab-paclitaxel administered on Days 1, 8, 
and 15. 
The last day of a complete treatment cycle is Day 28 (+/- 3 days). Day 1 of the next cycle starts 
on Day 29 (+/- 3 days). 
Treatment crossover from placebo in combination with nab-paclitaxel to alpelisib in 
combination with nab-paclitaxel will not be permitted in this study. 
6.1.1.2 
Dosing regimen for Part B1 
Table 6-2 
Investigational and control drug – Part B1 
Investigational/ 
Control Drug 
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
Open-label (OL) 
alpelisib/BYL719 
200 mg 
Tablet 
Oral Use 
Open-label 
participant packs; 
bottles 
Sponsor (global) 
OL 
alpelisib/BYL719 
50 mg 
Tablet 
Oral Use 
Open-label 
participant packs; 
bottles 
Sponsor (global) 
Nab-paclitaxel 5 
mg/mL 
Powder for 
suspension for 
Injection or Powder 
for infusion 
dispersion 
Intravenous 
Vials 
Sponsor 
(local/global), study 
site 
Alpelisib will be administered at 300 mg orally once daily on a continuous basis immediately 
after food starting on Cycle 1 Day 1 in a 28-day cycle. 
A non-sedating antihistamine, such as cetirizine once daily on a continuous basis, is 
recommended to start on Cycle 1 Day 1 for approximately 8 weeks for the prevention of rash 
associated with PI3K inhibition. For participants benefiting from the antihistamine, treatment 
can be continued beyond the first 8 weeks, if clinically indicated at the investigator’s discretion 
(Wang et al 2020). Refer to Section 6.5.2.3 for additional information on antihistamine 
treatment and incidence/severity of rash based on alpelisib clinical trial experience. 
Nab-paclitaxel at 100 mg/m2 will be administered approximately 1 hour after alpelisib on Days 
1, 8 and 15 of a 28-day cycle as a 30-minute i.v. infusion according to local standard practice. 
For instructions to reconstitute vials prior to administration, please refer to the local prescribing 
information for nab-paclitaxel. 

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A complete cycle of treatment is defined as 28 days (± 3 days) of once daily continuous 
treatment of alpelisib in combination with nab-paclitaxel administered on Days 1, 8 and 15. 
The last day of a complete treatment cycle is Day 28 (+/- 3 days). Day 1 of the next cycle starts 
on Day 29 (+/- 3 days). 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug and control drug are included in this trial. 
6.1.3 
Treatment arms/group 
In the double-blind, randomized, placebo-controlled parts (Parts A and B2), participants will be 
assigned to one of the following treatment arms in a 1:1 ratio: 
• Experimental arm (Arm 1): alpelisib + nab-paclitaxel or 
• Control arm (Arm 2): alpelisib matching placebo + nab-paclitaxel. 
In the open-label part B1, all participants will be assigned to the alpelisib + nab-paclitaxel 
combination. 
6.1.4 
Guidelines for continuation of treatment 
Refer to guidelines for management of toxicities and doses modifications instruction, see 
Section 6.5.1 
6.1.5 
Treatment duration 
Participants will continue to receive study treatment until disease progression is radiologically 
documented according to RECIST 1.1, unacceptable toxicity that precludes further treatment, 
or until discontinuation of study treatment due to any other reason (Section 9.1.1).  
Nab-paclitaxel and alpelisib may be discontinued independently of each other for unacceptable 
toxicities or at the discretion of the treating physician. 
Participants who complete participation in this trial and continue to derive clinical benefit from 
the treatment based on the investigator’s evaluation may receive post-trial access (PTA). PTA 
means the provision of treatment to trial participants following their completion of trial 
participation. PTA will be provided until one of the following is met: participant no longer 
derives clinical benefit, treatment is discontinued at the discretion of the investigator or the 
participant, launch or reimbursement (where applicable), treatment fails to achieve registration 
in the trial 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-trial 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. 
The PTA mechanism must comply with local laws and regulations in the participating trial 
countries.  If Novartis discontinues the PTA for this trial, Novartis will work with investigators 
to transition participants onto locally available alternative treatment, or standard of care. 

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6.1.5.1 
Treatment beyond disease progression 
Study treatment beyond disease progression per RECIST 1.1 as assessed locally by investigator 
will not be allowed in this study. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
The use of any concomitant medications/non-drug therapies deemed necessary to treat adverse 
events, manage cancer symptoms, concurrent diseases and supportive care agents, such as pain 
medications, anti-emetics and anti-diarrheal are allowed, except if specifically prohibited (See 
Section 6.2.2) 
The investigator should instruct the participant to notify the study site about any new 
medications and/or non-drug therapies/procedures he/she takes after signing the informed 
consent. All medications, procedures, and significant non-drug therapies (including vitamins, 
physical therapy, herbal/natural medications and blood transfusions) administered within 30 
days prior to the start of study treatment and up to 30 days after the last dose of study treatment 
must be recorded on the appropriate eCRF. 
Each concomitant drug must be individually assessed against all exclusion criteria/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. 
Oral anti-diabetics 
Participants who develop hyperglycemia during the study should be treated according to the 
ADA guidance and/or European Association for the study of Diabetes (EASD).  
Consultation with a diabetologist or healthcare provider experienced in the management of 
hyperglycemia is highly recommended for better assessment and management of alpelisib-
induced hyperglycemia. It is recommended to start treatment with metformin, however sodium-
glucose cotransporter 2 (SGLT2) inhibitors, as per local standard practices, may be a suitable 
alternative or add-on therapy to metformin. SGLT2 inhibitors are a class of diabetic medications 
that improve hyperglycemia primarily by promoting urinary glucose excretion. 
In the SOLAR-1 study, among the 284 participants who were randomized to receive alpelisib 
plus fulvestrant, 190 participants (67%) developed hyperglycemia, with 18 participants (6%) 
discontinuing alpelisib treatment due to hyperglycemia, as of 30-Sep-2019 (Lu et al 2020).   
Among those with hyperglycemia, 166 participants received concomitant anti-diabetic 
medications, primarily consisting of metformin (87%). However, in addition to metformin, 6 
participants also received an SGLT2 inhibitor, consisting of empagliflozin, ipragliflozin, or 
dapagliflozin (Lu et al 2020). All 6 participants had ≥ 1 risk factor at baseline for developing 
hyperglycemia, defined as prediabetes (n = 4; 1 of whom had documented history of type 2 
diabetes), diabetes (n = 2), and obesity (n = 2). The most severe hyperglycemia in these 
participants was grade (G) 3 (n = 5). After initiating an SGLT2 inhibitor, all subsequent 
hyperglycemia events were G 1/2, except one G 3 event with steroids as a confounding factor. 

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Among those 6 participants, the duration of alpelisib ranged from 9.5 to 27.7 months in 4 
participants who discontinued alpelisib; and notably, the remaining 2 participants continued to 
receive alpelisib after 37.0 and 40.0 months. None of the 6 participants discontinued alpelisib 
due to hyperglycemia. 
Based on these data, participants may benefit from the initiation of an SGLT2 inhibitor with 
metformin, which is available as a single oral combination pill or as two separate medications. 
Particularly in participants with at least one risk factor for the development of severe 
hyperglycemia, defined as prediabetes/diabetes, and/or obesity (Body Mass Index (BMI) ≥ 30), 
and/or age ≥ 75 years, early or prophylactic initiation of an SGLT2 inhibitor alone or in 
combination with metformin may help to reduce the incidence and frequency of severe 
hyperglycemia events. The decision to initiate an SGLT2 inhibitor alone in combination with 
metformin prophylactically or at the onset of hyperglycemia (first fasting glucose level above 
the normal range) is at the discretion of the investigator, and as per local standard practice.  
While the adverse drug profile of metformin IR (immediate release) and metformin XR 
(extended release) are generally similar, up to 25% of participants on metformin IR may 
experience gastrointestinal toxicities that lead to treatment discontinuation in 5-10% of 
participants (Jabbour and Ziring 2011). Metformin XR was developed to allow a slower release 
of drug into the upper gastrointestinal tract to reduce toxicities such as diarrhea. The use of 
metformin XR as a suitable alternative to metformin IR is justified by its better tolerability and 
once daily dosing, which may potentially allow for a more rapid dose titration and improved 
adherence. Therefore, the use of metformin XR can be considered as a suitable alternative to 
metformin IR, alone or in combination with an SGLT2 inhibitor, particularly for participants 
with at least one risk factor for the development of severe hyperglycemia, at the discretion of 
the Investigator (Jabbour and Ziring 2011).  
Gastric protection agents 
Alpelisib is characterized by a pH-dependent solubility but can be coadministered with acid 
reducing agents (ARAs, e.g. proton-pump inhibitors, H2-antagonists and antacids), as long as 
it is taken after food. In a joint food effect and acid reducing Drug-drug interaction (DDI) study 
food exhibited a more pronounced effect on the solubility of alpelisib than the effect of gastric 
pH value leading to a net decrease in AUC of on average by 21% when administered after a 
meal. 
Palliative radiotherapy 
Local radiotherapy for analgesic purposes or for lytic lesions at risk of fracture may be carried 
out if required. Participants requiring initiation of palliative radiotherapy during the course of 
the study should be assessed by appropriate imaging modalities to exclude disease progression 
and the reason for its use must be clearly documented. If disease progression is documented, 
the participant should discontinue study treatment. No dose modification of study treatment is 
needed during radiotherapy. 
Hematopoietic growth factors 
Hematopoietic growth factors may be used according to American Society of Clinical Oncology 
(ASCO) guidelines. 

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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 event for PI3K inhibitors like alpelisib, so corticosteroids should therefore be used with 
caution and participants should be closely monitored. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
Medications to be used with caution during combined alpelisib/placebo and nab-paclitaxel 
treatment in this study are listed below (Table 16-6 and Table 16-7 in Section 16.2). This list is 
not comprehensive and is only meant to be used as a guide. Please contact the medical monitor 
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/placebo 
and/or nab-paclitaxel 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 
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. everolimus, midazolam) and CYP3A4 substrates with narrow therapeutic 
window (e.g. fentanyl). Caution is recommended when alpelisib is used in combination 
with CYP3A4 substrates that also possess an additional time dependent inhibition and 
induction potential on CYP3A4 that affects their own metabolism (e.g. ribociclib, 
encorafenib, refer to Table 16-6). 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 alpelsib is co administered, based on PBPK 
simulations. 
• Inhibitors or inducers of CYP2C8 and strong inhibitors of CYP3A4: As paclitaxel is 
metabolized by CYP2C8 and CYP3A4 these drugs may increase or decrease the 
pharmacokinetics of paclitaxel, refer to Table 16-7. 
• Herbal Medications: The use of herbal preparations/medications and dietary supplements 
are permitted with caution unless explicitly prohibited (see Section 6.2.2) for being strong 

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inducers of CYP3A such as St. John’s Wort (Hypericum perforatum) and Avasimibe (see 
Table 16-8) or BCRP inhibitors such as Curcumin (see Table 16-9). 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. Since cannaboids have been shown to inhibit BCRP in vitro, 
medical cannabis should be used with caution. The use/frequency of use should be 
documented as a concomitant medication. Participants closely monitored for increased 
adverse reactions (as the relevance of this interaction in vivo is currently unknown). In 
case of unexpected toxicities, participants should stop using all herbal medications. 
6.2.1.2 
Use of bone modifying agents 
The use of bone modifying agents (BMA) (e.g. bisphosphonates, denosumab) regardless of 
indication is allowed provided participants have been on stable doses for at least 2 weeks prior 
to randomization. Stable dose should be maintained during the treatment period. 
BMAs (e.g. bisphosphonates, denosumab) may be given according to the local prescribing 
information and routine clinical practice, at the investigator’s discretion. 
Participants requiring initiation of BMAs (e.g. denosumab) treatment during the course of the 
study should be assessed by appropriate image modalities to exclude disease progression; if 
disease progression is documented, the participant should discontinue study treatment. If BMA 
is to be started after the first dose of study treatment, the reason for its use must be clearly 
documented. 
Osteonecrosis of the jaw (ONJ) is a known adverse reaction for BMAs. In the phase III Study 
CBYL719C2301, ONJ was reported in 4.2% participants (12/284) in the alpelisib plus 
fulvestrant arm compared to 1.4% participants (4/287) in the placebo plus fulvestrant arm. All 
participants experiencing ONJ were also exposed to prior or concomitant bisphosphonates (e.g. 
zoledronic acid). Therefore, in participants receiving alpelisib and bisphosphonates, an 
increased risk of development of ONJ cannot be excluded. For prevention and clinical 
management of ONJ, prescribing information of bisphosphonates should be followed. 
6.2.2 
Prohibited medication 
The following medications are prohibited during combined alpelisib/placebo and nab-paclitaxel 
treatment in this study (Table 16-9 in Section 16.2.2). This list is not comprehensive and is only 
meant to be used as a guide. Please contact the medical monitor with any questions 
• Strong inducers of CYP3A4: Avoid coadministration of alpelisib with a strong CYP3A4 
inducers as it could potentially reduce the effectiveness of alpelisib, refer to Table 16-8. 
• Inhibitors of BCRP: Avoid the use of BCRP inhibitors in participants treated with 
alpelisib. If unable to use alternative drugs, closely monitor for increased adverse 
reactions, refer to Table 16-9. 
• Other investigational and antineoplastic therapies 

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6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned by the clinical database when the participant is first enrolled for molecular pre-
screening and is retained as the primary identifier for the participant throughout his/her entire 
participation in the trial (except in case of rescreening, refer to Section 8.1).The Participant No. 
consists of the Center Number (Center No.) (as assigned by Novartis to the investigative site) 
with a sequential participant number suffixed to it. Upon signing the informed consent form, 
the participant is assigned to the next sequential Participant No. available. 
The investigator or designated staff will contact the Interactive Response Technology (IRT) and 
provide the requested identifying information to register the participant into the IRT. Once 
assigned, the Participant No. must not be reused for any other participant. 
A new main study 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 
participant number. 
6.3.2 
Treatment assignment, randomization 
The assignment of a participant to a particular study part will be coordinated via Interactive 
Response Technology (IRT) based on the PIK3CA mutation and PTEN expression status. 
Parts A and B2 (randomized) 
In the double-blind, randomized, placebo-controlled Parts A and B2, all eligible participants 
will be randomized prior to dosing at Cycle 1 Day 1 via IRT to one of the treatment arms 
(Section 6.1.1.1). 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. 
Part B1 open-label 
In the single-arm, open-label study part B1, 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 32 eligible participants will be enrolled via IRT for treatment 
with alpelisib in combination with nab-paclitaxel prior to dosing at C1D1. 
Note: Cycle 1 Day 1 visit and dosing should occur no later than 3 days after IRT registration. 
At study entry, participants with confirmed PIK3CA mutation status regardless of PTEN loss 
will be enrolled in Part A. 
Participants with a confirmed PTEN loss status and PIK3CA unknown or non mutant will be 
enrolled in part B1 until approximately 32 participants have been enrolled (Section 8.1). 

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At this point, the participants will only have the option to be enrolled in part A (providing 
PIK3CA mutation status is confirmed) until the decision is made to initiate part B2. Participants 
with PTEN loss and no PIK3CA mutation will be considered as screen failures. 
If it is decided to open part B2, participants will be enrolled to either Part A or part B2 based 
on their molecular status as described above. 
In Parts A and B2, randomization will be stratified by line of therapy in advanced/metastatic 
setting (1st line versus 2nd line), hormone receptor status at initial breast cancer diagnosis (HR+ 
versus HR-) and prior therapy with checkpoint inhibitors (Yes versus No). 
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. 
The 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.   
6.4 
Treatment blinding 
Part B1 
Treatment will be open to participants, investigator staff, persons performing the assessments, 
and the clinical trial team (CTT) at Novartis. 
Parts A and B2 
The CTT will remain blinded to the identity of the treatment from the time of 
randomization until reporting of the primary endpoint in each Study Part. Participants, 
investigator staff, and persons performing the assessments will remain blinded to the identity 
of the treatment from the time of randomization until all Part A participants have completed 6 
months of study treatment or have been discontinued from study treatment and upon protocol 
amendment 02 approval, 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 
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.   

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(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), following the Data Monitoring Committee (DMC) recommendations (e.g. after 
the interim analysis) (see Section 12.7), for regulatory reporting purposes or at the  time of Part 
A primary analysis. Parts A and B2 can be unblinded independently of each other. The decision 
was taken not to initiate Part B2. 
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 
should be discontinued from the study treatment.  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 trial. 
An independent statistical group external to Novartis, not involved in the trial conduct, will 
prepare semi-blinded data reports for the DMC. Details will be presented in the DMC charter. 
Upon unblinding, the following options will be permitted: 
• Participants in the experimental arm will be given the opportunity to continue to take 
alpelisib in combination with nab-paclitaxel, if they are benefiting based on investigator’s 
judgement and individualized benefit/risk assessment after discussion with the participant 
and documentation in the medical record.   
• Participants in the control arm will be allowed to continue on nab-paclitaxel, if they are 
benefiting based on investigator’s judgement and an individualized benefit/risk assessment 
after discussion with the participant and documentation in the medical record. No placebo 
tablets will be given. 
Participants randomized to the control arm will not be allowed to cross-over to the experimental 
arm to receive alpelisib.  
6.5 
Dose escalation and dose modification 
Dose escalation is not applicable. 
6.5.1 
Dose modifications 
For participants who do not tolerate the protocol-specified dosing schedule, dose interruptions, 
and/or reductions are permitted in order to allow participants to continue the study treatment. 
These dose modifications are summarized in Table 6-3, Table 6-4, Table 6-5, Table 6-6 and 
Table 6-7. Deviations to stepwise dose reductions are not allowed.  Dose changes must be 
recorded on the appropriate eCRF. 
6.5.1.1 
Alpelisib dose modifications 
Recommendations for dose reduction or dose interruption of alpelisib/placebo in the 
management of adverse reactions are summarized in Table 6-4. Clinical judgment of the 

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treating physician, including confirmation of lab values if deemed necessary, should guide the 
management plan of each participant based on individual benefit/risk assessment. 
A maximum of 2 dose reductions will be allowed after which treatment must be discontinued 
as indicated in Table 6-3. 
After treatment is resumed at a lower dose: 
• If the same toxicity reoccurs with the same severity, then the next treatment re-initiation 
must resume at a lower dose irrespective of duration, except if specified in Table 6-4. 
• Once the alpelisib/placebo dose has been reduced, no re-escalation will occur, even upon 
resolution of AE. 
If a participant requires a withholding of alpelisib/placebo dose the participant may continue on 
nab-paclitaxel, per investigator discretion. All scheduled assessments will continue to be 
performed as per protocol.  
Permanent treatment discontinuation is mandatory for specific events indicated as such in 
Table 6-4 or listed in Section 9. These dose changes must be recorded on the appropriate eCRF. 
Table 6-3 
Stepwise dose reduction for alpelisib/placebo 
Alpelisib/placebo dose level 
Dose and schedule 
Number of tablets & strength 
Starting dose 
300 mg/day continuously 
1 x 200 mg tablet and 2 x 50 mg 
tablet 
Dose level -1 
250 mg/day continuously 
1 x 200 mg tablet and 1 x 50 mg 
tablet 
Dose level -2 
200 mg/day continuously 
1 x 200 mg tablet 
Table 6-4 
Criteria for dose reduction / interruption and re-initiation of 
alpelisib/placebo treatment for adverse drug reactions 
Dose Modifications for alpelisib/placebo as specified below.  Nab-paclitaxel may be continued while 
alpelisib/placebo dose is being held, at the investigators discretion, and as specified. 
Worst toxicity - CTCAE Grade (value) 
Dose Modifications for alpelisib/placebo 
Investigations (FG - Fasting Glucose) 
Hyperglycemia (see also Section 6.5.2.4) 
Consultation with a diabetologist and or healthcare provider experienced in the management of hyperglycemia 
is highly recommended for better assessment and management of alpelisib-induced hyperglycemia. Always 
recommend/reinforce on lifestyle changes as per American Diabetes Association (ADA and/or European 
Association for the study of Diabetes (EASD), i.e. exercise and dietary advice (e.g. controlled carbohydrate 
intake, high fiber, low process food intake. Three macronutrient balance meals and 2 optional small snacks 
rather than one large meal). 

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Dose Modifications for alpelisib/placebo as specified below.  Nab-paclitaxel may be continued while 
alpelisib/placebo dose is being held, at the investigators discretion, and as specified. 
Worst toxicity - CTCAE Grade (value) 
Dose Modifications for alpelisib/placebo 
Note: this table provides dose management recommendations. Local standard clinical practice may be followed 
for monitoring and managing hyperglycemia. Fasting glucose testing may be performed both locally and/or 
centrally for rapid availability for safety evaluation and management guidance. However, dose reductions 
should only be based on FPG. As metformin is widely available, it is an appropriate choice as initial therapy for 
alpelisib-induced hyperglycemia. However, SGLT2 inhibitors, as per local standard practice, are acceptable as 
well and may be administered alone or in combination with metformin. The use of metformin XR can be 
considered as a suitable alternative to metformin IR, alone or in combination with an SGLT2 inhibitor, 
particularly for participants with at least one risk factor for the development of severe hyperglycemia, at the 
discretion of the Investigator and as per local standard practice. Refer to Section 6.5.2.4 (“Guidelines for the 
treatment of alpelisib induced hyperglycemia”) for additional details regarding the use of metformin XR and/or 
SGLT2 inhibitors. In case of intolerance to or unavailability of metformin, investigator’s judgment should be 
exercised and other oral anti-diabetic agents such as thiazolidinediones or dipeptidyl peptidase-4 Inhibitors can 
be used. 
SGLT2i may increase the risk of euglycemic diabetic ketoacidosis and therefore, monitoring with serum / urine 
ketones and consultation with a healthcare expert experienced in hyperglycemia management or a 
diabetologist should be considered (please refer to the label or standard of care). 
Grade 1 (FG > 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 apply only for values 
> 140 mg/dL (7.7 mmol/L) 
• 
Maintain dose level, and remind participant on lifestyle changes*. 
• Start/intensify metformin as per guidance below or in cooperation 
with a healthcare expert experienced in hyperglycemia 
management or a diabetologist. 
Metformin 500 mg orally once daily with dinner. If no gastrointestinal 
(GI) intolerance after several days, increase to 500 mg b.i.d., with 
breakfast and dinner. If tolerated, increase to 500 mg with breakfast, 
and 1000 mg with dinner. If tolerated, 1000 mg b.i.d. with breakfast 
and dinner. Alternatively, metformin XR once daily dosing may be 
considered instead of metformin IR.  
If not tolerated, reduce to prior tolerated dose.  
Titrate to the MTD over a period of 3 weeks. 
• 
Alternatively, consider starting an SGLT2 inhibitor alone or in 
combination with metformin, especially in participants at risk for 
developing severe hyperglycemia. Refer to Section 6.5.2.4 
(“Guidelines for the treatment of alpelisib induced 
hyperglycemia”). Starting dose and titration should be in 
accordance with the local prescribing information and consistent 
with local practice. 
• 
Monitor fasting glucose levels as clinically indicated and at least 
twice weekly for 8 weeks, then continue checking at least weekly 
until FG is within baseline values. 
Grade 2 (FG >160 - 250 mg/dL) [> 8.9 
- 13.9 mmol/L] 
 
• 
Maintain dose level and remind participant on lifestyle changes*, 
exclude confounding factors like e.g. urinary tract infection, 
consider consultation with a healthcare expert experienced in 
hyperglycemia management or a diabetologist. 
• 
Start/intensify oral anti-diabetic treatment with metformin or 
alternatively start an SGLT2 inhibitor alone or in combination 
with metformin. 
• 
Additional oral anti-diabetic agents may be initiated, if needed. If 
fasting glucose levels are still rising on maximum tolerated dose 
of metformin or persistently >160 mg/dL (>8.9 mmol/L), add an 
SGLT2 inhibitor if not already started, e.g. empagliflozin up to 25 
mg (max. dose). Alternatively an insulin-sensitizer, e.g. 
pioglitazone 30 mg (max. dose) can be added.  
• 
Monitor blood glucose levels as clinically indicated and at least 
twice weekly until FG resolves to ≤ Grade 1 

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Dose Modifications for alpelisib/placebo as specified below.  Nab-paclitaxel may be continued while 
alpelisib/placebo dose is being held, at the investigators discretion, and as specified. 
Worst toxicity - CTCAE Grade (value) 
Dose Modifications for alpelisib/placebo 
• 
If FPG does not resolve to ≤ Grade 1 (within 21 days after 
institution of appropriate anti-diabetic treatment, reduce 
alpelisib/placebo by 1 dose level 
• 
Continue with anti-diabetic treatment and check blood glucose 
levels at least weekly for 8 weeks, then continue checking at 
least every 2 weeks, alert treating physician if FG>250mg/dL 
Grade 3 
FG > 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. 
Regardless of fasting status, consider IV fluids if symptoms of 
hyperglycemia or signs of volume depletion. 
Exclude confounding factors like e.g. urinary tract infection and 
consider consultation with a diabetologist. 
Administer intravenous hydration and intervention for 
electrolyte/ketoacidosis/hyperosmolar disturbances as clinically 
appropriate. 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. 
Start or further intensify oral anti-diabetic treatment and titrate as 
outlined for Grade 2. 
Monitor fasting glucose levels as clinically indicated and at least twice 
weekly until FG resolves to ≤ Grade 1. 
• 
If FG resolves to ≤ 160 mg/dL within 3-5 days, while off study 
treatment and on metformin, re-start alpelisib/placebo and 
reduce 1 dose level, continue with anti-diabetic treatment. A 
second and third oral hypoglycemic agent may be initiated 
concomitantly, if needed, in consultation with a diabetologist. 
Check FG at least weekly for 8 weeks, then continue checking at 
least every 2 weeks, alert treating physician if FG>250mg/dL 
• 
If FG does not resolve to ≤ 160 mg/dL within 3-5 days while off 
study treatment and on metformin, consult a diabetologist for 
management of diabetes is strongly recommended.  
• 
If FG does not resolve to ≤ 160 mg/dL  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 
FG > 500 mg/dL [>27.8 mmol/L] 
• 
Omit alpelisib/placebo, confirm fasting status of the assessment. 
If non-fasting, re-check within 24 hours. 
Regardless of fasting status, consider IV fluids. 
• 
Exclude confounding factors like e.g. urinary tract infection. 
• 
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 FG is confirmed as > 500 mg/dL and confounding factors could 
be excluded, permanently discontinue participant from 
alpelisib/placebo. 
*For specific recommendations please see Section 6.5.2.4 
Investigations (Hepatic) Note: this is for newly occurred or worsened from baseline 
Isolated total Bilirubin elevation 

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Dose Modifications for alpelisib/placebo as specified below.  Nab-paclitaxel may be continued while 
alpelisib/placebo dose is being held, at the investigators discretion, and as specified. 
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 decrease 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 
Gastrointestinal 
Diarrhea is defined as: A disorder characterized by frequent and watery bowel movements. 
Colitis is defined as a disorder characterized by inflammation of the colon. 
Grade 1 (Increase of < 4 stools per 
day over baseline; mild increase in 
ostomy output compared to baseline) 
OR 
Asymptomatic colitis; clinical or 
diagnostic observations only; 
intervention not indicated 
• 
Maintain dose level but initiate appropriate medical therapy and 
monitor as clinically indicated 
Grade 2 (Increase of 4 - 6 stools per 
day over baseline; moderate increase 
in ostomy output compared to 
baseline; limiting instrumental 
Activities of Daily Living (ADL)) OR 
Abdominal pain; mucus or blood in 
stool 
• 
Omit dose until resolved to ≤ Grade 1, initiate appropriate 
medical therapy then restart at same dose 
• 
If diarrhea returns as ≥ grade 2, then omit dose until resolved to 
≤ grade 1, then decrease 1 dose level 
• 
Initiate or intensify appropriate medical therapy and monitor as 
clinically indicated. 
• 
For Grade 2 colitis consider additional treatment, such as 
steroids. 
Grade 3 (Increase of ≥7 stools per day 
over baseline; hospitalization 
indicated; severe increase in ostomy 
output compared to baseline; limiting 
self-care ADL) OR 
Severe abdominal pain; peritoneal 
signs 
• 
Omit dose until resolved to ≤ Grade 1, then decrease 1 dose 
level 
• 
Manage according to local standard of care medical 
management, including electrolyte monitoring, administration of 
antiemetics and antidiarrhoeal medicinal products and/or fluid 
replacement and electrolyte supplements, as clinically indicated 
• 
For Grade 3 colitis consider additional treatment, such as 
steroids. 
Grade 4 (Life-threatening 
consequences; urgent intervention 
indicated) 
• 
Discontinue participant from treatment 
• 
Manage according to local standard of care medical 
management, including electrolyte monitoring, administration of 
antiemetics and antidiarrhoeal medicinal products and/or fluid 
replacement and electrolyte supplements, as clinically indicated 
Note: Antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools, or overt 
diarrhea 

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Dose Modifications for alpelisib/placebo as specified below.  Nab-paclitaxel may be continued while 
alpelisib/placebo dose is being held, at the investigators discretion, and as specified. 
Worst toxicity - CTCAE Grade (value) 
Dose Modifications for alpelisib/placebo 
Investigations (Pancreatic) 
Pancreatitis 
Grade 2 or Grade 3 
 
• 
Omit dose until resolved to Grade ≤ 1, then resume treatment at 
decreased dose level.  
• 
If toxicity reoccurs, permanently discontinue participant from 
alpelisib/placebo 
Grade 4 
• 
Permanently discontinue participant from alpelisib/placebo 
Skin and subcutaneous tissue disorders 
Oral antihistamine administration may be considered prophylactically, at the time of initiation of treatment with 
alpelisib. Consultation with a dermatologist is highly recommended for better assessment and management of 
alpelisib-induced skin toxicity. (see also Section 6.5.2.3). Dermatologist consultation is mandated for serious 
cutaneous reactions (i.e. fulfilling seriousness criteria for AE Reporting) and for severe cutaneous reactions like 
Stevens-Johnson-Syndrome, Toxic Epidermal Necrolysis, Erythema Multiforme, Drug Reaction with 
Eosinophilia and Systemic Symptoms. 
Rash 
Grade 1 ( <10% body surface 
area(BSA) with active skin toxicity* 
• 
Maintain dose level 
• 
Initiate topical corticosteroids 3-4 x daily, preferred compounds 
to use are triamcinolone, betamethasone for up to 28 days, as 
long as skin toxicity is active. 
• 
If active rash is not resolved within 28 days of appropriate 
treatment, add low dose systemic corticosteroid (20-40 mg/d), 
such as prednisone 10 mg 3x daily. 
For participants with symptoms like burning, stinging and/or pruritus, 
add a non-sedating anti-histamine such as cetirizine once daily 
during daytime and a sedating anti-histamine such as 
diphenhydramine once daily at night.  
Grade 2 (10-30% BSA with active skin 
toxicity*) 
• 
Maintain dose level. 
• 
Initiate or intensify topical corticosteroids 3-4x daily, preferred 
compounds to use are triamcinolone or betamethasone for up to 
28 days, as long as skin toxicity is active 
• 
Add systemic corticosteroids 20-40mg/d. 
If rash improves to ≤ Grade 1 within 10 days systemic corticosteroid 
may be discontinued 
For participants with symptoms like burning, stinging and/or pruritus, 
add a non-sedating anti-histamine such as cetirizine once daily 
during daytime and a sedating anti-histamine such as 
diphenhydramine once daily at night. 
Grade 3 (>30% BSA with active skin 
toxicity*)  
• 
Omit alpelisib/placebo dose until rash /skin toxicity is improved to 
Grade 1 or resolved,  
• 
Strongly recommend documentation by photography and 
consider performing a skin biopsy. 
• 
Initiate topical corticosteroids 3-4x daily, preferred compounds to 
use are triamcinolone or betamethasone for at least 28 days. 
• 
Add systemic corticosteroids 20-40mg/d. 
• 
If rash improves to ≤ Grade 1 within 10 days systemic 
corticosteroid may be discontinued. 
• 
Re-start alpelisib/placebo dose once rash /skin toxicity is fading, 
but no longer active (Grade 1): 
- At reduced dose in case of first occurrence. 

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Dose Modifications for alpelisib/placebo as specified below.  Nab-paclitaxel may be continued while 
alpelisib/placebo dose is being held, at the investigators discretion, and as specified. 
Worst toxicity - CTCAE Grade (value) 
Dose Modifications for alpelisib/placebo 
- If rash/skin toxicity still active in up to 10% BSA after more than 14 
days, continue oral corticosteroid for at least 48 hours upon re-
challenge with alpelisib/placebo; 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 
add a non-sedating anti-histamine such as cetirizine once daily 
during daytime and a sedating anti-histamine such as 
diphenhydramine once daily at night. Antihistamine regimen should 
be continued for a minimum of 28 days after re-challenge with 
alpelisib/placebo. 
Grade 4 
(any % BSA associated with extensive 
superinfection, with IV antibiotics 
indicated; life-threatening 
consequences) 
• 
Permanently discontinue participant from alpelisib/placebo 
• 
Consult a dermatologist, strongly recommend documentation by 
photography and consider performing a skin biopsy if clinically 
indicated  
• 
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 
/Drug Reaction with Eosinophilia and 
Systemic Symptoms or other 
SJS/TEN/DRESS like severe skin 
reactions  
• 
Permanently discontinue participant from alpelisib/placebo 
• 
Consult a dermatologist, strongly recommend documentation by 
photography and consider performing a skin biopsy if clinically 
indicated  
• 
Follow local treatment guidelines for SJS/TEN/DRESS. 
*“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. 
Immune system disorders 
Hypersensitivity 
Please see specific instructions in Section 6.5.2.6 
Investigations (Pulmonary disorders) 
Pneumonitis 
Please see specific instructions in Section 6.5.2.2 
Investigations (Metabolic) 
Asymptomatic amylase and/or lipase elevation (see also Section 6.5.2.5) 
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  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) as specified in Section 6.5.2.5 

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Dose Modifications for alpelisib/placebo as specified below.  Nab-paclitaxel may be continued while 
alpelisib/placebo dose is being held, at the investigators discretion, and as specified. 
Worst toxicity - CTCAE Grade (value) 
Dose Modifications for alpelisib/placebo 
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  dose level 
Grade 4 
• 
Permanently discontinue participant from alpelisib/placebo 
• 
Omit dose for ≥ grade 3 vomiting or grade 3 nausea only if the 
vomiting or nausea cannot be controlled with optimal antiemetic 
(as per local practice) 
For additional details on the safety profile of alpelisib, please refer to the IB.  
6.5.1.2 
Nab-paclitaxel dose modifications 
For dose modifications due to toxicities that are suspected to be caused by Nab-Paclitaxel, 
please refer to Table 6-6, Table 6-7 and the nab-paclitaxel prescribing information and local 
clinical practice. Of note, the following toxicities are common for both alpelisib and nab-
paclitaxel: GI toxicity, skin toxicity, hypersensitivity, pneumonitis.  Additional guidance for 
pneumonitis and hypersensitivity can be found in Section 6.5.2.2 and Section 6.5.2.6. 
This section provides additional guidance because the dose regimen and dose strengths for nab-
paclitaxel in this study (100 mg/m2 on days 1, 8 and 15 of a 28-day cycle) differs to the approved 
dose strengths and regimen of 260 mg/m2 once every 3 weeks for advanced BC (see 
Section 4.2). The following guidelines should be considered for dose modifications for AEs 
that are suspected to be caused by Nab-Paclitaxel. 
Table 6-5 
Stepwise Dose reduction for Nab-paclitaxel 
Nab-paclitaxel dose level 
Dose 
Starting dose level 
100 mg/m2 
First Dose Reduction (20% of prior dose level) 
80 mg/m2 
Second Dose Reduction (20% of prior dose level) 
64 mg/m2 
Table 6-6 
Hematologic Toxicities requiring dose adjustments for Nab-Paclitaxel 
Toxicity 
Treatment Modification 
ANC < 1,500/μl on Day 
1 of a treatment cycle 
Hold Nab-paclitaxel until ANC ≥ 1,500μl 
ANC < 1,000/μl on Day 
8 or 15 of a treatment cycle 
Hold Nab-Paclitaxel until ANC ≥ 1,000μl. Monitor ANC at 
least weekly. Resume Nab-Paclitaxel when ANC have 
recovered, according to the following guidelines: 
• 
If ANC recovers to ≥ 1,000/μl in ≤ 1 week, restart Nab-
Paclitaxel at current dose. 
• 
If ANC recovers to ≥ 1,000/μl after 1-3 weeks, Nab-
Paclitaxel dose should be reduced by 20% for 
subsequent cycles. 

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Toxicity 
Treatment Modification 
• 
If ANC still < 1,000/μl after the 3-week withholding, 
permanently discontinue Nab-Paclitaxel. 
Platelets < 75,000/μl on Day 
1, 8, or 15 of a treatment cycle 
Hold Nab-Paclitaxel until platelets recover to ≥ 
75,000/μl. 
Resume Nab-Paclitaxel when platelets have 
recovered, according to the following guidelines: 
• 
If platelets recover to ≥ 75,000/μl in ≤ 1 week, restart 
Nab-Paclitaxel at the current dose. 
• 
If platelets recover to ≥ 75,000/μl after 1-3 weeks, 
Nab-Paclitaxel dose should be reduced by 20% for 
subsequent cycles. 
• 
If the platelet count fails to recover to ≥ 75,000/μl 
within 3 weeks, permanently discontinue Nab-
Paclitaxel. 
NOTE: See below for dose modifications for Grade 
3-4 thrombocytopenia. 
Grade 3/ 4 thrombocytopenia on Day 
1, 8, or 15 of a treatment cycle 
Hold Nab-Paclitaxel until thrombocytopenia Grade 
3/4 has improved to Grade 2 or less. Resume Nab-
Paclitaxel when thrombocytopenia have recovered, 
according to the following guideline: 
• 
The dose of Nab-Paclitaxel should be reduced by 20% 
for subsequent cycles 
Febrile Neutropenia* Grade 3 on Day 
1, 8, or 15 of a treatment cycle 
After the first occurrence of febrile neutropenia, at 
the investigator discretion, Nab-Paclitaxel may be 
given in subsequent cycles at either 
• 
The same doses, but with prophylactic ciprofloxacin 
500mg oral twice daily or an alternative prophylactic 
antibiotic regimen at the choice of the investigator, or 
• 
at a 20% reduced dose (either with or without 
prophylactic antibiotics). 
If a second episode of febrile neutropenia occurs 
• 
Nab-Paclitaxel should be reduced by 20% (based on 
the current dose) for subsequent cycles. 
If a third episode of febrile neutropenia occurs, 
• 
Nab-Paclitaxel should be permanently discontinued. 
*Febrile neutropenia is defined as fever ≥ 38.5 °C in the presence of neutropenia (ANC < 1,000/μl.) 
1. There will be no dose modifications for lymphopenia. 
2. There will be no dose modifications for Grade 2 – 4 anemia. Transfusions will be given as clinically indicated. 
The frequency and severity of sensory neuropathy increased with cumulative doses. Sensory 
neuropathy is dose- and schedule-dependent. The occurrence of Grade 1 or 2 sensory 
neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy 
develops, withhold nab-paclitaxel until improvement to Grade 1 or 2, followed by a dose 
reduction for all subsequent cycles. 
Once the nab-paclitaxel dose has been reduced, no re-escalation will occur, even upon 
resolution of AE. 
A maximum of 2 dose reductions will be allowed after which treatment must be discontinued, 
please refer to Table 6-5. 

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Table 6-7 
Overlapping toxicities with alpelisib requiring dose adjustments for 
Nab-Paclitaxel 
  
Dose modification 
Cutaneous toxicity 
  
Grade 2 or 3 
Reduce to next lower dose level; discontinue treatment if toxicity 
persists 
GI toxicity 
  
Grade 3 mucositis or diarrhea 
Withhold until improves to ≤ Grade 1; resume at next lower dose level 
If a participant requires a withholding of nab-paclitaxel dose, the participant may continue on 
alpelisib/placebo per investigator's discretion. All scheduled assessments will continue to be 
performed as per protocol. 
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/placebo and/or nab-paclitaxel). 
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 combination-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 total bilirubin (TBIL) increase may be 
indicative of potentially severe DILI. These events should be considered as clinically important 
and assessed appropriately to establish the diagnosis. The required clinical information, as 
detailed below, should be sought to obtain the medical diagnosis of the most likely cause of the 
observed laboratory abnormalities. 
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 elevated AST or ALT or TBIL value at baseline: [AST or ALT > 3.0 
x baseline] OR [AST or ALT > 8.0 x ULN], whichever occurs first, combined with [TBIL 
> 2 x baseline AND > 2.0 x ULN] 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed as the cause of liver injury. 

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A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre-
existing liver conditions or risk factors, should be collected. 
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, GGT, 
prothrombin time (PT)/INR, alkaline phosphatase (ALP), albumin, and creatine kinase.  If 
available, testing of Glutamate Dehydrogenase (GLDH) is additionally recommended.  
Evaluate status of liver metastasis (new or exacerbation) or vascular occlusion - e.g. using CT, 
MRI, or duplex sonography. 
Perform 
relevant 
examinations 
(ultrasound 
or 
MRI, 
endoscopic 
retrograde 
cholangiopancreatography (ERCP) as appropriate, to rule out an extrahepatic cause of 
cholestasis. Cholestasis is defined as an alkaline phosphatase (ALP) elevation > 2.0 x ULN with 
R value < 2 in participants without bone metastasis, or elevation of the liver-specific ALP 
isoenzyme in participants with bone metastasis. 
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 ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. In clinical 
situations where it is suspected that ALP elevations are from an extrahepatic source, the 
Gamma-glutamyltranspeptidase (GGT) can be used if available. GGT may be less specific than 
ALP as a marker of cholestatic injury, since GGT can also be elevated by enzyme induction or 
by ethanol consumption. It is more sensitive than ALP for detecting bile duct injury. 
If DILI is confirmed: permanently discontinue study treatment. 
If DILI is unlikely - interrupt treatment. Treat identified cause according to institutional 
guidelines. If resolved, reduce by one dose level. Re-administration of study treatment should 
be considered only if the investigator assesses benefit to outweight the risk. Any decision 
regarding re-administration of study drug/s and dose regimen should be discussed with the 
Novartis medical safety team. 
Table 6-8 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule out possible alternative causes of observed Liver Function Test (LFT) 
abnormalities. 
Table 6-8 
Alternative causes of liver disease 
Disease 
Assessment 
Hepatitis A, B, C, E 
IgM anti-Hepatitis A (HAV) ; HBsAg, IgM anti-HBc, Hepatitis 
B virus (HBV) DNA; anti-Hepatits C virus (HCV), HCV RNA, 
IgM & IgG anti-Hepatitis E virus (HEV), HEV RNA 
Cytomegalovirus (CMV), Herpes Simplex 
Virus (HSV), Epstein-Barr virus (EBV) infection 
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-
EBV 
Autoimmune hepatitis 
Antinuclear antibody (ANA) & Antismooth 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 CHF, hypotension, hypoxia, 
hepatic venous occlusion. Ultrasound or MRI. 

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Disease 
Assessment 
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 
Other causes should also be considered based upon participants’ medical history 
(hyperthyroidism / thyrotoxic hepatitis – T3, T4, TSH; cardiovascular disease / ischemic 
hepatitis – ECG, prior hypotensive episodes; Type 1 diabetes / glycogenic hepatitis). 
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. 
The term “drug-induced” indicates probably caused by the drug, not by something else, and 
only such a case can be considered a DILI case and should be reported as a Serious Adverse 
Event (SAE). 
All cases confirmed on repeat testing meeting 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 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 
Both alpelisib and nab-paclitaxel are associated with pneumonitis/interstitial lung disease. 
Closely monitor all participants for signs and symptoms of pneumonitis. 
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) and broncho-alveolar 
lavage (BAL); 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 nab-paclitaxel and 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 an adverse drug reaction 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 

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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, Erythema Multiforme or DRESS (Drug reaction with eosinophilia and systemic 
symptoms) is suspected. 
Workup for skin toxicities includes skin photography, a complete blood count with differential, 
and a full chemistry panel. A paired skin biopsy should be obtained (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, Novartis strongly recommends that photographs are taken 
and a skin biopsy is performed. Photographs and skin biopsy should be stored at the site for 
source documentation.  
In Study CBYL719C2301 (SOLAR-1), among the 86 participants in the alpelisib group who 
received prophylaxis prior to rash onset, 73% did not develop a rash, while among the 198 
participants from the alpelisib group who did not receive prophylaxis, 36% did not develop a 
rash. Similar trends were observed in the CBYL719C2402 (BYLieve) study, where 70% of 
participants who received prophylaxis (n=10) did not develop a rash compared with 53% of 
participants who did not receive prophylaxis (n=117) did not develop a rash (Patel and 
Seminario-Vidal 2020). Additionally, in a single center retrospective analysis of 102 patients 
receiving alpelisib, prophylaxis with non-sedating antihistamines (n=43) was correlated with a 
reduction in grade 1/2 rash events (OR 0.39, p=0.09) (Wang et al 2020).  
Based on these data, prophylactic treatment with non-sedating antihistamines (e.g. cetirizine 
(Zyrtec©), fexofenadine (Allegra), loratadine (Claritin)) can be started on Cycle 1 Day 1 and 
continued for approximately 8 weeks in all participants, especially in those with a history of 
atopy such as allergic rhinitis, asthma, atopic dermatitis, or drug allergies, at the discretion of 
the investigator. Preventive strategies, including the administration of non-sedating, oral 
antihistamines before starting alpelisib and prior to rash onset, may decrease incidence and 
severity of rash based on alpelisib clinical trial experience. 
Recommended therapies for skin toxicity events of all grades and as clinically 
indicated include: 
• Consultation with a dermatologist should always be considered. Mid to High potency 
topical steroids: triamcinolone or fluocinonide 0.05% twice daily for at least 28 days. 
Recommend spray, lotion, or cream preparation for ease of application on trunk. For scalp 
involvement, recommend a foam preparation. 
• Gamma-aminobutyric acid (GABA) Agonists: gabapentin 300mg every 8 hours, 
pregabalin 50-75 mg every 8 hours (adjust as tolerated). Depending on participant’s 
clinical condition be aware of potential and common side effects observed with GABA 
agonists such as: somnolence, dizziness (both drugs) and peripheral edema (gabapentin) 
among others adverse events. 
For grade 4 skin events or any grade of severe cutaneous reactions (including SJS, TEN, 
DRESS, EM), alpelisib treatment must be permanently discontinued without any re-challenge. 

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If dry skin has been reported it is recommended that participants use mild and fragrance-free 
soaps and detergents. 
Although preclinical experiments demonstrated that alpelisib has no potential phototoxic effect, 
participants should 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. FG 100 – 125 mg/dL; 5.6 - 6.9 mmol/L) 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 FG while on alpelisib/placebo treatment. However even 
participants with FPG within normal limits at screening may develop alpelisib-induced 
hyperglycemia which is an on-target effect seen with PI3K inhibitors. Participants should 
always be instructed to follow dietary guidelines provided by the American Diabetes 
Association and/or the European Association for the study of Diabetes, 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.Hyperglycemic hyperosmolar non-ketotic syndrome (HHNKS) and diabetic 
ketoacidosis (DKA) are two of the most serious metabolic complications associated with 
hyperglycemia. DKA is characterized by ketoacidosis and a comparatively lower 
hyperglycemic level (blood glucose 250 mg/dL-600 mg/dL), while HHNKS is characterized by 
more severe hyperglycemia (blood glucose > 600 mg/dL) together with hyperosmolarity and 
dehydration without significant ketoacidosis. HHNKS is also known as non-ketotic 
hyperosmolar syndrome, hyperosmolar hyperglycemic state or hyperglycemic hyperosmolar 
non-ketotic coma. Most patients with HHNKS have a known history of diabetes mellitus Type 
2. HHNKS usually develops over a course of many days to weeks, unlike DKA which can 
develop over the course of a few hours or days.Detailed guidelines for the management of 
alpelisib induced hyperglycemia are provided in Table 6-4. This includes early administration 
of metforminor a SGLT2 inhibitor (alone or in combination with metformin).  
Metformin XR was developed to allow a slower release of drug into the upper gastrointestinal 
tract to reduce toxicities such as diarrhea. The use of metformin XR can be considered as a 
suitable alternative to metformin IR due to its better tolerability and once daily dosing, alone or 
in combination with an SGLT2 inhibitor, particularly for participants with at least one risk 
factor for the development of severe hyperglycemia, at the discretion of the Investigator and as 
per local standard practice (Jabbour and Ziring 2011).  
Local standard clinical practice may be followed for monitoring and managing hyperglycemia. 
Fasting glucose testing may be performed both locally and/or centrally for rapid availability for 

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safety evaluation and management guidance. However, it is strongly recommended that dose 
reduction will be based on FPG only. 
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.  
If metformin or an anti-diabetic agent is interrupted for radiologic assessments or another 
reason, then alternative hyperglycemia management should be considered for those days to 
ensure optimal hyperglycemia management. 
Consultation with a diabetologist or healthcare provider experienced in the management of 
hyperglycemia 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, 
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 v4.03 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. 
See also dose modification guidelines described in Table 6-6. 
6.5.2.6 
Guidelines for hypersensitivity 
Both alpelisib and nab-paclitaxel are associated with hypersensitivity reactions, including 
anaphylaxis and angioedema. These are manifested by symptoms including, but not limited to: 
dyspnea, flushing, rash, fever, hypotension, dizziness, tachycardia and facial or laryngeal 
oedema. Alpelisib and/or nab-paclitaxel should be permanently discontinued and should not be 
re-introduced in participants with serious hypersensitivity reactions. Appropriate treatment 
should be promptly initiated. 

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6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
The investigator must promote compliance 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. 
Alpelisib and paclitaxel concentrations will be determined as detailed in pharmacokinetics 
Section 8.5.2. On PK sampling days, compliance will be assured by administrations of 
alpelisib/placebo after food under the supervision of investigator or his/her designee. 
6.6.2 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study participant who presents with an emergency 
condition. Blinding codes may also be broken after a patient discontinues treatment due to 
disease progression if deemed essential to allow the investigator to select the patient’s next 
treatment regimen, and after discussion and agreement with the sponsor. 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 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 
• 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.  
Following protocol amendment 02, the emergency unblinding procedures are no longer 
applicable as participants will be unblinded and made aware of their study treatment. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section. Participants will be provided with an adequate supply of study drug 

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(alpelisib/placebo) for self-administration at home, including instructions for administration, 
until at least their next scheduled study visit. Participants will receive alpelisib/placebo on an 
outpatient basis.  
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the IRT and obtaining the medication number(s). The study medication has a 2-part 
label (base plus tear-off label), immediately before dispensing the medication kit to the 
participant, site personnel will detach the outer part of the label from the packaging and affix it 
to the source document. 
Only qualified and trained personnel to the preparation procedure will handle, prepare and 
dispense Nab-paclitaxel as described in the local Prescribing Information. 
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 even without performing an on-site visit. The dispatch of IMP 
from the site to the participant’s home remains under the accountability of the Investigator. 
Each shipment/provisioning will be for a maximum of one cycle of alpelisib/placebo (4 weeks 
supply). In this case, regular phone calls or virtual contacts (every 4 weeks or more frequently 
if needed) will occur between the site and the participant for instructional purposes, safety 
monitoring, investigation of any adverse events, ensuring participants continue to benefit from 
treatment, and discussion of the participant's health status until the participants can resume visits 
at the study site. 
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 
instructions specified on the labels and in the Investigator’s Brochure (for alpelisib/placebo). 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis 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 trial. 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. 

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The site may destroy and document destruction of unused study treatment, drug labels and 
packaging 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 
Not applicable.  
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 or alpelisib/placebo administration 
Participants should be instructed to take the dose of alpelisib/placebo once daily at 
approximately the same time each day immediately after food (preferably in the morning). An 
exception is on the days of blood collection at the study site, at which time the participants 
should take their doses at the study site at any later point of time. 
Alpelisib /placebo tablets should be swallowed whole (tablets should not be chewed, crushed 
or split prior to swallowing). Tablets that are broken, cracked, or otherwise not intact should 
not be ingested. 
On the days of nab-paclitaxel administration, alpelisib/placebo tablets should be taken 1 hour 
prior to the infusion of nab-paclitaxel. 
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/placebo should be taken at its usual time. If 
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. 
During the treatment phase, the participant should record if the dose was taken or not in the 
alpelisib/placebo participant diary. 
6.7.2.1.1 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, participants should be instructed to arrive at the site in fasted state. The following 
additional guidelines should be followed: 
• The participants must be fasting overnight for at least 8-12 hours prior to the blood 
collection for fasting glucose, lipid profile, amylase/lipase samples.  Water, 
coffee/tea (unsweetened and without milk) is allowed during all fasting periods; however 
juice is not permitted during the fasting period. 

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• 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/placebo at home 
• The participants must take alpelisib/placebo immediately after food 
• PRO assessments must be collected prior to any clinical assessments, drug dosing or 
diagnostic testing. 
• If a pre-dose ECG measurement should be collected, then the ECG measurement should 
occur before dosing of alpelisib/placebo 
• If a pre-dose PK sample should be obtained, then the sample should be collected after the 
ECG and before dosing of alpelisib/placebo 
• 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/placebo 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/placebo and/or nab-
paclitaxel infusion. 
• Post-dose Insulin level should be collected 1h (+/- 15min) after dosing of 
alpelisib/placebo, except at screening and EOT. 
• ECG and PK sample collection will be performed according to Section 8.4.2, 
Section 8.5.2 
Figure 6-1 
Study drug administration on scheduled visit days 
 
*Please refer to schedule of assessments in Table 8-2 and Table 8-3 
**Please refer to PK Blood collection logs Section 8.5.2.1 
***Until all participants have completed 6 months of study treatment or have been discontinued from 
study treatment 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC)-approved informed consent. 
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her understanding. If the participant is capable of doing so, he/she must 
indicate agreement by personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 

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Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Council for Harmonization (ICH) Good Clinical Practice 
(GCP) guidelines and regulatory requirements and is considered appropriate for this study. Any 
changes to the proposed consent form suggested by the investigator must be agreed by Novartis 
before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB) and/or prescribing information for marketed drugs. 
This information will be included in the participant informed consent and should be discussed 
with the participant during the study as needed. Any new information regarding the safety 
profile of the investigational drug that is identified between IB updates will be communicated 
as appropriate, for example, via an investigator notification or an aggregate safety finding. New 
information might require an update to the informed consent and then must be discussed with 
the participant. 
The following informed consents are included in this study: 
• Molecular Pre-screening consent 
• Main study consent, which also included:  
• A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study 
• As applicable, Pregnancy Outcomes Reporting Consent for female participants or the 
female partners of any male participants who took study treatment 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
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, 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 and person obtaining informed consent, etc.). 

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8 
Visit schedule and assessments 
The following assessment schedules (Table 8-2 and Table 8-3) list all of the assessments when 
they are perfomed.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 these assessment schedules 
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 to return for the end of treatment visit as 
soon as possible, and attend the follow-up visits as indicated in the Assessment Schedules.  
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 final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and the adverse event and 
concomitant medications 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. If allowable by a local Health Authority and depending on operational 
capabilities, phone calls, or virtual contacts (e.g. tele consult) can replace on-site study visits, 
for the duration of the disruption until it is safe for the participant to visit the site again. 
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: 

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Table 8-1 
Allowable visit windows 
Visit Name 
Window 
Molecular Pre-screening 
Anytime before main screening 
Main Screening 
Within 28 days of first dose of study treatment however 
selected assessments should be performed -14 days prior 
start of study treatment (see Table 8-2 and Table 8-3) 
C1D1 visit and dosing 
No later than 3 days after IRT registration (Section 6.3.2) 
All assessments during the treatment period 
(except nab-paclitaxel injections) 
+/- 3 days 
Nab-paclitaxel injections (On days 1, 8 and 15 
of each cycle) 
+/- 1 day 
PK sampling 
Please refer to Tables in Section 8.5.2.1 
Tumor assessments 
+/- 7 days 
PRO assessments** 
+/- 7 days 
End of treatment 
≤ 14 days after last dose of study treatment 
30 days safety follow-up visit 
+/- 3 days 
Follow-up after disease progression (8 weeks 
post progression)** 
+/- 14 days 
Efficacy follow-up visit** 
+/- 7 days 
Survival follow-up visit (every 12 weeks)** 
+/- 7 days 
Note: *Imaging assessments should be scheduled using the randomization date as the reference date (not the 
date of the previous tumor assessment) and should be respected regardless of whether treatment with study 
treatment is temporarily withheld or unscheduled assessments performed. Tumor assessments will be 
performed as clinically indicated per local standard of care once all participants have completed 6 months of 
study treatment or have been discontinued from study treatment 
**: until all participants have completed 6 months of study treatment or have been discontinued from study 
treatment 

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Table 8-2 
Assessment Schedule, Parts A and B2 
Period 
Pre-screening 
 
Screening
/Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent 
cycles) 
 
 
Visit Name 
 Molecular 
Pre-Screening 
Main 
Screening Day 1 
Da
y 8 
Da
y 
15 
Da
y 1 
Da
y 8 
Day 
15 
Day 1 Da
y 8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from 
last dose) 
Safety 
Follow
-up 
Efficacy 
Follow-up, if 
applicable 5 
Follow 
up 
after 
diseas
e 
progre
ssion 5 
Survival 
Follow-up 5 
Days 
anytime 
before main 
screening  
-28 to -1 
1 
8 
15 1 
8 
15 
1 
8 
15 
- 
30 
Days 
after 
last 
dose 
Follow tumor 
assessments 
8 
weeks 
after 
PD 
Every 12 
weeks 
Informed 
consent 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Tumor tissue: 
New/recent 
biopsy or 
archival tumor 
block/slides 
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demography 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion / 
Exclusion 
criteria 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical 
history/current 
medical 
conditions 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  

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Period 
Pre-screening 
 
Screening
/Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent 
cycles) 
 
 
Visit Name 
 Molecular 
Pre-Screening 
Main 
Screening Day 1 
Da
y 8 
Da
y 
15 
Da
y 1 
Da
y 8 
Day 
15 
Day 1 Da
y 8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from 
last dose) 
Safety 
Follow
-up 
Efficacy 
Follow-up, if 
applicable 5 
Follow 
up 
after 
diseas
e 
progre
ssion 5 
Survival 
Follow-up 5 
Days 
anytime 
before main 
screening  
-28 to -1 
1 
8 
15 1 
8 
15 
1 
8 
15 
- 
30 
Days 
after 
last 
dose 
Follow tumor 
assessments 
8 
weeks 
after 
PD 
Every 12 
weeks 
Diagnosis and 
Extent of 
Cancer 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Information on 
prior local 
testing for 
BRCA status 
and PD-L1 
status, if 
available 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Information on 
prior local 
PIK3CA 
mutation 
testing, if 
applicable 
X  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Eligibility 
checklist (within 
IRT) 
  
S 
  
  
  
  
  
  
  
  
  
  
  
  
  
  

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Period 
Pre-screening 
 
Screening
/Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent 
cycles) 
 
 
Visit Name 
 Molecular 
Pre-Screening 
Main 
Screening Day 1 
Da
y 8 
Da
y 
15 
Da
y 1 
Da
y 8 
Day 
15 
Day 1 Da
y 8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from 
last dose) 
Safety 
Follow
-up 
Efficacy 
Follow-up, if 
applicable 5 
Follow 
up 
after 
diseas
e 
progre
ssion 5 
Survival 
Follow-up 5 
Days 
anytime 
before main 
screening  
-28 to -1 
1 
8 
15 1 
8 
15 
1 
8 
15 
- 
30 
Days 
after 
last 
dose 
Follow tumor 
assessments 
8 
weeks 
after 
PD 
Every 12 
weeks 
Locally 
confirmed 
TNBC status in 
advanced 
setting 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Prior 
antineoplastic 
therapy 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Prior/concomita
nt medication 
  
X 
Continuous up to 30 days after last dose of study treatment 
  
  
  
Procedures 
and Significant 
Non-Drug 
therapies 
  
X 
Continuous up to 30 days after last dose of study treatment 
  
  
  
IRT 
Registration 
(after molecular 
pre-screening 
ICF signature) 
S 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  

Novartis 
Confidential 
Page 102 of 213 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CBYL719H12301 
 
Period 
Pre-screening 
 
Screening
/Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent 
cycles) 
 
 
Visit Name 
 Molecular 
Pre-Screening 
Main 
Screening Day 1 
Da
y 8 
Da
y 
15 
Da
y 1 
Da
y 8 
Day 
15 
Day 1 Da
y 8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from 
last dose) 
Safety 
Follow
-up 
Efficacy 
Follow-up, if 
applicable 5 
Follow 
up 
after 
diseas
e 
progre
ssion 5 
Survival 
Follow-up 5 
Days 
anytime 
before main 
screening  
-28 to -1 
1 
8 
15 1 
8 
15 
1 
8 
15 
- 
30 
Days 
after 
last 
dose 
Follow tumor 
assessments 
8 
weeks 
after 
PD 
Every 12 
weeks 
IRT 
Registration 
(after main ICF 
signature) 
 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT 
Randomization 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
IRT Study Drug 
Dispensation8 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
  
  
End of phase 
disposition 
  
X 
  
  
  
  
  
  
  
  
  
X 
  
X 
  
  
Physical 
Examination 
  
S1, 3 
  
 
 
S3  
 
S4 
 
 
S3 
  
  
  
  
Performance 
status (ECOG) 
  
X1 
  
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
Body Height 
  
X1 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Body Weight 
  
X1 
  
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
Vital Signs 
  
X1 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
  
  
  
  

Novartis 
Confidential 
Page 103 of 213 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CBYL719H12301 
 
Period 
Pre-screening 
 
Screening
/Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent 
cycles) 
 
 
Visit Name 
 Molecular 
Pre-Screening 
Main 
Screening Day 1 
Da
y 8 
Da
y 
15 
Da
y 1 
Da
y 8 
Day 
15 
Day 1 Da
y 8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from 
last dose) 
Safety 
Follow
-up 
Efficacy 
Follow-up, if 
applicable 5 
Follow 
up 
after 
diseas
e 
progre
ssion 5 
Survival 
Follow-up 5 
Days 
anytime 
before main 
screening  
-28 to -1 
1 
8 
15 1 
8 
15 
1 
8 
15 
- 
30 
Days 
after 
last 
dose 
Follow tumor 
assessments 
8 
weeks 
after 
PD 
Every 12 
weeks 
Hematology 
  
X1 
  
X 
X 
X 
X 
X 
X 
X 7 X 7 
X 
  
  
  
  
Fasting 
Chemistry 
(Full) 
  
X1 
  
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
Fasting 
Chemistry 
(Partial) 
  
  
  
X 
X 
  
X 
X 
  
  
  
  
  
  
  
  
Fasting Plasma 
Glucose 
  
X1 
  
X 
X 
X 
X 
X 
X 
  
  
X 
  
  
  
  
Urinalysis 
  
X1 
As clinically indicated 
X 
  
  
  
  
Fasting lipid 
panel 
  
X1 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  

Novartis 
Confidential 
Page 104 of 213 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CBYL719H12301 
 
Period 
Pre-screening 
 
Screening
/Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent 
cycles) 
 
 
Visit Name 
 Molecular 
Pre-Screening 
Main 
Screening Day 1 
Da
y 8 
Da
y 
15 
Da
y 1 
Da
y 8 
Day 
15 
Day 1 Da
y 8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from 
last dose) 
Safety 
Follow
-up 
Efficacy 
Follow-up, if 
applicable 5 
Follow 
up 
after 
diseas
e 
progre
ssion 5 
Survival 
Follow-up 5 
Days 
anytime 
before main 
screening  
-28 to -1 
1 
8 
15 1 
8 
15 
1 
8 
15 
- 
30 
Days 
after 
last 
dose 
Follow tumor 
assessments 
8 
weeks 
after 
PD 
Every 12 
weeks 
HbA1C 
  
X1 
  
  
  
X 
  
  
every 
3 
cycles 
from 
C5D1 
onwar
ds 
  
  
X 
  
  
  
  
Coagulation 
panel 
  
X1 
  
  
  
X 
  
  
every 
2 
cycles 
from 
C4D1 
onwar
ds 
  
  
X 
  
  
  
  
Fasting Lipase, 
Fasting 
Amylase 
  
X1 
  
X 
  
X 
  
  
X 
  
  
X 
  
  
  
  

Novartis 
Confidential 
Page 105 of 213 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CBYL719H12301 
 
Period 
Pre-screening 
 
Screening
/Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent 
cycles) 
 
 
Visit Name 
 Molecular 
Pre-Screening 
Main 
Screening Day 1 
Da
y 8 
Da
y 
15 
Da
y 1 
Da
y 8 
Day 
15 
Day 1 Da
y 8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from 
last dose) 
Safety 
Follow
-up 
Efficacy 
Follow-up, if 
applicable 5 
Follow 
up 
after 
diseas
e 
progre
ssion 5 
Survival 
Follow-up 5 
Days 
anytime 
before main 
screening  
-28 to -1 
1 
8 
15 1 
8 
15 
1 
8 
15 
- 
30 
Days 
after 
last 
dose 
Follow tumor 
assessments 
8 
weeks 
after 
PD 
Every 12 
weeks 
Insulin level 
  
X1 
  
  
  
X2 
  
  
every 
2 
cycles 
from 
C4D1 
onwar
ds2 
  
  
X 
  
  
  
  
Serum 
pregnancy test 
(central) 
  
X1 
  
  
  
  
  
  
  
  
  
X 
X 
  
  
  
Serum 
pregnancy test 
(local) 
  
  
S 
  
  
S 
  
  
S 
  
  
  
  
  
  
  

Novartis 
Confidential 
Page 106 of 213 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CBYL719H12301 
 
Period 
Pre-screening 
 
Screening
/Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent 
cycles) 
 
 
Visit Name 
 Molecular 
Pre-Screening 
Main 
Screening Day 1 
Da
y 8 
Da
y 
15 
Da
y 1 
Da
y 8 
Day 
15 
Day 1 Da
y 8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from 
last dose) 
Safety 
Follow
-up 
Efficacy 
Follow-up, if 
applicable 5 
Follow 
up 
after 
diseas
e 
progre
ssion 5 
Survival 
Follow-up 5 
Days 
anytime 
before main 
screening  
-28 to -1 
1 
8 
15 1 
8 
15 
1 
8 
15 
- 
30 
Days 
after 
last 
dose 
Follow tumor 
assessments 
8 
weeks 
after 
PD 
Every 12 
weeks 
Tumor 
Assessment 6 
(Section 8.3.1 & 
Table 8-4) 
  
X 
Every 8 weeks (+/- 7 days) during the first 18 months and 
every 12 weeks (+/- 7 days) thereafter until disease 
progression, death, withdrawal of consent, loss to follow-up. 
If a participant 
discontinues 
treatment for 
reason other 
than radiological 
documentation 
of progression, 
an efficacy 
assessment 
should be 
performed at the 
time of End of 
Treatment 
unless imaging 
tumor 
assessment 
was performed 
within 21 days. 
  
Tumor 
assessments 
must be 
continued if study 
treatment was 
stopped for other 
reason than 
disease 
progression, 
death, withdrawal 
of consent, lost to 
follow-up 
irrespective of 
initiation of new 
antineoplastic 
therapy (Every 8 
weeks (+/- 7 
days) during the 
first 18 months 
and every 12 
weeks (+/- 7 
days) thereafter) 
  
  

Novartis 
Confidential 
Page 107 of 213 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CBYL719H12301 
 
Period 
Pre-screening 
 
Screening
/Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent 
cycles) 
 
 
Visit Name 
 Molecular 
Pre-Screening 
Main 
Screening Day 1 
Da
y 8 
Da
y 
15 
Da
y 1 
Da
y 8 
Day 
15 
Day 1 Da
y 8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from 
last dose) 
Safety 
Follow
-up 
Efficacy 
Follow-up, if 
applicable 5 
Follow 
up 
after 
diseas
e 
progre
ssion 5 
Survival 
Follow-up 5 
Days 
anytime 
before main 
screening  
-28 to -1 
1 
8 
15 1 
8 
15 
1 
8 
15 
- 
30 
Days 
after 
last 
dose 
Follow tumor 
assessments 
8 
weeks 
after 
PD 
Every 12 
weeks 
Whole body 
bone scan 
X (within 42 days prior to 
randomization) 
As clinically indicated 
  
  
  
  
Electrocardiogr
am (ECG), 
performed 
locally 
  
X 
Predose 
  
  
  
  
  
C3D1 
and 
C6D1 
at 
predo
se, 
there
after 
only 
as 
clinica
lly 
indica
ted  
  
  
X 
  
  
  
  

Novartis 
Confidential 
Page 108 of 213 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CBYL719H12301 
 
Period 
Pre-screening 
 
Screening
/Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent 
cycles) 
 
 
Visit Name 
 Molecular 
Pre-Screening 
Main 
Screening Day 1 
Da
y 8 
Da
y 
15 
Da
y 1 
Da
y 8 
Day 
15 
Day 1 Da
y 8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from 
last dose) 
Safety 
Follow
-up 
Efficacy 
Follow-up, if 
applicable 5 
Follow 
up 
after 
diseas
e 
progre
ssion 5 
Survival 
Follow-up 5 
Days 
anytime 
before main 
screening  
-28 to -1 
1 
8 
15 1 
8 
15 
1 
8 
15 
- 
30 
Days 
after 
last 
dose 
Follow tumor 
assessments 
8 
weeks 
after 
PD 
Every 12 
weeks 
Cardiac 
imaging (MRI 
or MUGA or 
ECHO) 
  
X 
As clinically indicated 
X 
  
  
  
  
Adverse Events Suspected 
SAEs 
Continuous, up to 30 days after the last dose of study treatment 
  
  
  
Pharmacokineti
c sample 
collection 
  
  
For collection time points please refer to Section 
8.5.2.1 
  
  
  
  
  
Meal record 
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
Blood for 
circulating DNA 
5 
  
  
X 
  
  
X 
  
  
every 
2 
cycles 
from 
C4D1 
onwar
ds 
  
  
X 
  
  
  
  

Novartis 
Confidential 
Page 109 of 213 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CBYL719H12301 
 
Period 
Pre-screening 
 
Screening
/Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent 
cycles) 
 
 
Visit Name 
 Molecular 
Pre-Screening 
Main 
Screening Day 1 
Da
y 8 
Da
y 
15 
Da
y 1 
Da
y 8 
Day 
15 
Day 1 Da
y 8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from 
last dose) 
Safety 
Follow
-up 
Efficacy 
Follow-up, if 
applicable 5 
Follow 
up 
after 
diseas
e 
progre
ssion 5 
Survival 
Follow-up 5 
Days 
anytime 
before main 
screening  
-28 to -1 
1 
8 
15 1 
8 
15 
1 
8 
15 
- 
30 
Days 
after 
last 
dose 
Follow tumor 
assessments 
8 
weeks 
after 
PD 
Every 12 
weeks 
Skin biopsies 
and skin 
photography (if 
clinically 
indicated for 
G3/G4 skin 
toxicity) 5 
  
  
Anytime at the appearance of G3/4 skin toxicity, or any suspected 
severe cutaneous reactions. Refer to Section 6.5.2.3 
  
  
  
  

Novartis 
Confidential 
Page 110 of 213 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CBYL719H12301 
 
Period 
Pre-screening 
 
Screening
/Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent 
cycles) 
 
 
Visit Name 
 Molecular 
Pre-Screening 
Main 
Screening Day 1 
Da
y 8 
Da
y 
15 
Da
y 1 
Da
y 8 
Day 
15 
Day 1 Da
y 8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from 
last dose) 
Safety 
Follow
-up 
Efficacy 
Follow-up, if 
applicable 5 
Follow 
up 
after 
diseas
e 
progre
ssion 5 
Survival 
Follow-up 5 
Days 
anytime 
before main 
screening  
-28 to -1 
1 
8 
15 1 
8 
15 
1 
8 
15 
- 
30 
Days 
after 
last 
dose 
Follow tumor 
assessments 
8 
weeks 
after 
PD 
Every 12 
weeks 
Alpelisib/Place
bo 
  
  
Daily 
  
  
  
  
  

Novartis 
Confidential 
Page 111 of 213 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CBYL719H12301 
 
Period 
Pre-screening 
 
Screening
/Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent 
cycles) 
 
 
Visit Name 
 Molecular 
Pre-Screening 
Main 
Screening Day 1 
Da
y 8 
Da
y 
15 
Da
y 1 
Da
y 8 
Day 
15 
Day 1 Da
y 8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from 
last dose) 
Safety 
Follow
-up 
Efficacy 
Follow-up, if 
applicable 5 
Follow 
up 
after 
diseas
e 
progre
ssion 5 
Survival 
Follow-up 5 
Days 
anytime 
before main 
screening  
-28 to -1 
1 
8 
15 1 
8 
15 
1 
8 
15 
- 
30 
Days 
after 
last 
dose 
Follow tumor 
assessments 
8 
weeks 
after 
PD 
Every 12 
weeks 
Participant 
dosing diary 
  
  
Starts at C1D1 and continues until last dose (source 
documentation) 
  
  
  
  
  
Nab-paclitaxel 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
Antineoplastic 
therapies since 
discontinuation 
of study 
treatment 
  
  
  
  
  
  
  
  
  
  
  
X 
X 
X 
  
X 
Follow up visit 
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
X 
  
Follow up call 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Within 14 days prior to randomization 
2 Post-alpelisib dose 
3 Complete physical exam 
4 Short Physical exam  
5 Until all participants have completed 6 months of study treatment or have been discontinued from study treatment 

Novartis 
Confidential 
Page 112 of 213 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CBYL719H12301 
 
Period 
Pre-screening 
 
Screening
/Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent 
cycles) 
 
 
Visit Name 
 Molecular 
Pre-Screening 
Main 
Screening Day 1 
Da
y 8 
Da
y 
15 
Da
y 1 
Da
y 8 
Day 
15 
Day 1 Da
y 8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from 
last dose) 
Safety 
Follow
-up 
Efficacy 
Follow-up, if 
applicable 5 
Follow 
up 
after 
diseas
e 
progre
ssion 5 
Survival 
Follow-up 5 
Days 
anytime 
before main 
screening  
-28 to -1 
1 
8 
15 1 
8 
15 
1 
8 
15 
- 
30 
Days 
after 
last 
dose 
Follow tumor 
assessments 
8 
weeks 
after 
PD 
Every 12 
weeks 
6 Tumor assessments will continue as clinically indicated per local standard of care once all participants have completed 6 months of study treatment or have been 
discontinued from study treatment 
7 To be performed if participants are receiving nab-paclitaxel  
8 Placebo dispensing and administration will stop after participant’s unblinding 

Novartis 
Confidential 
Page 113 of 213 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CBYL719H12301 
 
Table 8-3 
Assessment Schedule, Part B1 
Period 
Pre-
screening 
 
Screening/
Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent cycles)  
 
Visit Name 
 Molecular 
Pre-
Screening 
Main 
Screening 
Day 
1 
D
ay 
8 
D
ay 
15 
D
ay 
1 
D
ay 
8 
D
ay 
15 
Day 1 
Day 
8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from last 
dose) 
Safety 
Follow-up 
Efficacy Follow-
up, if applicable 
5 
Survival 
Follow-
up 5 
Days 
anytime 
before 
main 
screening  
-28 to -1  
1 
8 15 1 8 15 1 
8 
15 
- 
30 Days after 
last dose 
Follow tumor 
assessments 
Every 12 
weeks 
Informed consent 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Tumor tissue: New/recent 
biopsy or archival tumor 
block/slides 
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demography 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion / Exclusion criteria 
X  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history/current medical 
conditions 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Diagnosis and Extent of Cancer   
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Information on prior local testing 
for BRCA status and PD-L1 
status, if available 
  
 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Information on prior local 
PIK3CA mutation testing, if 
applicable 
X  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
Eligibility checklist (within IRT) 
  
S 
  
  
  
  
  
  
  
  
  
  
  
  
  
Locally confirmed TNBC status 
in advanced setting 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Prior antineoplastic therapy 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  

Novartis 
Confidential 
Page 114 of 213 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CBYL719H12301 
 
Period 
Pre-
screening 
 
Screening/
Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent cycles)  
 
Visit Name 
 Molecular 
Pre-
Screening 
Main 
Screening 
Day 
1 
D
ay 
8 
D
ay 
15 
D
ay 
1 
D
ay 
8 
D
ay 
15 
Day 1 
Day 
8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from last 
dose) 
Safety 
Follow-up 
Efficacy Follow-
up, if applicable 
5 
Survival 
Follow-
up 5 
Days 
anytime 
before 
main 
screening  
-28 to -1  
1 
8 15 1 8 15 1 
8 
15 
- 
30 Days after 
last dose 
Follow tumor 
assessments 
Every 12 
weeks 
Prior/concomitant medication 
  
X 
Continuous up to 30 days after last dose of study treatment 
  
  
Procedures and Significant Non-
Drug therapies 
  
X 
Continuous up to 30 days after last dose of study treatment 
  
  
IRT Registration (after molecular 
pre-screening ICF signature) 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT Registration (after main ICF 
signature) 
 
S 
  
  
  
  
  
  
  
  
  
  
  
  
  
IRT treatment assignment 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
IRT Study Drug Dispensation 
  
  
X 
  
  
X   
  
X 
  
  
  
  
  
  
End of phase disposition 
  
 
X 
  
  
  
  
  
  
  
  
  
X 
  
X 
  
Physical Examination 
  
S1, 3 
  
 
 
S3  
 
S4 
 
 
S3 
  
  
  
Performance status (ECOG) 
  
X1 
  
  
  
 
  
  
 
  
  
 
  
  
  
Body Height 
  
X1 
  
  
  
  
  
  
  
  
  
  
  
  
  
Body Weight 
  
X1 
  
  
  
X   
  
X 
  
  
X 
  
  
  
Vital Signs 
  
X1 
X 
X X X X X X 
X 
X 
X 
  
  
  
Hematology 
  
X 
  
X X X X X X 
X7 
X7 
X 
  
  
  
Fasting Chemistry (Full) 
  
X1 
  
  
  
X   
  
X 
  
  
X 
  
  
  
Fasting Chemistry (Partial) 
  
  
  
X X   
X X   
  
  
  
  
  
  

Novartis 
Confidential 
Page 115 of 213 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CBYL719H12301 
 
Period 
Pre-
screening 
 
Screening/
Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent cycles)  
 
Visit Name 
 Molecular 
Pre-
Screening 
Main 
Screening 
Day 
1 
D
ay 
8 
D
ay 
15 
D
ay 
1 
D
ay 
8 
D
ay 
15 
Day 1 
Day 
8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from last 
dose) 
Safety 
Follow-up 
Efficacy Follow-
up, if applicable 
5 
Survival 
Follow-
up 5 
Days 
anytime 
before 
main 
screening  
-28 to -1  
1 
8 15 1 8 15 1 
8 
15 
- 
30 Days after 
last dose 
Follow tumor 
assessments 
Every 12 
weeks 
Fasting Plasma Glucose 
  
X1 
  
X X X X X X 
  
  
X 
  
  
  
Urinalysis 
  
X1 
As clinically indicated 
X 
  
  
  
Fasting lipid panel 
  
X1 
  
  
  
  
  
  
  
  
  
X 
  
  
  
HbA1C 
  
X1 
  
  
  
X 
  
  
every 3 
cycles 
from 
C5D1 
onwards 
  
  
X 
  
  
  
Coagulation panel 
  
X1 
  
  
  
X 
  
  
every 2 
cycles 
from 
C4D1 
onwards 
  
  
X 
  
  
  
Fasting Lipase, Fasting Amylase   
X1 
  
X   
X   
  
X 
  
  
X 
  
  
  
Insulin level 
  
X1 
  
  
  
X2 
  
  
every 2 
cycles 
from 
C4D1 
onwards2 
  
  
X 
  
  
  
Serum pregnancy test (central) 
  
X1 
  
  
  
  
  
  
  
  
  
X 
X 
  
  
Serum pregnancy test (local) 
  
  
S 
  
  
S   
  
S 
  
  
  
  
  
  

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Period 
Pre-
screening 
 
Screening/
Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent cycles)  
 
Visit Name 
 Molecular 
Pre-
Screening 
Main 
Screening 
Day 
1 
D
ay 
8 
D
ay 
15 
D
ay 
1 
D
ay 
8 
D
ay 
15 
Day 1 
Day 
8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from last 
dose) 
Safety 
Follow-up 
Efficacy Follow-
up, if applicable 
5 
Survival 
Follow-
up 5 
Days 
anytime 
before 
main 
screening  
-28 to -1  
1 
8 15 1 8 15 1 
8 
15 
- 
30 Days after 
last dose 
Follow tumor 
assessments 
Every 12 
weeks 
Tumor Assessment 6 
(Section 8.3.1 & Table 8-4) 
  
X 
Every 8 weeks (+/- 7 days) during the first 18 
months and every 12 weeks (+/- 7 days) 
thereafter until disease progression, death, 
withdrawal of consent, loss to follow-up. 
If a participant 
discontinues 
treatment for 
reason other 
than 
radiological 
documentation 
of progression, 
an efficacy 
assessment 
should be 
performed at 
the time of End 
of Treatment 
unless imaging 
tumor 
assessment 
was performed 
within 21 days. 
  
Tumor 
assessments 
must be 
continued if study 
treatment was 
stopped for other 
reason than 
disease 
progression, 
death, withdrawal 
of consent, lost to 
follow-up 
irrespective of 
initiation of new 
antineoplastic 
therapy (Every 8 
weeks (+/- 7 
days) during the 
first 18 months 
and every 12 
weeks (+/- 7 
days) thereafter) 
  
Whole body bone scan 
X (within 42 days prior 
to randomization) 
As clinically indicated 
  
  
  

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Period 
Pre-
screening 
 
Screening/
Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent cycles)  
 
Visit Name 
 Molecular 
Pre-
Screening 
Main 
Screening 
Day 
1 
D
ay 
8 
D
ay 
15 
D
ay 
1 
D
ay 
8 
D
ay 
15 
Day 1 
Day 
8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from last 
dose) 
Safety 
Follow-up 
Efficacy Follow-
up, if applicable 
5 
Survival 
Follow-
up 5 
Days 
anytime 
before 
main 
screening  
-28 to -1  
1 
8 15 1 8 15 1 
8 
15 
- 
30 Days after 
last dose 
Follow tumor 
assessments 
Every 12 
weeks 
Electrocardiogram (ECG), 
performed locally 
  
X 
Pred
ose 
  
  
  
  
  
C3D1 and 
C6D1 at 
predose, 
thereafter 
only as 
clinically 
indicated  
  
  
X 
  
  
  
Cardiac imaging (MRI or MUGA 
or ECHO) 
  
X 
As clinically indicated 
X 
  
  
  
Adverse Events 
Suspected 
SAEs 
Continuous, up to 30 days after the last dose of study treatment 
  
  
Pharmacokinetic sample 
collection 
  
  
For collection time points please refer to 
Section 8.5.2.1 
  
  
  
  
Meal record 
  
  
  
X   
  
  
  
  
  
  
  
  
  
  
Skin biopsies 
and skin photography (if 
clinically indicated for G3/G4 
skin toxicity) 5 
  
  
Anytime at the appearance of G3/4 skin toxicity, or any 
suspected severe cutaneous reactions. Refer to Section 
6.5.2.3 
  
  
  
Alpelisib 
  
  
Daily 
  
  
  
  
Participant dosing diary 
  
  
Starts at C1D1 and continues until last dose 
(source documentation) 
  
  
  
  

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Period 
Pre-
screening 
 
Screening/
Baseline 
Treatment 
End of Study 
Treatment 
Post-Treatment Follow-Up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and 
subsequent cycles)  
 
Visit Name 
 Molecular 
Pre-
Screening 
Main 
Screening 
Day 
1 
D
ay 
8 
D
ay 
15 
D
ay 
1 
D
ay 
8 
D
ay 
15 
Day 1 
Day 
8 
Day 
15 
End of Study 
Treatment 
(within 14 
days from last 
dose) 
Safety 
Follow-up 
Efficacy Follow-
up, if applicable 
5 
Survival 
Follow-
up 5 
Days 
anytime 
before 
main 
screening  
-28 to -1  
1 
8 15 1 8 15 1 
8 
15 
- 
30 Days after 
last dose 
Follow tumor 
assessments 
Every 12 
weeks 
Nab-paclitaxel 
  
  
X 
X X X X X X 
X 
X 
  
  
  
  
Antineoplastic therapies since 
discontinuation of study 
treatment 
  
  
  
  
  
  
  
  
  
  
  
X 
X 
X 
X 
Follow up visit 
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
  
Follow up call 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Within 14 days prior to randomization 
2 Post-alpelisib dose 
3 Complete physical exam 
4 Short Physical exam  
5 Until all participants have completed 6 months of study treatment or have been discontinued from study treatment  
6 Tumor assessments will continue as clinically indicated per local standard of care once all participants have completed 6 months of study treatment or have been 
discontinued from study treatment  
7 To be performed if participants are receiving nab-paclitaxel 

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8.1 
Screening 
All study participants must be thoroughly informed about all aspects of the study, including the 
study treatment, visit schedule, required evaluations, and all regulatory requirements for 
informed consent. Written informed consent must be obtained before any study specific 
assessments are performed, including molecular pre-screening and screening using the 
respective consent forms: the molecular Pre-screening consent and main study consent.  If the 
participant is unable to read, an impartial witness should be present during the entire informed 
consent discussion. For details of screening assessments, refer to Table 8-2 and Table 8-3 .  
Molecular Pre-screening  
For eligibility into the study Part A, participants must have a  PIK3CA mutation as centrally 
confirmed by a Novartis designated laboratory based on tumor tissue, or if the results are 
already available, by a local laboratory using either a FDA-approved PIK3CA CDx test for 
alpelisib or the CE-IVD QIAGEN therascreen® PIK3CA RGQ PCR test without central 
confirmation. PIK3CA mutation results generated by research use only version of the Qiagen 
test, or other laboratory-developed tests, are not acceptable. Participants who are confirmed to 
have PIK3CA mutations by a local laboratory still need to submit a tumor tissue sample to 
assess PTEN expression status during pre-screening.  
For eligibility into part B1 of the study, participants must have a tumor tissue PTEN loss and 
PIK3CA unknown or non-mutant. For eligibility into part B2 of the study, participants must 
have a tumor tissue PTEN loss without concurrent PIK3CA mutation.  
PIK3CA status is defined as ‘unknown’ if the PIK3CA results from the PIK3CA mutation assay 
are reported as invalid based on specified assay control parameters. A PCR based test is used 
to detect 11 specific PIK3CA sequences in DNA from a tumor sample, each sequence matching 
one of the 11 mutations targeted by alpelisib. In this assay the quality of DNA extracted from 
the provided tissue sample is important as fragmented DNA may increase the possibility of non-
specific amplification in one of the 11 PIK3CA sequences, without the sequence actually being 
present. Therefore control reactions are used to detect for non-specific amplification as opposed 
to targeted amplification of the gene sequence. If these assay controls show non-specific 
amplification, then the PIK3CA test results are considered invalid and the PIK3CA status is 
therefore unknown.  
PTEN loss is defined by reduction in PTEN protein expression level below a predefined 
threshold based on an immunohistochemistry test. The lack of PIK3CA mutation must be 
centrally confirmed by a Novartis designated laboratory, or if the results are already available, 
by a local laboratory using either a FDA-approved PIK3CA CDx test for alpelisib or the CE-
IVD QIAGEN therascreen® PIK3CA RGQ PCR test without central confirmation. 
All participants must sign the molecular pre-screening informed consent form. 
1. Upon participant signature of the molecular pre-screening ICF, the archival tumor sample 
or new tumor biopsy should be collected and shipped to a Novartis designated laboratory 
for PIK3CA and PTEN status analysis (refer to Table 8-15 in Section 8.5.3 for number of 
slides required) as soon as possible to allow time for analyses and availability of 
biomarker results by the time main screening procedures commence.  

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• Note: Acceptable biopsies for deep tumor tissue include core needle biopsies; and for 
cutaneous and subcutaneous lesions include excisional, incisional, punch, or forceps 
biopsies. NOT ACCEPTABLE are fine-needle aspiration, brushings, cell pellets from 
pleural effusion, bone biopsy, bone marrow aspirates and lavage samples. 
2. The participant will be assigned a participant number by the  clinical database (see 
Section 6.3.1) and be registered into the IRT system. The participant number assigned 
should be the next sequential participant number available in the clinical database for that 
site. 
3. Demographic information is collected in the eCRF (see Section 8.2). 
4. The Novartis designated laboratory will provide the PIK3CA mutation and PTEN 
expression analysis results to the investigational site. 
A formalin fixed paraffin embedded (FFPE) tissue block is preferred for analysis. If a tissue 
block cannot be sent, then unstained FFPE slides at 5 µm thickness are acceptable (refer to 
Table 8-15 in Section 8.5.3 for details on number of slides required). Ideally the samples should 
contain at least 80% tumor. If an archival tumor sample (preferably collected within 3 years) is 
not available, a newly collected formalin fixed biopsy is required. If more than one archival 
samples is available, tumor sample from the most recent archival biopsy is preferred. Please 
refer to the laboratory manual for sample requirements. 
Participants who have PIK3CA mutation status confirmed by a local laboratory using either a 
FDA-approved PIK3CA CDx test for alpelisib or the CE-IVD QIAGEN therascreen® PIK3CA 
RGQ PCR test can continue the screening, and no central confirmation will be required. All 
participants from countries without a health authority approved test for alpelisib must be tested 
centrally. The PIK3CA mutation status must be documented in the source documents before 
the participant can be consented for screening. Tumor sample or slides must still be provided 
to determine PTEN expression status by a Novartis designated central laboratory. The 
results will be communicated to the site.  
Participants with the following pre-screening biomarkers results will be considered as screen 
failure patients: 
• PIK3CA non mutant and PTEN normal 
• unknown PIK3CA mutation and unknown PTEN expression 
• unknown PIK3CA mutation and PTEN loss (Part A/B2) 
• unknown PIK3CA mutation and PTEN normal 
Patients who fail the molecular pre-screening cannot be re-screened. 
If a tumor block or new biopsy is provided, the remaining tissue from screen failure samples 
will be returned to the site. If a participant is enrolled, the remaining block will be sent to a 
Novartis-designated vendor. Only if the site requests the sample to be returned, a few slides will 
be cut out prior to sending the remaining block back to the site. 
Main Screening 
Main screening assessments can begin once a participant has been confirmed to meet the 
molecular pre-screening criteria and has signed the main study ICF.  The main screening 
assessments consist of all eligibility assessments except for molecular assessment to determine 

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the PIK3CA and PTEN status. Those main screening assessments, must be performed within 
28 days of first dose of study treatment to confirm participant’s eligibility with the exception of 
the central serum pregnancy test and selected assessments that must be conducted within 14 
days prior to start of study treatment as per Table 8-2 and Table 8-3 . It is highly recommended 
to send the serum pregnancy sample to the central laboratory no later than 7 days prior the start 
of study treatment in order to receive the result prior to participant's randomization/enrollment. 
For participants who may have had procedures previously performed as part of the participant’s 
routine disease care (prior to signing the main study informed consent), the following 
procedures can be used providing a proper documentation in participant’s file is available: 
• Any imaging assessments within 28 days of start of study treatment (Cycle 1 Day 1) 
(within 42 days for the whole body bone scan) 
A participant who has a laboratory test result(s) that does not satisfy the entrance criteria may 
have the test(s) repeated. These test(s) may be repeated as soon as the investigator believes the 
retest result(s) is/are likely to be within the acceptable range to satisfy the entrance criteria, but 
should be completed within 28 days of screening period. In this case, the participant will not be 
required to sign another ICF, and the original participant ID number assigned by the investigator 
will be used. In the event that the laboratory test(s) cannot be performed within 28 days of 
screening period or the re-test(s) do not meet the entrance criteria, or other eligibility criteria 
have changed and are not met anymore, the participant will be considered a screen failure. 
A new informed consent form must be signed if the investigator chooses to re-screen a 
participant after he/she screen failed. 
Re-screening of participant is only allowed once per participant if the participant was not 
registered as entering the treatment phase before (i.e. IRT randomization/treatment assignment). 
In this case a new participant number will be generated, and a specific rescreen form will be 
added in the eCRF, to collect the original participant number. This data will be used to link the 
two participant numbers for reporting and validation. 
All required screening activities that were performed at initial screening and which made the 
patient screen failed must be repeated when the participant is re-screened to satisfy the window 
requirements defined in Table 8-2 and Table 8-3. The molecular pre-screening PIK3CA/PTEN 
testing does not need to be repeated once a participant is re-screened. 
Once the number of participants screened and enrolled is likely to ensure target enrollment, the 
Sponsor may close the study to further screening. In this case, the participants who screen failed 
will not be permitted to re-screen. 
8.1.1 
Eligibility screening 
Following IRT registration at molecular pre-screening and main screening, participant 
eligibility will be checked according to study inclusion and exclusion criteria as described in 
Section 5 once all screening procedures are completed. A list of procedures to be performed 
during the screening period is summarized in Table 8-2 and Table 8-3. Results of all 
screening/baseline evaluations must be reviewed by the investigator or his/her designee prior 
to start study treatment of each participant to ensure that all inclusion and exclusion criteria 
have been satisfied. When all screening procedures are completed and the participant’s 
eligibility is confirmed (i.e. all inclusion/exclusion criteria have been verified), the key 

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eligibility criteria checklist embedded in the IRT system will be completed prior to the first 
dose of study drug. Please refer to Section 6.3.2 and as well as comply with detailed guidelines 
in the IRT manual.  
8.1.2 
Information to be collected on screening failures 
Participants who sign the informed consent form and subsequently are found to be ineligible 
prior to enrollment/randomization will be considered a screen failure. 
This includes participants who has signed the molecular pre-screening ICF and do not continue 
to the screening period (e.g. as they do not meet the molecular eligibility criteria) or those who 
are found not eligible after signing the main study consent.  The data for these two cases of 
screening failures will be handled in the same manner.   
The reason for screen failure should be recorded on the appropriate eCRF. The demographic 
information, informed consent, local PIK3CA mutation and inclusion/exclusion 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 10.1.3). For participants who fail the 
molecular pre-screening, only SAEs possibly related to a study procedure will be reported. 
If the participant is a molecular pre-screening failure or fails to be randomized or enrolled, the 
IRT must be notified within 2 days. 
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/randomized participants: 
- Demography information (gender, age, race and ethnicity as allowed by local regulations) is 
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). 
- Medical History/current medical conditions (including BRCA mutation and PD-L1 expression 
status, if available) present before signing the informed consent. Investigators will have the 
discretion to record abnormal test findings on the appropriate eCRF whenever, in their 
judgment, the test abnormality occurred prior to the informed consent signature. 
• Disease baseline characteristics including diagnosis, history, extent of cancer, prior 
antineoplastic therapy 
• Prior/concomitant therapy: all medications and significant non-drug therapies taken within 
30 days prior to first dose of study treatment  
• Blood sample for biomarkers 
• Tumor biopsy for biomarkers (unless archival biopsy provided as per Section 8.5.3) 
• Quality of life questionnaires (EORTC QLQ-C30, BPI-SF and EQ-5D-5L)  

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Furthermore the following assessments will be performed to assess the eligibility of the 
participant: 
• Vital signs including body temperature, blood pressure and pulse 
• ECOG performance status 
• ECG  
• Cardiac imaging 
• Tumor evaluation 
• Laboratory evaluations  
• Complete physical examination 
• Stratification factors 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with eCRF. 
8.3 
Efficacy 
8.3.1 
Imaging tumor assessments 
Tumor response will be assessed locally according to the Novartis guideline version 3.2 
(Section 16.1) based on RECIST 1.1 (Eisenhauer et al 2009). The imaging assessment 
collection plan is presented in Table 8-4.The local investigator’s assessment will be used for 
treatment decision making. 
With protocol amendment 02, the central collection of the imaging data, information via the 
Baseline Clinical Form and Cytology Form stops and the BIRC assessment will not be 
performed for any participant enrolled in the study.  
All known lesions (measurable, non-measurable) should be accounted for at screening within 
28 days before Cycle 1 Day 1 when assessing objective tumor status. Imaging assessments for 
response evaluation will be performed every 8 weeks (+/-7 days) after randomization during 
the first 18 months and every 12 weeks (+/- 7 days) thereafter. The 8-week (or 12-week) interval 
should be respected regardless of whether study treatment is temporarily withheld or 
unscheduled assessments are performed. Assessment modality must remain the same 
throughout the study (e.g. contrast CT or MRI scan) using RECIST v1.1 criteria. Local 
assessments will be used for the primary analysis.. Tumor assessments will continue as 
clinically indicated upon completion of Part A primary analysis. 
If participants start on new antineoplastic therapy before documented disease progression, every 
effort should be made to continue local collection of tumor assessments until all participants 
have completed 6 months of study treatment or have been discontinued from study treatment. 
Assessment of survival will be performed every 3 months after study treatment discontinuation 
or upon termination of the efficacy follow-up phase until all participants have completed 6 
months of study treatment or have been discontinued from study treatment. 

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Table 8-4 
Imaging Assessment Collection Plan 
Procedure 
Screening/Baseline2 
During Treatment/Follow-up 
Chest, abdomen and pelvis CT or 
MRI (with intravenous contrast 
enhancement) 
Mandated 
Every 8 weeks (+/- 7 days) during 
the first 18 months and every 12 
weeks (+/- 7 days) thereafter until 
disease progression, end of 
treatment1, death, withdrawal of 
consent, or lost to follow-up3 
Brain CT or MRI 
Mandated 
If lesions were documented at 
baseline, follow same schedule as 
CT/MRI of chest, abdomen, and 
pelvis3 
Whole body bone scan 
Mandated, within 42 days (6 
weeks) prior to randomization 
As clinically indicated 
Localized bone CT, MRI, or x-ray 
Mandated for skeletal 
abnormalities identified on the 
whole body bone scan that are not 
visible on the chest, abdomen and 
pelvis CT or MRI 
If lesions were documented at 
baseline, follow same schedule as 
CT/MRI of chest, abdomen, and 
pelvis3 
Color photography (with 
scale/ruler) 
Mandated if any skin lesions 
present at screening 
If lesions were documented at 
baseline, follow same schedule as 
CT/MRI of chest, abdomen, and 
pelvis3 
CT or MRI of other metastatic sites 
(e.g. neck) 
Mandated if suspected lesion at 
screening 
If lesions were documented at 
baseline, follow same schedule as 
CT/MRI of chest, abdomen, and 
pelvis3 
1Tumor evaluation at End of treatment (EOT) is required for participants who discontinue study treatment 
before the first scheduled post-baseline tumor assessment (week 8) and for participants whose previous tumor 
assessment did not demonstrate progressive disease (PD) and was done more than 21 days prior to end of 
treatment visit. 
2 Any imaging assessments already completed during the regular work-up of the participant within 28 days 
prior to start of treatment or within 42 days for the whole body bone scan, including before signing the main 
study ICF, can be considered as the baseline images for this study. 
3 Imaging assessments will continue as clinically indicated once all participants have completed 6 months of 
study treatment or have been discontinued from study treatment. 
Baseline imaging assessments 
Imaging assessments will be performed at screening/baseline within 28 days of start of 
treatment (Day -28 to Day -1 prior to Cycle 1 Day 1). 
Any imaging assessments already completed during the regular work-up of the participant 
within 28 days prior to start of treatment (42 days for the whole body scan), including before 
signing the main study ICF, can be considered as the baseline images for this study. Any 
imaging assessments obtained after randomization cannot be considered baseline images. The 
following assessments are required at screening/baseline: 
• Chest, abdomen, and pelvis CT or MRI 
• Brain CT or MRI 
• Whole body bone scan 
• Localized bone CT, MRI, or x-ray, for any lesions identified on the whole body bone scan 
that are not visible on the chest, abdomen, and pelvis CT or MRI 

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• Color photography for any skin lesions present at screening 
• CT or MRI of other metastatic sites (e.g. neck), if suspected lesion at screening 
If a participant is known to have a contraindication to CT intravenous (IV) contrast media or 
develops a contraindication during the trial, a non-contrast CT of the chest (MRI is not 
recommended due to respiratory artifacts; however, if CT is not feasible per local regulations, 
MRI can be performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen and 
pelvis should be performed. 
Contrast enhanced brain MRI is preferred, however, if MRI contrast is contraindicated, then 
MRI without contrast or CT with/without contrast is acceptable. 
A whole body bone scan should be performed per institutional standard of care [e.g. Tc-99 bone 
scan, whole body bone MRI, Fluorodeoxyglucose positron emission tomography (FDG-PET), 
or sodium fluoride (NaF) PET]. Localized CT, MRI, or X-rays should be acquired for all 
skeletal lesions identified on the screening whole body bone scan, which are not visible on the 
chest, abdomen, and pelvis CT/MRI. 
If clinically indicated, CT or MRI of other areas (e.g. neck) of disease as appropriate should be 
performed. 
If skin lesions are present at screening, color photography should be acquired using a digital 
camera in clear focus, including a scale/ruler, in such a way that the size of the lesion(s) can be 
determined from the photograph. Further guidance on photography will be outlined in the 
Imaging Vendor Manual. 
Any potentially measurable lesion that has been previously treated with radiotherapy should be 
considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable 
lesion. 
Chest x-rays and ultrasound should not be used to measure tumor lesions. 
Post-baseline imaging assessments 
Imaging assessments as described in Table 8-4 should be performed at the timepoints specified 
using the same imaging modality used at baseline, irrespective of study treatment interruption 
or actual dosing (see Table 8-2 and Table 8-3). Imaging assessments for response evaluation 
will be performed every 8 weeks (+/- 7 days) during the first 18 months, and every 12 weeks 
(+/- 7 days) thereafter until disease progression, death, lost to follow-up, or withdrawal of 
consent/opposition to use data/biological samples. Imaging assessments should be scheduled 
using the randomization date as the reference date (not the date of the previous tumor 
assessment) and should be respected regardless of whether treatment with study treatment is 
temporarily withheld or unscheduled assessments performed. Once all participants have 
completed 6 months of study treatment or have been discontinued from study treatment, 
imaging assessments will continue as clinically indicated.  
All participants who discontinue from study treatment due to disease progression must have 
their progression clearly documented according to RECIST v1.1. If a participant did not 
discontinue study treatment due to disease progression per investigator, death, lost to follow-
up, or withdrawal of consent/opposition to use data/biological samples to efficacy follow-up, 

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then tumor assessments should continue to be performed according to the planned schedule 
until disease progression (per investigator), death, lost to follow-up or withdrawn withdrawal 
of consent/ opposition to use data/biological samples for efficacy follow-up. 
An additional tumor assessment must be performed to confirm response (CR or PR) no less 
than 4 weeks after the criteria for response are first met. 
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a participant, as necessary. 
Clinical suspicion of disease progression at any time requires a physical examination and 
imaging assessments to be performed promptly rather than waiting for the next scheduled 
imaging assessment. 
Each lesion that is measured at baseline must be measured by the same method (either same 
imaging method or by photography, including a metric ruler) and when possible, the same local 
radiologist/physician throughout the study so that the comparison is consistent. If an off-
schedule imaging assessment is performed because progression is suspected, subsequent 
imaging assessments should be performed in accordance with the original imaging schedule. 
Combined PET/CT may be used only if the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of IV contrast media. At the discretion of the 
Investigators, FDG-PET scans may be performed to document progressive disease per RECIST 
1.1 (Section 16.1). 
If a participant starts on a new antineoplastic therapy before documented disease progression, 
every effort should be made to continue to collect tumor assessment according to the planned 
schedule until all participants have completed 6 months of study treatment or have been 
discontinued from study treatment.  
8.3.2 
Blinded independent review committee (BIRC) assessment 
With the decision to halt recruitment in Part A and to not initiate Part B2, no BIRC assessments 
will be made for any participants enrolled in the study. 
8.3.3 
Appropriateness of efficacy assessments 
The measurements are standard based on the new response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1) (Eisenhauer et al 2009). 
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 and Table 8-6 ), ECG, cardiac function evaluation by MRI/Echocardiogram 
(ECHO)/MUGA scan, laboratory testing (hematology, coagulation, serum chemistry, and 
urinalysis) 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.  As per Section 4.6, during a Public Health emergency as declared by 

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Local or Regional authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents 
on-site study visits, regular phone or virtual calls can occur (every 4 weeks or more frequently 
if needed) for safety monitoring and discussion of the participant´s health status until it is safe 
for the participant to visit the site again. 
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. A complete physical examination will be completed at screening, C2D1 and 
EOT. 
A short physical exam will be performed at Day 1 of each cycle starting at C3D1 as 
indicated in Table 8-2 and Table 8-3 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 [SBP and 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 eCRF that captures medical history. 
Significant findings made after signing informed consent which meet the definition of an 
Adverse Event must be recorded as an adverse event (see Section 10). 
Vital signs 
Vital signs include blood pressure (supine position preferred when ECG is collected), 
pulse measurement, and body temperature. 
Height and weight 
Height in centimeters (cm) 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 and Table 8-3 
The performance status will be assessed according to the ECOG Performance status scale as 
described in Table 8-6 following the schedule given in Table 8-2 and Table 8-3. 
Table 8-6 
ECOG performance status 
Grade 
ECOG Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
8.4.1 
Laboratory evaluations 
Clinical laboratory analyses (hematology, biochemistry, coagulation, fasting lipase, fasting 
amylase, fasting lipid panel, fasting glucose, insulin level, HbA1C and urinalysis) are to be 
performed by the central laboratory. In case of urgent safety management of hyperglycemia, 
fasting plasma glucose assessment may be allowed to be done locally according to the schedule 
of assessments and collection plan outlined respectively in Table 8-2 and Table 8-3. 

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All laboratory assessments will be performed by the local laboratory once all participants have 
completed 6 months of study treatment or have been discontinued from study treatment. 
Note: as hyperglycemia typically occurs within the first weeks of treatment, fasting plasma 
glucose at Day 8 and Day 15 of Cycle 1 should be performed both locally and centrally for 
rapid availability for safety evaluation and dose adjustments. 
Unscheduled local laboratory assessments may be performed if medically indicated to assess a 
(potential) adverse event or when the treating physician cannot wait for central laboratory 
results for decision making (e.g. dose modifications).  In these particular situations, if possible, 
the blood sample obtained at the same time point should be submitted to the central laboratory 
for analysis in parallel with local analysis.  In addition, if participants cannot visit the site for 
safety lab assessments conducted through central labs, local lab collection may be used 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.  If participants cannot visit the 
site for protocol specified safety lab assessments, an alternative lab (local) collection site may 
be used.  
The results of the local laboratory will be recorded in the eCRF if any of the following criteria 
are met: 
• A treatment decision was made based on the local results, or 
• Local lab results document an adverse event not reported by the central lab, or 
• Local lab results document an adverse event severity worse than the one reported by the 
central lab, or 
• There are no concomitant central results available  
• Local lab results after all participants have completed 6 months of study treatment or have 
been discontinued from study treatment 
For assessment of participants’ eligibility to the study, only laboratory results from the 
central laboratory will be used, with the exception of Follicle-stimulating hormone (FSH) and 
plasma estradiol levels to determine menopausal status (see Section 8.4.3). 
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate. 
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. Additional analyses are left to the discretion of the investigator. 
Visit windows of +/- 3 days 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 

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responsible for reviewing all laboratory reports for participants in the study and evaluating any 
abnormalities for clinical significance. 
Table 8-7 
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, percentages are acceptable) 
Fasting Chemistry (Full) 
Albumin, Alkaline phosphatase, ALT , AST , Gamma-glutamyl-transferase (GGT), 
Lactate dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, Sodium, 
Potassium, Creatinine, Creatine kinase, Direct Bilirubin, Indirect Bilirubin, Total 
Bilirubin, Total Protein, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase 
(fasting), Lipase (fasting), Glucose (fasting) 
Fasting Chemistry 
(Partial) 
Creatinine, Creatine Kinase, ALT, AST, Total Bilirubin 
Fasting Lipid panel 
Total Cholesterol, LDL, HDL, Triglycerides 
Urinalysis 
Macroscopic Panel (Dipstick) (WBC, Blood, Protein and Glucose) 
Coagulation 
International normalized ratio [INR]), Partial thromboplastin time (PTT) or 
Activated partial thromboplastin time (APTT)  
Additional tests 
HbA1c, Insulin level 
Pregnancy Test  
For women of child-
bearing potential only 
Serum (central laboratory at screening, EOT and 30 days safety follow-up), serum 
(local laboratory at Day 1 of each cycle) 
Details on the collections, shipment of samples and reporting of results by the central laboratory 
are provided to investigators in the central laboratory manual. All laboratory assessments will 
be performed by the local laboratory once all participants have completed 6 months of study 
treatment or have been discontinued from study treatment. 
8.4.2 
Electrocardiogram (ECG) 
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, and blood sampling. The QTcF must be used for clinical decisions 
e.g., at the Screening visit (as applicable) to assess eligibility. The investigator must calculate 
QTcF if it is not auto-calculated by the ECG machine. 
Single 12 lead ECGs are collected with ECG machines available at the site. The original ECGs 
on non-heat-sensitive paper and a certified copy on non-heat sensitive paper, appropriately 
signed, must be collected and archived at the study site. 
For any ECGs with participant safety concerns, two additional ECGs must be performed to 
confirm the safety finding. A monitoring or review process should be in place for clinically 
significant ECG findings throughout the study and especially at baseline before administration 
of study treatment. 
Any identifier details must be redacted e.g. participant initials, date of birth. 
In the event that a clinically significant ECG abnormality is identified at the site (e.g. severe 
arrhythmia, conduction abnormality of QTcF > 500 ms) the ECG is repeated to confirm the 
diagnosis. If the participant is hemodynamically compromised, the investigator or a medically 

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qualified person must initiate appropriate safety procedures without delay (for example 
cardioversion). 
Clinically significant abnormalities must be recorded on the eCRF as either medical 
history/current medical conditions or adverse events as appropriate. 
A standard 12 lead ECG will be performed as presented in Table 8-8. Of note more frequent 
ECG monitoring may be considered if at increased risk for ECG abnormalities due to the use 
of drugs that prolong the QT interval and/or induce Torsades de Pointes 
Table 8-8 
ECG collection plan  
Visit 
Day 
Time 
ECG Type 
Screening 
-28 to -1 
Anytime 
12 Lead, single 
Cycle 1 
1 
Pre-dose (baseline ECG) 
12 Lead, single 
Cycle 3 and Cycle 6 
1 
Pre-dose 
12 Lead, single 
EOT 
NA 
Anytime 
12 Lead, single 
Unscheduled sample (as 
clinically indicated or as 
deemed appropriate by 
the investigator e.g. if the 
participant takes drugs 
that prolong the QT 
interval and/or induce 
Torsades de Pointes) 
NA 
Anytime 
12 Lead, single 
Interpretation of the tracing must be made by a qualified physician and documented on the 
appropriate eCRF. 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 eCRF. Clinically significant findings 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. 
Please refer to Figure 8-1 for the timing of ECG study procedures. 
Figure 8-1 
Timing of study procedures 
 
. 

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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 eCRF. New or worsened clinically significant findings occurring after informed 
consent must be recorded as adverse events. 
8.4.2.1 
Cardiac imaging - MRI (magnetic resonance imaging), MUGA (multiple 
gated acquisition) scan or echocardiogram 
The left ventricular heart function will be evaluated by MRI, ECHO or MUGA at Screening to 
confirm eligibility and at EOT. Additional cardiac imaging during treatment is to be performed 
if indicated by clinical signs or symptoms. The same imaging modality should be used. 
8.4.3 
Pregnancy and assessments of fertility 
A condom 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. In addition, 
male participants should not donate sperm for the time period specified above (see exclusion 
criteria 24 in Section 5.2). 
All women of childbearing potential as defined in the inclusion/exclusion criteria who are not 
surgically sterile will have serum pregnancy testing as follows. 
• At screening, within 14 days of first dose of study treatment (central laboratory) 
• During study treatment, on Day 1 of each cycle (local laboratory) 
• At the EOT visit (central laboratory) 
• During the 30 days safety follow-up visit (central laboratory) 
Any local positive serum test needs to be confirmed with a central serum test. If positive, the 
participant must be discontinued from the study treatment. 
Results will be required to be retained as source documentation. 
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. Male participants must notify the investigator in case their partner 
becomes pregnant during the treatment period and should keep using a condom during sexual 
intercourse as to prevent delivery of study treatment via seminal fluid to their partner. 
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 (if allowed by local 
regulations) 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 

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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 
Medical documentation of 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile, surgical bilateral oophorectomy, hysterectomy, or bilateral tubal ligation must 
be retained as source documents to confirm post-menopausal status. 
In case of oophorectomy alone, hormone level assessment (FSH, estradiol) will be done locally 
at screening to confirm the woman is not of childbearing potential, if applicable. Refer to 
Section 5.2. 
8.4.4 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population. 
8.5 
Additional assessments 
 
 
 
 
 

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8.5.2 
Pharmacokinetics 
No drug-drug interaction is anticipated between alpelisib and paclitaxel based on the known 
pharmacology of both drugs. The phase Ib Study CBYL719Z2101 which investigated the 
combination of alpelisib and solvent-based paclitaxel in participants with solid tumors 
confirmed no change in paclitaxel PK under repeated continuous administration of alpelisib 
(Rodon et al 2018). 
No pharmacokinetic interactions were detected when alpelisib and nab-paclitaxel were co-
administered in a phase I dose-escalation study in participants with PIK3CA-altered or wild-
type, HER2-negative breast cancer (Sharma et al 2018 [CBYL719XUS06T]); though PK was 
only assessed after the first dose. 
Thus, PK samples will be collected in a sparse manner, independent of the study Part, 
to primarily characterize the exposure of alpelisib in the participants with triple negative breast 
cancer, when administered together with nab-paclitaxel. For nab-paclitaxel, a sample will be 
collected in study Part 
 B1 at selected timepoints to characterize the maximum 
concentration of paclitaxel in systemic circulation when co-administered with continuous daily 
doses of alpelisib. 
PK samples will be collected at the visits defined in Table 8-2, and Table 8-3. Follow 
instructions outlined in the laboratory manual and flow chart regarding sample collection, 
numbering, processing and shipment. See the potential use of residual samples for more 
information. 
Following implementation of protocol Amendment 02, PK samples collection will stop.  
Alpelisib/placebo pharmacokinetic blood sampling schedules 
Mandatory blood samples for sparse PK assessments of alpelisib will be collected in all 
participants enrolled in the study independent of study Part. In the randomized, double-blinded 
Part 
 B2 of the study, measurement of alpelisib will be performed only in participants 
randomized to the alpelisib arm. 
Two post-dose samples will be collected at Cycle 1 Day 8 at the steady state of alpelisib (post-
dose after alpelisib/placebo is started) to adequately capture both volume of distribution and 
clearance if population PK analysis should be conducted and to capture a concentration within 
the Tmax range for alpelisib.  
8.5.2.1 
Pharmacokinetic blood collection and handling 
Complete instructions for sample collection, processing, handling and shipment will be 
provided in the [CBYL719H12301 Laboratory Manual] and flow chart. 
For post-dose or end of infusion PK samples, only the time window specified in the blood 
collection log tables are allowed, while other pre-dose PK samples may be obtained within 1 
day from the scheduled date. 
All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted 
in a forearm vein in accordance with the assessment schedule and institutional guidelines. At 
the specified time points, blood draws in the volume specified in the blood collection log tables 
will be collected into tubes containing K3-EDTA (alpelisib) and Na-heparin (paclitaxel). 

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Both alpelisib and paclitaxel plasma samples tubes will be centrifuged to separate plasma and 
plasma will be immediately split and transferred into separate pre-labeled tubes as primary and 
backup samples. Plasma samples will be stored frozen in an upright position until shipment to 
the bioanalytical lab for analysis. 
 
 
 
 
Exact dates and clock times of drug administrations and actual blood draws will be collected 
on the appropriate eCRF pages. The time of the meal prior to PK sampling, where post dose 
time points are collected for alpelisib on Day 8, should be recorded in the appropriate  eCRF 
page. On days of PK collection and on the day of previous administration the exact time of 
dosing, date sample taken and actual time of sampling must be entered on the eCRF. 
To ensure compliance with sampling procedures on the days of PK collection, participants will 
take their alpelisib/placebo doses at the clinic under the supervision of the investigator or his/her 
designee. Participants who forget to postpone their dose until they arrive at the site on pre-dose 
sampling days, instead take their medication at home will not participate in PK analysis for that 
day; they should not have blood samples collected. PK assessment for these participants should 
be postponed to the next day if possible. Dosing information before alpelisib/placebo PK 
sampling may be recorded, if feasible, at every PK visit for PK analysis. Any sampling problems 
must be noted on the eCRF and on appropriate source documentation. 
If vomiting occurs within 4 hrs following study-drug administration of alpelisib/placebo on 
Cycle 1 Day 8, where post-dose time points are collected, the time (using the 24 hrs clock) of 
vomiting should be recorded in a separate section of the eCRF and on the transmittal forms, 
which accompany the sample. No additional study medication should be taken in an effort to 
replace the material that has been vomited.  
If the participant experiences an AE related to one or both drugs that fits the criteria of a SAE, 
or discontinues one or both drugs due to related toxicities, an unscheduled PK blood sample 
must be obtained whenever possible and as soon as possible after the last dose of alpelisib 
(preferably within 2 weeks after the last dose). 
Following implementation of protocol Amendment 02, PK samples collection will stop.  

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Table 8-12 
Pharmacokinetic blood collection log- alpelisib/placebo - Part B2 
Not applicable following protocol amendment 02. 
Cycle 
Day 
Scheduled 
Time Point 
Alpelisib/Placebo 
Dose Ref. ID§ 
PK Sample 
No 
Blood 
Volume 
(mL) 
1 
8 
Pre-dose* 
301 
3011 
301 
2 
1 
8 
1 h post dose ± 
10 min 
301 
- 
302 
2 

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Cycle 
Day 
Scheduled 
Time Point 
Alpelisib/Placebo 
Dose Ref. ID§ 
PK Sample 
No 
Blood 
Volume 
(mL) 
1 
8 
3 h post dose + 
30 min** 
301 
- 
303 
2 
1 
15 
Pre-dose* 
302 
3021 
304 
2 
2 
1 
Pre-dose* 
303 
3031 
305 
2 
4 
1 
Pre-dose* 
304 
3041 
306 
2 
6 
1 
Pre-dose* 
305 
3051 
307 
2 
Anytime 
Unscheduled 
  
3001+ 
2 
* Take sample prior to study treatment dose; at days of PK evaluation oral treatment doses should be taken at 
the clinical site 
** Sample should be collected within 30 min after recommended scheduled timepoint of 3 hours, not before 
+ Refer to Lab manual for naming conventions 
§ Four digit dose reference ID for pre-dose samples ending on 1 refers to the dose taken before the PK sample 
(last dose information) 

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8.5.2.2 
Analytical method 
Plasma concentrations of alpelisib and paclitaxel will be measured by a designated CRO using 
validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) assays. The lower 
limits of quantitation (LLOQ) are currently 5.0 ng/mL for both alpelisib and paclitaxel. Values 
below the assay LLOQ will be reported as 0 ng/mL. All concentrations below the LLOQ or 
missing data will be labeled as such in the concentration data listings. 

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9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation from study treatment 
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason and can be initiated by either the participant or the investigator. Nab-
paclitaxel and alpelisib may be discontinued independently of each other for 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 6.5.1 
• Progressive disease per RECIST 1.1 as per investigator's assessment (see Section 8.3) 
• 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 
• Study terminated by sponsor 
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. 
Participants who discontinue from study treatment should return for the end of treatment and 
follow-up visits indicated in the Assessment Schedule (refer to Section 8). 
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. 
After discontinuation from study treatment for reasons other than documented progressive 
disease per RECIST v1.1, death, lost to follow-up, or withdrawal of consent/ opposition to use 
data/biological samples, at a minimum, in abbreviated visits, the following data should be 
collected at clinic visits or via telephone/email contact: 
• New antineoplastic therapy, if applicable 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 

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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 participants who discontinue treatment for reasons other than documented disease 
progression, death, lost to follow-up, or withdrawal of consent/ opposition to use data/biological 
samples, tumor assessments must continue to be performed every 8 weeks during the first 18 
months and every 12 weeks thereafter until documented disease progression (per investigator), 
death, lost to follow-up, or withdrawal of consent/opposition to use data/biological samples, 
irrespective of initiation of new antineoplastic therapy.  
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 and exercise of participants’ data 
privacy rights 
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 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 his/her consent/ 
exercise data privacy rights and record this information. The Investigator shall clearly 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. 

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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 
Section 8). 
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 or fail to 
respond to any site attempts to contact them without stating an intention to discontinue from 
study treatment or discontinue from study or withdraw consent (or exercise other participants’ 
data privacy rights), 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), for regulatory or medical reasons or decision based on recommendations from 
applicable board(s) after review of safety and efficacy data. 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 sponsor depending on the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial. 
9.2 
Study completion and post-study treatment 
Study completion is defined as when the last participant, regardless of Study Part, finishes their 
last study visit (safety and efficacy follow-up periods (as applicable)) and any repeat 
assessments associated with these visits 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. 
At the end of the study, every effort will be made to continue provision of alpelisib outside this 
study through an alternative setting to participants who in the opinion of the Investigator are 
still deriving clinical benefit. 

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Parts A and B2 
The primary analysis for Parts A and B2 will occur when all participants have completed 6 
months of study treatment or have been discontinued from study treatment, whichever occurs 
earlier (refer to Section 12.4). At this time, the primary clinical study report (CSR) will be 
produced. After the primary analysis, the study will remain open for participants who benefit 
from study treatment, as assessed by the investigator, until a PTA mechanism is available. 
Participants still being followed on the study after the primary analysis timepoint will continue 
as per the schedule of assessments. 
Conduct of Parts A and B2 will end once the final analysis of study data is conducted. All 
available data from all participants up to this cutoff date will be analyzed. 
There is no analysis for Part B2 since it was never intiated. 
Part B1 
The primary analysis of part B1 occured when all enrolled participants have completed 6 
months of study treatment or have been discontinued from study treatment, whichever occurs 
earlier. Six-month ORR and safety data guided the decision to not initiate Part B2. Participants 
still being treated/followed on the study after the primary analysis time point will continue as 
per the schedule of assessments. 
9.2.1 
Follow-up for safety evaluations 
All participants who discontinue study treatment, including those who refuse to return for an 
EOT visit, will be contacted for safety evaluations (i.e., assessment of adverse events and/or 
Serious Adverse Events, concomitant medications) 30 days after last administration of study 
treatment. The information collected is kept as source documentation. All SAEs reported during 
this time period must be reported as described in Section 10.1.3. Participant whose treatment is 
interrupted or permanently discontinued due to an adverse event, including abnormal laboratory 
value, must be followed until resolution or stabilization of the event, whichever comes first. 
If participants refuse to return for safety evaluation visits or are unable to do so, every effort 
should be made to contact them by telephone to determine their status. Attempts to contact the 
participant should be documented in the source documents (e.g., dates of telephone calls, 
registered letters, etc.). 
9.2.2 
Follow-up for efficacy evaluations 
Participants who discontinue study treatment for reasons other than disease progression as per 
RECIST 1.1, death, lost to follow-up or withdrawal of consent/opposition to use data/biological 
samples, should continue tumor assessment until disease progression as per RECIST 1.1, death, 
lost to follow-up or withdrawal of consent/opposition to use data/biological samples at the same 
intervals as per Table 8-4. 
In Parts A and B2, PRO assessments will also be conducted following the same frequency. 
Tumor assessments and collection of PRO data in the efficacy follow-up will stop after all 
participants have completed 6 months of study treatment or have been discontinued from study 
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Part B2 was never initiated. 
9.2.3 
Follow-up after disease progression 
Participants enrolled in Parts A and B2 will return to the site 8 weeks after documentation of 
disease progression to perform the PRO assessments (Table 8-9). 
The collection of PRO data will stop after all participants have completed 6 months of study 
treatment or have been discontinued from the study treatment. 
Part B2 was never initiated. 
9.2.4 
Survival follow-up  
Participants will enter the survival follow-up period once they complete the safety follow-up 
period and efficacy follow-up period after treatment discontinuation (whichever is longer). 
Participants will then be contacted by telephone every 12 weeks to follow-up on their survival 
status. Any new antineoplastic therapies that have been started since study treatment 
discontinuation and date of progression on subsequent therapies will also be collected during 
these phone calls. 
Additional survival assessments may be performed outside the 12 weeks follow-up schedules 
if a survival update is required for an interim assessment to meet safety or regulatory needs. 
Survival information will be documented in the source documents and relevant eCRFs. 
The collection of survival data and new antineoplastic therapies will stop after all participants 
have completed 6 months of study treatment or have been discontinued from the study 
treatment. 
10 
Safety monitoring, reporting and committees 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
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 trial related medical 
questions or problems. 
For patients who sign the molecular pre-screening ICF, AEs which occur after signature of this 
consent will only be captured if they meet the definition of serious as outlined in Section 10.1.2 
and Section 10.1.3 and are reported to be causally related with study procedures (e.g. an 

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invasive procedure such as biopsy). Once the main study ICF is signed, 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 (as far as possible) (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 4.03 including Grade 5 (AEs leading to deaths).  
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 trial 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 cohorts, not on a 
single participant 
3. Its duration (start and end dates or ongoing, and the outcome 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 
• Drug interrupted/withdrawn 
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. 
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 
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made at each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the interventions required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors), should not be reported as a 
serious adverse event, except if the investigator considers that progression of malignancy is 
related to study treatment. 
Adverse events separate from the progression of malignancy (i.e. deep vein thrombosis at the 
time of progression or hemoptysis concurrent with finding of disease 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 
A 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:  
• 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 
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• 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). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
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 if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE (with the exception of progression of malignancy as 
described in Section 10.1.1) , regardless of causality, occurring after the participant has 
provided main study 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 
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 eSAE with 
paper backup Serious Adverse Event Report Form; all applicable sections of the form must be 
completed in order to provide a clinically thorough report. 
For participants who sign the molecular pre-screening ICF, SAE collection will start upon 
signing the molecular pre-screening ICF. SAEs will only be reported if the event is suspected 
to be causally related to a study procedure as assessed by the investigator (e.g. an invasive 
procedure such as biopsy). If the main ICF is not signed, SAE collection ends 30 days after the 
last study related procedure. 
For participants who sign the main study ICF, SAE collection starts at time of main study 
informed consent whether the participant is a screen failure or not.  
SAEs will be followed until resolution or until clinically relevant improvement or stabilization.   
For screen failure participants, SAEs will be collected until the time the participant is deemed 
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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 24 hours of the 
investigator receiving the follow-up information. (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An 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, a Chief Medical Office and 
Patient Safety (CMO&PS) Department associate may urgently require further information from 
the investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 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 (if submitted under EU CTR) or EU Guidance 2011/C 172/01 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. 
10.1.4 
Pregnancy reporting 
Pregnancies 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study treatment and until time period for post 
treatment contraception determined in Section 5.2.  
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
Any post study pregnancy-related SAE considered reasonably related to the study treatment by 
the Investigator will be reported to Novartis. While the Investigator is not obligated to actively 
seek this information in former study participants/pregnant female partner, he/she may learn of 
an SAE through spontaneous reporting. 
If a female trial 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 

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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 the Novartis CMO&PS. 
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. 
If a female partner of a male trial participant who took study treatment in this study becomes 
pregnant, pregnancy outcomes 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 (European Medicines Agency (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 eCRF irrespective of whether or not associated with an AE/SAE Study treatment 
errors and uses outside of what is foreseen in the protocol, 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 
Section 10.1.1, Section 10.1.2 and Section 10.1.3. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
• To ensure participant safety and enhance reliability in determining the hepatotoxic 
potential of an investigational drug, a standardized process for identification, monitoring 
and evaluation of liver events has to be followed. 
Please refer to Table 16-10 in Section 16.3 for complete definitions of liver laboratory triggers 
and liver events. 
Once a participant is exposed to study treatment, every liver event defined in Table 16-10 
should be followed up by the investigator or designated personnel at the trial site, as summarized 
below. Repeat liver chemistry tests (i.e. ALT, AST, Total bilirubin (TBL), PT/INR, ALP and 
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•  These liver chemistry repeats will be performed using the central laboratory. If results 
will not be available from the central laboratory, then the repeats can also be performed at 
a local laboratory to monitor the safety of the participant. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded on the appropriate eCRF. 
• If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the investigational drug (refer to Section 9.1.1), if appropriate 
• Hospitalization of the participant if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include  
• These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease 
All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF. 
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 trial, 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 trial, safety 
data, and critical efficacy variables and recommend to the sponsor whether to continue, modify, 
or terminate a trial. 
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 the sponsor and the DMC. 
10.2.3 
Steering Committee 
The Steering Committee (SC) will be established comprising investigators participating in the 
trial, i.e. not being members of the DMC, a patient advocate and Novartis/sponsor 
representatives from the Clinical Trial 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 trial 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. 

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11 
Data Collection and Database management 
11.1 
Data collection 
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. 
Data not requiring a separate written record will be defined in the protocol and Assessment 
Schedule (Table 8-2 and Table 8-3) and can be recorded directly on the CRFs. All other data 
captured for this study will have an external originating source (either written or electronic) 
with the CRF not being considered as source. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. Data collected by third parties (such as IRT, imaging, safety 
lab, 
 PK and PROs) will be sent electronically to Novartis.  
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, pharmacokinetic (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). 
PRO data collected using an electronic tablet device will be documented into a separate study-
specific database supplied and managed by a designated vendor. All PRO data will be sent 
electronically to Novartis personnel (or a designated CRO). 
Dates of pre-screening, screening, randomization, screen failure and study discontinuation as 
well as randomization codes and data about all study treatment (s) dispensed to the participant 

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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 shut down or upon request of 
Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate (at the time of Part A primary analysis), it will be locked and the 
treatment codes will be unblinded and made available for data analysis. 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. eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of participant records, the accuracy of data capture / data 
entry, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis CRA organization. Additionally, a central analytics organization may analyze data & 
identify risks & trends for site operational parameters, and provide reports to Novartis clinical 
teams to assist with trial oversight. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
participant’s file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
It is planned that the data from all centers participating in the study will be combined, so that 
an adequate number of participants are available for analysis. Novartis and/or a designated CRO 
will perform all analyses. 

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Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
Part A 
The primary descriptive efficacy and safety analyses for Part A will be performed when all 
participants have completed 6 months of study treatment or have been discontinued from study 
treatment. Any additional data for participants continuing to receive study treatment past this 
time and for participants continuing for efficacy follow-up (PFS, OS), as allowed by the 
protocol, will be further summarized in the final study closeout report. 
Part B1 
The primary efficacy and safety analyses for Part B1 will be performed after all enrolled 
participants have completed 6 months treatment or have been discontinued from study treatment 
whichever occurs earlier. Any additional data for participants continuing to receive study 
treatment past this time and for patients continuing for efficacy follow-up (PFS, OS), as allowed 
by the protocol, will be further summarized in the final study report for Part B2 or in the CSR 
for Part A if Part B2 will not be initiated. 
Part B2 
The primary efficacy and safety analyses for Part B2 will be performed after observing 
approximately 192 PFS events per local assessment, should Part B2 reach the final PFS analysis. 
Any additional data for participants continuing to receive study treatment past this time and for 
participants continuing for efficacy follow-up (PFS, OS), as allowed by the protocol, will be 
further summarized in a study report at the time of the final OS analysis after observing 
approximately 197 OS events, or when statistical significance is reached at any interim OS 
analysis. 
Part B2 was never initiated. 
12.1 
Analysis sets 
Parts A and  B2 
The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned by randomization. According to the intent to treat principle, participants will be 
analyzed according to the treatment and strata they have been assigned to during the 
randomization procedure. The FAS will be the primary population for all efficacy analyses. 
The Safety Set includes all participants who received at least one dose of any study treatment 
(i.e. at least one dose of any component of alpelisib/placebo, nab-paclitaxel). Participants will 
be analyzed according to the study treatment received, where treatment received is defined as 
the randomized/assigned treatment if the participant took at least one dose of that treatment or 
the first treatment received if the randomized treatment was never received. 
The Pharmacokinetic Analysis Set (PAS) consists of all participants who received at least one 
dose of study medication defined as alpelisib/placebo or nab-paclitaxel and provide at least one 
evaluable PK concentration. 

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Part B2 was never initiated. 
Part B1 
The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned and who received at least one dose of study treatment. Participants will be analyzed 
according to the treatment they have been assigned to. 
The Safety Set includes all participants who received at least one dose of any study 
treatment (i.e. at least one dose of any component of alpelisib or nab-paclitaxel). Participants 
will be analyzed according to the study treatment received, where treatment received is defined 
as the assigned treatment if the participant took at least one dose of that treatment or the first 
treatment received if the assigned treatment was never received. 
 
 
 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the FAS and Safety Set (if the latter differs 
from the FAS) for each Study Part. 
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 treatment group for for each Study Part. 
12.3 
Treatments 
For all Study parts: 
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, placebo, nab-paclitaxel 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 for each study part. 
The number of participants with dose adjustments (reduction, interruption, or permanent 
discontinuation) and the reasons will be summarized by treatment group, and all dosing data 
will be listed. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group. 

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12.4 
Analysis supporting objectives 
Part A:  
The primary objective of Part A is to assess PFS for treatment with alpelisib in combination 
with nab-paclitaxel compared to placebo in combination with nab-paclitaxel. 
Part B1:  
The primary objective of Part B1 is to assess the antitumor activity of alpelisib in combination 
with nab-paclitaxel. 
Part B2: 
The primary objective of Part B2 is to determine whether treatment with alpelisib in 
combination with nab-paclitaxel prolongs PFS compared to placebo in combination with nab-
paclitaxel. Part B2 was never initiated. 
12.4.1 
Definition of primary endpoint(s) 
Parts A and B2 
The primary endpoint (variable attribute of the primary estimand; refer to Section 2.1) is PFS, 
defined as the time from the date of randomization to the date of the first documented 
progression or death due to any cause. If a participant has not had an event, PFS will be censored 
at the date of the last adequate tumor assessment (see RECIST 1.1 in Section 16.1 for further 
details). Clinical deterioration without objective radiological evidence will not be considered as 
documented disease progression. PFS will be assessed via a local radiology assessment 
according 
to 
RECIST 
1.1. 
Censoring 
conventions 
(i.e. handling 
of 
missing 
values/censoring/discontinuations) are provided in Section 12.4.3.  
Part B2 was never initiated. 
Part B1 
The primary endpoint is ORR with confirmed response at 6 months, based on local radiology 
assessments in participants with measurable disease at baseline. ORR is defined as the 
proportion of participants with best overall response (BOR) of confirmed complete response 
(CR) or confirmed partial response (PR) according to RECIST 1.1. If no valid post-baseline 
tumor assessments are available, the best overall response must be “Unknown” unless 
progression is reported. Participants whose BOR is unknown or missing will be determined to 
be non-responders. Details on the handling of missing values/discontinuations are provided 
in Section 12.4.3.  
12.4.2 
Statistical model, hypothesis, and method of analysis 
Parts A 
The primary efficacy analysis is to compare and summarize PFS between two treatment groups 
descriptively. 

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The primary efficacy variable, PFS (variable attribute of the primary estimand; refer to 
Section 2.1) will be analyzed based on the FAS according to the randomized treatment group 
and strata assigned at randomization. The PFS distribution will be estimated using the Kaplan-
Meier method, and Kaplan-Meier curves, medians and 95% confidence intervals of the medians 
will be presented for each treatment group. The hazard ratio for PFS will be calculated, along 
with its 95% confidence interval, from a stratified Cox model using the randomization 
stratification factors, i.e. (i) line of therapy in advanced/metastatic setting (1st line versus 
2nd line), ii) hormone receptor status at initial breast cancer diagnosis (HR+ versus HR-), and 
iii) prior therapy with checkpoint inhibitors (Yes/No). Given no inferential analysis will be 
conducted, no p-value will be calculated. 
Part B1 
A response rate of 35% is considered a minimum clinically meaningful improvement in this 
study population based on data from first and second line mTNBC patients treated with either 
nab-paclitaxel or paclitaxel in the PAKT study (Schmid et al 2018), the LOTUS study 
(Kim et al 2017), the IMpassion130 study (Schmid et al 2018), as well as information provided 
in the Abraxane USPI (Nab-Paclitaxel FDA label 2015) the Abraxane EU label (Nab-Paclitaxel 
EU label 2018). Therefore, proof of preliminary efficacy of alpelisib in combination with nab-
paclitaxel will be declared if both of the following conditions are met: 
• the mean of the posterior distribution of ORR is at least 35% 
and 
• the posterior probability that the ORR is ≥ 25% is at least 0.9 
The posterior distribution of ORR will be derived from the prior distribution and all available 
data from the participants included in the FAS. A minimally informative unimodal Beta prior 
(Neuenschwander et al 2008) will be used for ORR (see Section 16.4 for further details). 
Additionally, ORR will be summarized by a two-sided exact binomial 95% confidence interval 
(Clopper and Pearson 1934). Waterfall graphs, which display the best percentage change from 
baseline in the sum of diameters of all target lesions for each participant with measurable 
disease at baseline, will be used to depict the anti-tumor activity of each treatment group. ORR 
as per blinded independent central review will be presented by treatment group, along with 95% 
confidence intervals.Part B2 (Not applicable as of protocol amendment 02): 
The primary efficacy analysis will be the comparison of PFS between the two treatment groups 
using a stratified log-rank test at an overall one-sided 2.5% level of significance for Parts A and 
B2 individually. The stratification will be based on the randomization stratification factors, 
i.e. (i) line of therapy in advanced/metastatic setting (1st line versus 2nd line), ii) hormone 
receptor status at initial breast cancer diagnosis (HR+ versus HR-), and iii) prior therapy with 
checkpoint inhibitors (Yes/No). 
Assuming proportional hazards model for PFS, the following statistical hypotheses will be 
tested to address the primary efficacy objective: 
H01: θ1 ≥ 0 vs. Ha1: θ1 < 0 
where θ1 is the log-hazard ratio (alpelisib + nab-paclitaxel arm vs. placebo + nab-paclitaxel) of 
PFS. 

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The primary efficacy variable, PFS (variable attribute of the primary estimand; refer to 
Section 2.1), will be analyzed at the interim analysis and final analysis of a group sequential 
design, using a Haybittle-Peto boundary. Analyses will be based on the FAS according to the 
randomized treatment group and strata assigned at randomization. The PFS distribution will be 
estimated using the Kaplan-Meier method, and Kaplan-Meier curves, medians and 95% 
confidence intervals of the medians will be presented for each treatment group. The hazard ratio 
for PFS will be calculated, along with its 95% confidence interval, from a stratified Cox model 
using the same stratification factors as for the log-rank test. 
Part B2 was never initiated. 
Part B1 
A response rate of 35% is considered a minimum clinically meaningful improvement in this 
study population based on data from first and second line mTNBC patients treated with either 
nab-paclitaxel or paclitaxel in the PAKT study (Schmid et al 2018), the LOTUS study 
(Kim et al 2017), the IMpassion130 study (Schmid et al 2018), as well as information provided 
in the Abraxane USPI (Nab-Paclitaxel FDA label 2015) the Abraxane EU label (Nab-Paclitaxel 
EU label 2018). Therefore, proof of preliminary efficacy of alpelisib in combination with nab-
paclitaxel will be declared if both of the following conditions are met: 
• the mean of the posterior distribution of ORR is at least 35% 
and 
• the posterior probability that the ORR is ≥ 25% is at least 0.9 
The posterior distribution of ORR will be derived from the prior distribution and all available 
data from the participants included in the FAS. A minimally informative unimodal Beta prior 
(Neuenschwander et al 2008) will be used for ORR (see Section 16.4 for further details). 
Additionally, ORR will be summarized by a two-sided exact binomial 95% confidence interval 
(Clopper and Pearson 1934). Waterfall graphs, which display the best percentage change from 
baseline in the sum of diameters of all target lesions for each participant with measurable 
disease at baseline, will be used to depict the anti-tumor activity of each treatment group. ORR 
as per blinded independent central review will be presented by treatment group, along with 95% 
confidence intervals. 
12.4.3 
Handling of intercurrent events of primary estimand 
Parts A & B2 
The primary estimand will account for intercurrent event as explained in the following: 
1. Discontinuation of study treatment: tumor assessment data collected after 
discontinuation of study treatment will be used for the primary analysis irrespective of the 
study treatment discontinuation reason (treatment policy strategy). 
Part B2 was never initiated. 

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Part B1 
The primary estimand analysis of this estimand will account for the first of the following two 
intercurrent events to occur: 
1. Discontinuation of study treatment: tumor assessment data collected within 30 days 
after discontinuation of study treatment will be used in the analysis. Tumor assessment 
data collected more than 30 days after discontinuation of study treatment will be excluded 
from the analysis (While on treatment strategy). 
2. Start of new anti-neoplastic therapy: tumor assessment data collected after the initiation 
of new anti-neoplastic therapy will be excluded from the analysis (While on treatment 
strategy). 
12.4.4 
Handling of missing values not related to intercurrent event 
In Parts A and B2 the primary analysis, PFS will be censored at the date of the last adequate 
tumor assessment if no PFS event is observed prior to the analysis cut-off date. 
PFS events documented after the initiation of new anti-neoplastic therapy (i.e. RECIST 1.1. 
documented disease progression or death) will be considered for the primary analysis provided 
tumor assessments continue after initiation of new cancer therapy. 
If a PFS event is observed after one or more missing or non-adequate tumor assessments, the 
actual date of event will be used (see RECIST 1.1 in Section 16.1). 
Part B2 was never initiated. 
12.4.5 
Supplementary analyses  
Supplementary analyses will be provided in the Statistical Analysis Plan. 
12.5 
Analysis supporting secondary objectives  
Parts A and B2 
The secondary objectives in Parts A and B2 are to compare the two treatment groups with 
respect to overall survival (OS), and to evaluate the overall response rate (ORR), clinical benefit 
rate (CBR), time to response (TTR), duration of response (DOR), and safety. 
OS was originally identified as the key secondary endpoint (variable attribute of the key 
secondary estimand) in each of Parts A and B2. With the recruitment halt and protocol 
amendment 02, OS was moved to be a secondary endpoint, rather than a key secondary 
endpoint; no formal testing for OS will be performed. Instead, similar descriptive summaries as 
for PFS will be provided. 
Part B2 was never initiated. 
Part B1 
The secondary objectives in Part B1 are to evaluate additional efficacy parameters with respect 
to PFS, overall survival (OS), and to evaluate clinical benefit rate (CBR), time to response 
(TTR), duration of response (DOR), and safety. 

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No statistical testing of secondary endpoints in Part B1 will be undertaken. 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
12.5.1.1 Key secondary estimand 
Not applicable after Amendment 02. 
12.5.1.2 Other secondary efficacy endpoints 
OS is defined as the time from date of randomization to date of death due to any cause. If a 
participant is not known to have died, then OS will be censored at the latest date the participant 
was known to be alive (on or before the cut-off date). 
OS will be analyzed in the FAS according to the treatment group and strata assigned at 
randomization (Parts A and B2) or at enrollment (Part B1). The OS distribution will be 
estimated using the Kaplan-Meier method, and the Kaplan-Meier curves, medians and 95% 
confidence intervals of the medians will be presented for each treatment group. The hazard ratio 
for OS will be calculated, along with its 95% confidence interval, using a stratified Cox model. 
 
Overall response rate (ORR) with confirmed response is defined as the proportion of 
participants with BOR of confirmed complete response (CR) or confirmed partial response 
(PR), as per local review and according to RECIST 1.1 (see Section 16.1 for details). 
ORR with confirmed response will be calculated based on the FAS and according to the Intent 
To Treat (ITT) principle. ORR and its 95% confidence interval will be presented by treatment 
group.  
As supplemental analyses in Parts A and B2, the following will also be calculated and presented 
by treatment group together with approximate 95% confidence intervals: 
• ORR with confirmed response per local review for participants with measurable disease at 
baseline, 
• ORR with unconfirmed responses per local review based on the FAS, 
• ORR with unconfirmed responses per local review for participants with measurable 
disease at baseline 
Clinical benefit rate (CBR) with confirmed response is defined as the proportion of participants 
with a best overall response of confirmed complete response (CR), or confirmed partial 
response (PR), or an overall response of stable disease (SD) lasting for a duration of at least 24 
weeks. CR, PR, and SD are defined as per local review according to RECIST 1.1 
(see Section 16.1 for details). 
CBR with confirmed response will be calculated based on the FAS and according to the ITT 
principle. CBR with confirmed response and its 95% confidence interval will be presented by 
treatment group. In Parts A and B2, as supplemental analyses, the following will also be 
calculated and presented by treatment group together with approximate 95% confidence 
intervals: 
• CBR with confirmed response per local review for participants with measurable disease at 
baseline, 

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• CBR with unconfirmed responses per local review based on the FAS, 
• CBR with unconfirmed responses per local review for participants with measurable 
disease at baseline. 
Time to response (TTR) is defined as the time from the date of randomization to the first 
documented response of either complete response (CR) or partial response (PR), which must 
be subsequently confirmed (although date of initial response is used, not date of confirmation). 
CR and PR are based on tumor response data as per local review and according to RECIST 1.1 
(see Section 16.1 for details). 
All participants in the FAS will be included in TTR calculations. participants without a 
confirmed CR or PR will be censored at the study-maximum follow-up time (i.e. Last Patient 
Last Visit (LPLV)-First Patient First Visit (FPFV)) for participants with a PFS event (i.e. 
disease progression or death due to any cause), or at the date of the last adequate tumor 
assessment for participants without a PFS event. TTR will be listed and summarized by 
treatment group. 
Duration of response (DOR) with confirmed response only applies to participants whose best 
overall response is confirmed complete response (CR) or confirmed partial response (PR) 
according to RECIST 1.1 based on tumor response data per local review. The start date is the 
date of first documented response of CR or PR (i.e. the start date of response, not the date when 
response was confirmed), and the end date is defined as the date of the first documented 
progression or death due to underlying cancer. Participants continuing without progression or 
death due to underlying cancer will be censored at the date of their last adequate tumor 
assessment. DOR will be listed and summarized by treatment group for all participants in the 
FAS with confirmed BOR of CR or PR. As a supplemental analysis, DOR with unconfirmed 
response based on the FAS will also be listed and summarized by treatment group. 
An analysis of PFS based on local radiology assessments and using RECIST 1.1 criteria for 
participants by PIK3CA mutation status as measured in ctDNA at baseline will be conducted 
using the same analytical conventions as the primary analysis. 
12.5.2 
Safety endpoints 
For all safety analyses, each Study Part will be summarized separately and the safety set will 
be used. All listings and tables will be presented by treatment group. 
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 addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period or starting 
in the screening period and worsening during the treatment period (treatment-emergent AEs). 
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 

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3. Post-treatment period: starting at day 31 after last dose of study medication. 
Adverse events 
All information obtained on adverse events will be displayed by treatment group  and 
participant. 
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of double-blind 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways: 
• by treatment, system organ class and preferred term. 
• by treatment, system organ class, preferred term and maximum severity. 
• by treatment, Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation, and adverse events 
leading to dose adjustment. 
A participant with multiple adverse events within a system organ class is only counted once 
towards the total of the system organ class. 
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 and post-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. 
Vital signs 
All vital signs data will be listed by treatment group, participant, and visit/time and if ranges 
are available, abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by treatment and visit/time. 
12-lead ECG 
1. PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each 
participant during the study. ECG data will be read and interpreted (locally). 
2. Categorical Analysis of QT/QTc interval data based on the number of participants meeting 
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baseline will be presented. In addition, a listing of these participants will be produced (by 
treatment group). 
All ECG data will be listed by treatment group, participant and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time. 
Cardiac Imaging 
Shift tables comparing baseline to end of treatment LVEF will be provided for each Study Part. 
part. 
If there is any change in the methodology used at EOT compared to baseline, the EOT values 
for which the methodology differs from baseline will be discarded. 
Clinical laboratory evaluations 
All laboratory data will be listed by treatment group, participant, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
treatment and visit/time. 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. 
 
 
 
 
 

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12.7 
Interim analyses 
Interim analyses are planned for the monitoring of safety data by DMC in all Study Parts, and 
will be performed approximately every 6 months during the course of the study.  
Part B1 
No interim efficacy analysis is planned for Part B1. The primary analysis has been performed 
after all participants had completed 6 months treatment or had discontinued treatment prior to 
6 months, whichever was earlier.   
Part A 
No interim efficacy analysis will be performed for Part A. After the halt of recruitment, the 
primary PFS analysis for Part A will be performed when all participants have completed 6 
months of study treatment or have discontinued from study treatment, whichever occurs earlier. 
Part B2 
Not applicable. Part B2 was not initiated based on the results from Part B1. 
12.8 
Sample size calculation  
Note the below subsections illustrate how the original sample size was considered. Based on 
the decision of recruitment halt, Part A will not wait for the required number of PFS/OS events 
to perform the originally planned inerim/final analysis, instead similar as Part B1, the primary 
analysis for Part A will be descriptive only and will be undertaken when all participants have 

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completed 6 months of study treatment or have been discontinued from study treatment, 
whichever occurs earlier.  
12.8.1 
Primary endpoint(s) 
The sample size calculation in Parts A and B2 is based on the primary variable of PFS. The 
hypotheses to be tested and details of the testing strategy are described in Section 12.4.2. 
The median PFS in the control arm (placebo + nab-paclitaxel) of this study is estimated to be 
approximately 5 months, based on data from first and second line mTNBC patients treated with 
either nab-paclitaxel or paclitaxel in the PAKT study (Schmid et al 2018), the LOTUS study 
(Kim et al 2017), and the Impassion130 study (Schmid et al 2018). 
It is expected that treatment with alpelisib plus nab-paclitaxel will result in a 40% reduction in 
the hazard rate for PFS, i.e. an expected hazard ratio of 0.6 (which corresponds to an increase 
in median PFS to 8.33 months under the exponential model assumption). 
Part A 
In order to ensure 90% power to test the null hypothesis: PFS hazard ratio = 1, versus the 
specific alternative hypothesis: PFS hazard ratio = 0.6, it is calculated that a total of 192 PFS 
events need to be observed. This calculation assumes analysis by a one-sided log-rank test at 
the overall 2.5% level of significance, participants randomized to the two treatment arms in a 
1:1 ratio, and a 3-look group sequential design with a gamma spending function to define a 
futility rule at the 1st interim analysis and a Haybittle-Peto alpha spending function, using 
information fractions of (0.40, 0.85, 1). 
Assuming that enrollment will continue for 29 months enrolling 3 participants/month up to 
month 6, 8 participants/month up to month 12 and 11 participants/month thereafter, assuming 
losses to follow-up for PFS of 10%, a total of 252 participants will need to be randomized to 
observe the targeted 192 PFS events at about 6 months after the randomization date of the last 
participant, i.e. 35 months after the randomization date of the first participant. 
Part B2 
In order to ensure 90% power to test the null hypothesis: PFS hazard ratio = 1, versus the 
specific alternative hypothesis: PFS hazard ratio = 0.6, it is calculated that a total of 192 PFS 
events need to be observed. This calculation assumes analysis by a one-sided log-rank test at 
the overall 2.5% level of significance, participants randomized to the two treatment arms in a 
1:1 ratio, and a 3-look group sequential design with a gamma spending function to define a 
futility rule at the 1st interim analysis and a Haybittle-Peto alpha spending function, using 
information fractions of (0.40, 0.75, 1). 
Assuming that enrollment will continue for 16.5 months enrolling 12 participants/month up to 
month 6 and 20 participants/month thereafter, assuming losses to follow-up for PFS of 10%, a 
total of 282 participants will need to be randomized to observe the targeted 192 PFS events at 
about 5.5 months after the randomization date of the last participant, i.e. 22 months after the 
randomization date of the first participant. 
These calculations were made using the software package East 6.4. 

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Part B2 was never initiated. 
Part B1 
The sample size calculation is based on the primary variable ORR considering the statistical 
model, hypothesis and method of analysis detailed in Section 12.4.2. Proof of preliminary 
efficacy (PPE) will be declared if both of the following conditions are met: 
• the mean of the posterior distribution of ORR is at least 35% 
and 
• the posterior probability that the ORR is ≥ 25% is at least 0.9 
Approximately 32 participants will be enrolled. With 32 participants, the probability of 
declaring proof of preliminary efficacy (PPE) is at most 8% when ORR ≤25%. The probability 
of declaring PPE is at least 80% for ORR ≥ 45% (Table 12-1). 
Table 12-1 
Part B1 PPE Operating characteristics 
True ORR 
Probability of declaring PPE 
(≥12 responders) 
Probability of missing PPE (≤11 
responders) 
25% 
0.079 
0.921 
30% 
0.228 
0.772 
35% 
0.448 
0.552 
40% 
0.675 
0.325 
45% 
0.847 
0.153 
12.8.2 
Secondary endpoint(s) 
Part A 
Per original design, OS, as the key secondary variable, will be formally statistically tested, 
provided that the primary variable of PFS is statistically significant. The hypotheses to be tested 
and details of the testing strategy are provided in Section 12.5.1. The median OS in the control 
arm (placebo + nab-paclitaxel) of this study is estimated to be approximately 12 months, based 
on data from first and second line mTNBC patients treated with either nab-paclitaxel or 
paclitaxel in the PAKT study (Schmid et al 2018), the LOTUS study (Kim et al 2017), and the 
IMpassion130 study (Schmid et al 2018). It is hypothesized that treatment with alpelisib plus 
nab-paclitaxel will result in a 33.3% reduction in the hazard rate for OS, i.e., an expected hazard 
ratio of 0.667 (which corresponds to an increase in median OS to 18 months under the 
exponential model assumption). Then in order to ensure 80% power to test the null hypothesis: 
OS hazard ratio = 1, versus the specific alternative hypothesis: OS hazard ratio = 0.667, it is 
calculated that a total of 198 deaths need to be observed. This calculation assumes analysis by 
a one-sided log-rank test at the overall 2.5% level of significance, participants randomized to 
the two treatment arms in a 1:1 ratio, and a 3-look group sequential design with a Lan-DeMets 
(O'Brien and Fleming 1979) alpha spending function using information fractions of (0.66 [if at 
final PFS analysis], 0.85, 1). 
Based on the same number of participants that are planned to be enrolled in this study to provide 
sufficient power for the primary endpoint (i.e. 252 participants), and assuming losses to follow-
up for OS of 10%, it is estimated that these 198 deaths will be observed approximately 66 

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months after the randomization date of the first participant. Therefore the cut-off date for the 
final analysis of OS will be approximately 31 months after the cut-off date for the final analysis 
of PFS. These calculations were made using the software package East 6.4. 
Part B2 
OS, as the key secondary variable, will be formally statistically tested, provided that the primary 
variable PFS is statistically significant. The hypotheses to be tested and details of the testing 
strategy are provided in Section 12.5.1. The median OS in the control arm (placebo + nab-
paclitaxel) of this study is estimated to be approximately 12 months, based on data from first 
and second line mTNBC patients treated with either nab-paclitaxel or paclitaxel in the PAKT 
study (Schmid et al 2018), the LOTUS study (Kim et al 2017), and the Impassion130 study 
(Schmid et al 2019). It is hypothesized that treatment with alpelisib plus nab-paclitaxel will 
result in a 33.3% reduction in the hazard rate for OS, i.e., an expected hazard ratio of 0.667 
(which corresponds to an increase in median OS to 18 months under the exponential model 
assumption). Then in order to ensure 80% power to test the null hypothesis: OS hazard ratio = 
1, versus the specific alternative hypothesis: OS hazard ratio = 0.667, it is calculated that a total 
of 197 deaths need to be observed. This calculation assumes analysis by a one-sided log-rank 
test at the overall 2.5% level of significance, participants randomized to the two treatment arms 
in a 1:1 ratio, and a 3-look group sequential design with a Lan-DeMets 
(O'Brien and Fleming 1979) alpha spending function using information fractions of (0.60 [if at 
final PFS analysis], 0.85, 1). 
Based on the same number of participants that are planned to be enrolled in this study to provide 
sufficient power for the primary endpoint (i.e. 282 participants), and assuming losses to follow-
up for OS of 10%, it is estimated that these 197 deaths will be observed approximately 41 
months after the randomization date of the first participant. Therefore the cut-off date for the 
final analysis of OS will be approximately 19 months after the cut-off date for the final analysis 
of PFS. These calculations were made using the software package East 6.4. 
Part B2 was never initiated. 
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 
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.  
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 

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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 
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.  
The Investigator will be also responsible for: 
• 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.  
• Informing Novartis immediately if an inspection of the clinical site is requested by a 
regulatory authority. 
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 EudraCT or CTIS public website. In addition, after study completion (defined as 
last participant last visit) and finalization of the study report the results of this trial will be 
submitted for publication and posted in a publicly accessible database of clinical trial results, 
such as the Novartis clinical trial results website and all required Health Authority websites 
(e.g. Clinicaltrials.gov, EudraCT or CTIS public website etc.). 
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 trial investigator 
meetings. 
Any data analysis carried out independently by the Investigator should be submitted to Novartis 
before publication or presentation. 

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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 trial. 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. 
Monitoring details describing strategy, including 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), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan, contracts. 
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. 
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 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 modifications to 
these requirements with Novartis. 
• Thank You letter – at study start 
• Plain language trial summary - after CSR publication 
• Individual study results - after CSR publication 

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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 
Aaronson NK, Ahmedzai S, Bergman B, et al (1993) The European Organization for 
Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in 
international clinical trials in oncology. J. Natl. Cancer Inst.; 365-76. 
Amit O, Mannino F, Stone AM, et al (2011) Blinded independent central review of 
progression in cancer clinical trials: results from a meta-analysis. Eur. J. Cancer; 47(12):1772-
8. 
André F, Ciruelos E, Rubovszky G, et al (2019) Alpelisib for PIK3CA-Mutated, Hormone 
Receptor-Positive Advanced Breast Cancer. N. Engl. J. Med.; 380(20):1929-40. 
Bajaj P, Latremouille-Viau D, Guerin A et al (2017) What are the treatment patterns and 
overall survival (OS) in patients with metastatic triple-negative breast cancer (mTNBC) in US 
clinical practice?; 78-108. 
Bareche Y, Venet D, Ignatiadis M, et al (2018) Unravelling triple-negative breast cancer 
molecular heterogeneity using an integrative multiomic analysis. Ann. Oncol.; 29(4):895-902. 
Bjordal K, de Graeff A, Fayers PM, et al (2000) A 12 country field study of the EORTC 
QLQ-C30 (version 3.0) and the head and neck cancer specific module (EORTC QLQ-
H&N35) in head and neck patients. EORTC Quality of Life Group. Eur. J. Cancer; 
36(14):1796-807. 
Board RE, Wardley AM, Dixon JM, et al (2010) Detection of PIK3CA mutations in 
circulating free DNA in patients with breast cancer. Breast Cancer Res. Treat.; 120(2):461-7. 
Brufsky A (2017) nab-Paclitaxel for the treatment of breast cancer: an update across treatment 
settings. Exp Hematol Oncol; 6:7. 
Burke JE, Perisic O, Masson GR, et al (2012) Oncogenic mutations mimic and enhance 
dynamic events in the natural activation of phosphoinositide 3-kinase p110α (PIK3CA). Proc. 
Natl. Acad. Sci. U.S.A.; 109(38):15259-64. 
Burstein MD, Tsimelzon A, Poage GM, et al (2015) Comprehensive genomic analysis 
identifies novel subtypes and targets of triple-negative breast cancer. Clin. Cancer Res.; 1688-
98. 
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.; 30(23):2919-
28. 
Campbell RA, Bhat-Nakshatri P, Patel NM, et al (2001) Phosphatidylinositol 3-kinase/AKT-
mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J. 
Biol. Chem.; 276(13):9817-24. 
Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast 
tumours. Nature; 490(7418):61-70 

Novartis 
Confidential 
Page 176 of 213 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CBYL719H12301 
 
Cardoso F, Costa A, Senkus E, et al (2017) 3rd ESO–ESMO International Consensus 
Guidelines for Advanced Breast Cancer (ABC 3); 16–33. 
Cardoso F, Senkus E, Costa A, et al (2018) 4th ESO-ESMO International Consensus 
Guidelines for Advanced Breast Cancer (ABC 4)†. Ann. Oncol.; 29(8):1634-57. 
Chan TO, Rodeck U, Chan AM, et al (2002) Small GTPases and tyrosine kinases coregulate a 
molecular switch in the phosphoinositide 3-kinase regulatory subunit. Cancer Cell; 1(2):181-
91. 
Chen L, Yang L, Yao L, et al (2018) Characterization of PIK3CA and PIK3R1 somatic 
mutations in Chinese breast cancer patients. Nat Commun; 9(1):1357. 
Clark AS, West K, Streicher S, et al (2002) Constitutive and inducible Akt activity promotes 
resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol. Cancer 
Ther.; 1(9):707-17. 
Cleeland CS (2009) The Brief Pain Inventory. User Guide. 
Cleeland CS, Ryan KM (1994) Pain assessment: global use of the Brief Pain Inventory. Ann. 
Acad. Med. Singap.; 23(2)129-38. 
Clopper CJ, Pearson ES (1934) The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial; 404-13. 
Cossu-Rocca P, Orrù S, Muroni MR, et al (2015) Analysis of PIK3CA Mutations and 
Activation Pathways in Triple Negative Breast Cancer. PLoS ONE; 10(11):e0141763. 
Curtis C, Shah SP, Chin SF, et al (2012) The genomic and transcriptomic architecture of 
2,000 breast tumours reveals novel subgroups. Nature; 486(7403):346-52. 
D. Juric, H. Burris, Baselga J (2014) Phase I study of the PI3Kα inhibitor BYL719, as a single 
agent in patients with advanced solid tumors (aST). 
De Mattos-Arruda L, Weigelt B, Cortes J, et al (2014) Capturing intra-tumor genetic 
heterogeneity by de novo mutation profiling of circulating cell-free tumor DNA: a proof-of-
principle. Ann. Oncol.; 25(9):1729-35. 
Denkert C, Liedtke C, Tutt A, et al (2017) Molecular alterations in triple-negative breast 
cancer-the road to new treatment strategies. Lancet; 2430-42. 
Dent S, Zee B, Dancey J, et al (2001) Application of a new multinomial phase II stopping rule 
using response and early progression. J. Clin. Oncol.; 19(3):785-91. 
Dodd LE, Korn EL, Freidlin B, et al (2011) An audit strategy for progression-free survival. 
Biometrics; 67(3):1092-9. 
Duffaud F, Therasse P (2000) [New guidelines to evaluate the response to treatment in solid 
tumors]. Bull Cancer; 87(12):881-6. 
Eisenhauer EA, Therasse P, Bogaerts J, et al (2009) New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer; 45(2):228-47. 

Novartis 
Confidential 
Page 177 of 213 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CBYL719H12301 
 
Ellis MJ, Tao Y, Luo J, et al (2008) Outcome prediction for estrogen receptor-positive breast 
cancer based on postneoadjuvant endocrine therapy tumor characteristics. J. Natl. Cancer 
Inst.; 100(19):1380-8. 
Emens LA, Middleton G (2015) The interplay of immunotherapy and chemotherapy: 
harnessing potential synergies. Cancer Immunol Res; 3(5):436-43. 
Fayers PM (2001) Interpreting quality of life data: population-based reference data for the 
EORTC QLQ-C30. Eur. J. Cancer; 37(11):1331-4. 
Fietz T, Tesch H, Rauh J, et al (2017) Palliative systemic therapy and overall survival of 
1,395 patients with advanced breast cancer - Results from the prospective German TMK 
cohort study. Breast; 34:122-30. 
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.; 1117-29. 
Gerratana L, Basile D, Buono G, et al (2018) Androgen receptor in triple negative breast 
cancer: A potential target for the targetless subtype. Cancer Treat. Rev.; 68:102-10. 
Glimm E, Maurer W, Bretz F (2010) Hierarchical testing of multiple endpoints in group-
sequential trials. Stat Med; 29(2):219-28. 
Goetz MP, Gradishar WJ, Anderson BO, et al (2019) NCCN Guidelines Insights: Breast 
Cancer, Version 3.2018. J Natl Compr Canc Netw; 17(2):118-26. 
Gonzalez-Angulo AM, Ferrer-Lozano J, Stemke-Hale K, et al (2011) PI3K pathway 
mutations and PTEN levels in primary and metastatic breast cancer. Mol. Cancer Ther.; 
10(6):1093-101. 
Gradishar WJ, Anderson BO, Balassanian R, et al (2017) NCCN Guidelines Insights: Breast 
Cancer, Version 1.2017. J Natl Compr Canc Netw; 15(4):433-51. 
Gradishar WJ, Krasnojon D, Cheporov S, et al (2009) Significantly longer progression-free 
survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic 
breast cancer. J. Clin. Oncol.; 27(22):3611-9. 
Gradishar WJ, Tjulandin S, Davidson N, et al (2005) Phase III trial of nanoparticle albumin-
bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with 
breast cancer. J. Clin. Oncol.; 23(31):7794-803. 
Hammond ME, Hayes DF, Dowsett M, et al (2010) American Society of Clinical 
Oncology/College of American Pathologists guideline recommendations for 
immunohistochemical testing of estrogen and progesterone receptors in breast cancer 
(unabridged version). Arch. Pathol. Lab. Med.; 134(7):e48-72. 
Haybittle JL (1971) Repeated assessment of results in clinical trials of cancer treatment. Br J 
Radiol; 44(526):793-7. 
Higgins MJ, Jelovac D, Barnathan E, et al (2012) Detection of tumor PIK3CA status in 
metastatic breast cancer using peripheral blood. Clin. Cancer Res.; 18(12):3462-9. 

Novartis 
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Page 178 of 213 
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Protocol No. CBYL719H12301 
 
Hu L, Hofmann J, Lu Y, et al (2002) Inhibition of phosphatidylinositol 3'-kinase increases 
efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Cancer Res.; 62(4):1087-
92. 
Jabbour S, Ziring B (2011) Advantages of extended-release metformin in patients with type 2 
diabetes mellitus. Postgraduate medicine; 123(1):15–23. 
Jiang YZ, Ma D, Suo C, et al (2019) Genomic and Transcriptomic Landscape of Triple-
Negative Breast Cancers: Subtypes and Treatment Strategies. Cancer Cell; 35(3):428-40.e5. 
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):1291-99. 
Kaplanov I, Carmi Y, Kornetsky R, et al (2019) Blocking IL-1β reverses the 
immunosuppression in mouse breast cancer and synergizes with anti-PD-1 for tumor 
abrogation. Proc. Natl. Acad. Sci. U.S.A.; 116(4):1361-69. 
Kassam F, Enright K, Dent R, et al (2009) Survival outcomes for patients with metastatic 
triple-negative breast cancer: implications for clinical practice and trial design. Clin. Breast 
Cancer; 9(1):29-33. 
Kernan WN, Viscoli CM, Makuch RW, et al (1999) Stratified randomization for clinical 
trials. J Clin Epidemiol; 52(1):19-26. 
Kim SB, Dent R, Im SA, et al (2017) Ipatasertib plus paclitaxel versus placebo plus paclitaxel 
as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, 
randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol.; 18(10):1360-72. 
Kohler BA, Sherman RL, Howlader N, et al (2015) Annual Report to the Nation on the Status 
of Cancer, 1975-2011, Featuring Incidence of Breast Cancer Subtypes by Race/Ethnicity, 
Poverty, and State. J. Natl. Cancer Inst.; 107(6):djv048. 
Kok M et al (2017) Adaptive phase II randomized non-comparative trial of nivolumab after 
induction treatment in triple negative breast cancer: TONIC-trial; Presented at ESMO 2017 . 
Lan KKG, DeMets DL (1983) Discrete sequential boundaries for clinical trials; 659–63. 
Lebert JM, Lester R, Powell E, et al (2018) Advances in the systemic treatment of triple-
negative breast cancer. Curr Oncol; 25(1 Suppl):142S-150S. 
Lee CF, Luo N, Ng R, et al (2013) Comparison of the measurement properties between a 
short and generic instrument, the 5-level EuroQoL Group's 5-dimension (EQ-5D-5L) 
questionnaire, and a longer and disease-specific instrument, the Functional Assessment of 
Cancer Therapy-Breast (FACT-B), in Asian breast cancer patients. Qual Life Res; 
22(7):1745-51. 
Lehmann BD, Bauer JA, Chen X, et al (2011) Identification of human triple-negative breast 
cancer subtypes and preclinical models for selection of targeted therapies. J. Clin. Invest.; 
121(7):2750-67. 
Liedtke C, Mazouni C, Hess KR, et al (2008) Response to neoadjuvant therapy and long-term 
survival in patients with triple-negative breast cancer. J. Clin. Oncol.; 26(8):1275-81. 

Novartis 
Confidential 
Page 179 of 213 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CBYL719H12301 
 
Lin NU, Vanderplas A, Hughes ME, et al (2012) Clinicopathologic features, patterns of 
recurrence, and survival among women with triple-negative breast cancer in the National 
Comprehensive Cancer Network. Cancer; 118(22):5463-72. 
Litton JK, Rugo HS, Ettl J, et al (2018) Talazoparib in Patients with Advanced Breast Cancer 
and a Germline BRCA Mutation. N. Engl. J. Med.; 379(8):753-63. 
Liu P, Cheng H, Roberts TM, et al (2009) Targeting the phosphoinositide 3-kinase pathway in 
cancer. Nat Rev Drug Discov; 8(8):627-44. 
Lu Y-S, Chiu J, Airoldi M, et al (2020) Sodium-glucose cotransporter-2 (SGLT-2) inhibitors 
for alpelisib (ALP)-induced hyperglycemia: A report of 6 cases from SOLAR-1 [abstract]. 
Ann Oncol; 31(S4):S363. 
Marra A, Viale G, Curigliano G (2019) Recent advances in triple negative breast cancer: the 
immunotherapy era. BMC Med; 17(1):90. 
Martín M (2015) nab-Paclitaxel dose and schedule in breast cancer. Breast Cancer Res.; 
17:81. 
Massihnia D, Galvano A, Fanale D, et al (2016) Triple negative breast cancer: shedding light 
onto the role of pi3k/akt/mtor pathway. Oncotarget; 7(37):60712-22. 
McCubrey JA, Steelman LS, Abrams SL, et al (2006) Roles of the RAF/MEK/ERK and 
PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv. Enzyme 
Regul.; 46:249-79. 
Miles D, Kim SB, McNally VA et al (2016) A multistage, phase 2 study evaluating the safety 
and efficacy of cobimetinib (C) in combination with paclitaxel (P) as first-line treatment for 
patients with metastatic triple-negative breast cancer (TNBC). 
Millis SZ, Gatalica Z, Winkler J, et al (2015) Predictive Biomarker Profiling of > 6000 Breast 
Cancer Patients Shows Heterogeneity in TNBC, With Treatment Implications. Clin. Breast 
Cancer; 15(6):473-81.e3. 
Mills JN, Rutkovsky AC, Giordano A (2018) Mechanisms of resistance in estrogen receptor 
positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors. Curr Opin 
Pharmacol; 41:59-65. 
Morgan PH, Lutz MW, Kenakin TP (1988) KRAX is important operational determinant of 
tissue response. KRAX as parameter for classification. Trends Pharmacol. Sci.; 9(10):351. 
Mosele FF, Lusque A, André F (2019) Outcome and mutational landscape of patients with 
PIK3CA-mutated metastatic breast cancer (mBC); iii47-iii64. 
Moynahan ME, Sung P, Asham M (2015) Monitoring PIK3CA mutant allele fraction (AF) in 
cell-free DNA (cfDNA) in metastatic breast cancer (MBC) patients treated with PI3Kα–
inhibitor plus letrozole (L) or exemestane (E); 517. 
Murray S, Briasoulis E, Linardou H, et al (2012) Taxane resistance in breast cancer: 
mechanisms, predictive biomarkers and circumvention strategies. Cancer Treat. Rev.; 
38(7):890-903. 

Novartis 
Confidential 
Page 180 of 213 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CBYL719H12301 
 
Mustacchi G, De Laurentiis M (2015) The role of taxanes in triple-negative breast cancer: 
literature review. Drug Des Devel Ther; 9:4303-18. 
NCCN (2017) NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 
4.2017. 
NCCN (2019) Clinical Practice Guidelines in Oncology: Breast Cancer. 
Nanda R, Chow LQ, Dees EC, et al (2016) Pembrolizumab in Patients With Advanced Triple-
Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J. Clin. Oncol.; 34(21):2460-7. 
Neuenschwander B, Branson M, Gsponer T (2008) Critical aspects of the Bayesian approach 
to phase I cancer trials. Stat Med; 27(13):2420-39. 
O'Brien PC, Fleming TR (1979) A multiple testing procedure for clinical trials. Biometrics; 
35(3):549-56. 
O'Dea AP, Sharma P (2017) Management of Metastatic Triple-Negative Breast Cancer. In: 
Tan AR, (eds). Triple-Negative Breast Cancer- A Clinician’s Guide. Charlotte: Springer 
Nature, p. 95-116. 
O'Reilly EA, Gubbins L, Sharma S, et al (2015) The fate of chemoresistance in triple negative 
breast cancer (TNBC). BBA Clin; 3:257-75. 
Park JH, Ahn JH, Kim SB (2018) How shall we treat early triple-negative breast cancer 
(TNBC): from the current standard to upcoming immuno-molecular strategies. ESMO Open; 
3(Suppl 1):e000357. 
Pascual J, Turner NC (2019) Targeting the PI3-kinase pathway in triple negative breast 
cancer. Ann. Oncol. 
Patel AB., Seminario-Vidal, L (2020). Incidence, Characteristics, and Management of 
Alpelisib-Associated Rash in Patients With Advanced Breast Cancer. Fall Clinical 
Dermatology Conferene. 29-Oct-2020 – 01-Nov-2020, Las Vegas (NV)Peto R, Pike MC, 
Armitage P, et al (1976) Design and analysis of randomized clinical trials requiring prolonged 
observation of each patient. I. Introduction and design. Br. J. Cancer; 34(6):585-612. 
Rabin R, de Charro F (2001) EQ-5D: a measure of health status from the EuroQol Group. 
Ann. Med.; 33(5):337-43. 
Robson M, Im SA, Senkus E, et al (2017) Olaparib for Metastatic Breast Cancer in Patients 
with a Germline BRCA Mutation. N. Engl. J. Med.; 377(6):523-33. 
Robson ME, Tung N, Conte P, et al (2019) OlympiAD final overall survival and tolerability 
results: Olaparib versus chemotherapy treatment of physician's choice in patients with a 
germline BRCA mutation and HER2-negative metastatic breast cancer. Ann. Oncol.; 
30(4):558-66. 
Rodon J, Curigliano G, Delord JP, et al (2018) A Phase Ib, open-label, dose-finding study of 
alpelisib in combination with paclitaxel in patients with advanced solid tumors. Oncotarget; 
9(60):31709-18. 

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Rodon J, Dienstmann R, Serra V, et al (2013) Development of PI3K inhibitors: lessons 
learned from early clinical trials. Nat Rev Clin Oncol; 10(3):143-53. 
Rugo HS, Barry WT, Moreno-Aspitia A, et al (2015) Randomized Phase III Trial of 
Paclitaxel Once Per Week Compared With Nanoparticle Albumin-Bound Nab-Paclitaxel 
Once Per Week or Ixabepilone With Bevacizumab As First-Line Chemotherapy for Locally 
Recurrent or Metastatic Breast Cancer: CALGB 40502/NCCTG N063H (Alliance). J. Clin. 
Oncol.; 33(21):2361-9. 
Schettini F, Giuliano M, De Placido S, et al (2016) Nab-paclitaxel for the treatment of triple-
negative breast cancer: Rationale, clinical data and future perspectives. Cancer Treat. Rev.; 
50:129-41. 
Schmid P, Abraham J, Turner N (2018) AZD5363 (Capivasertip) plus paclitaxel versus 
placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer 
(PAKT): a randomised, double-blind, placebo-controlled, phase II trial; 1007. 
Schmid P, Adams S, Rugo HS (2019) IMpassion130: updated overall survival (OS) from a 
global, randomized, double-blind, placebo-controlled, Phase III study of atezolizumab (atezo) 
+ nab-paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative 
breast cancer (mTNBC); Hall D1. 
Schmid P, Adams S, Rugo HS, et al (2018) Atezolizumab and Nab-Paclitaxel in Advanced 
Triple-Negative Breast Cancer. N. Engl. J. Med.; 379(22):2108-21. 
Senkus E, Kyriakides S, Ohno S, et al (2015) Primary breast cancer: ESMO Clinical Practice 
Guidelines for diagnosis, treatment and follow-up. Ann. Oncol.; 26 Suppl 5:v8-30. 
Sharma P et al (2018) Clinical and biomarker results from phase I/II study of PI3K inhibitor 
BYL 719 (alpelisib) plus nab-paclitaxel in HER2-negative metastatic breast cancer [abstract]. 
J. Clin. Oncol; 36(15_suppl):1018-1018. 
Sharma P, Abramson VG, O'Dea AP, et al (2021) Clinical and biomarker results from phase 
I/II study of PI3K inhibitor alpelisib plus nab-paclitaxel in HER2-negative metastatic breast 
cancer. Clin Cancer Res. 
Shi Y, Jin J, Ji W, et al (2018) Therapeutic landscape in mutational triple negative breast 
cancer. Mol. Cancer; 17(1):99. 
Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA Cancer J Clin; 7-34. 
Stover DG, Gil Del Alcazar CR, Brock J, et al (2018) Phase II study of ruxolitinib, a selective 
JAK1/2 inhibitor, in patients with metastatic triple-negative breast cancer. NPJ Breast Cancer; 
4:10. 
The EuroQol Group (1990) EuroQol-a new facility for the measurement of health-related 
quality of life. Health Policy; 16(3):199-208. 
Therasse P, Arbuck SG, Eisenhauer EA, et al (2000) New guidelines to evaluate the response 
to treatment in solid tumors. European Organization for Research and Treatment of Cancer, 
National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl. 
Cancer Inst.; 92(3):205-16. 

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Traina TA, Yardley DA, Miller K et al (2017) Overall survival (OS) in patients with 
diagnostic positive (Dx+) breast cancer: Subgroup analysis from a phase 2 study of 
enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in AR+ triple-negative breast 
cancer (TNBC) treated with 0-1 prior lines of therapy; 1089. 
Untch M, Jackisch C, Schneeweiss A, et al (2016) Nab-paclitaxel versus solvent-based 
paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a 
randomised, phase 3 trial. Lancet Oncol.; 17(3):345-56. 
Wallin JJ, Guan J, Prior WW, et al (2012) GDC-0941, a novel class I selective PI3K inhibitor, 
enhances the efficacy of docetaxel in human breast cancer models by increasing cell death in 
vitro and in vivo. Clin. Cancer Res.; 18(14):3901-11. 
Wang DG, Barrios DM, Blinder VS, et al (2020) Dermatologic adverse events related to the 
PI3Kα inhibitor alpelisib (BYL719) in patients with breast cancer. Breast Cancer Res Treat. 
183(1): 227-237.  
Weisman PS, Ng CK, Brogi E, et al (2016) Genetic alterations of triple negative breast cancer 
by targeted next-generation sequencing and correlation with tumor morphology. Mod. Pathol.; 
29(5):476-88. 
Wu TC, Xu K, Martinek J, et al (2018) IL1 Receptor Antagonist Controls Transcriptional 
Signature of Inflammation in Patients with Metastatic Breast Cancer. Cancer Res.; 
78(18):5243-58. 
Yardley DA (2013) nab-Paclitaxel mechanisms of action and delivery. J Control Release; 
170(3):365-72. 
Yardley DA, Coleman R, Conte P, et al (2018) nab-Paclitaxel plus carboplatin or gemcitabine 
versus gemcitabine plus carboplatin as first-line treatment of patients with triple-negative 
metastatic breast cancer: results from the tnAcity trial. Ann. Oncol.; 29(8):1763-70. 
Zeichner SB, Terawaki H, Gogineni K (2016) A Review of Systemic Treatment in Metastatic 
Triple-Negative Breast Cancer. Breast Cancer (Auckl); 10:25-36. 
Zhang S, Yu D (2010) PI(3)king apart PTEN's role in cancer. Clin. Cancer Res.; 16(17):4325-
30. 
Zhang W, Cai J, Chen S, et al (2015) Paclitaxel resistance in MCF-7/PTX cells is reversed by 
paeonol through suppression of the SET/phosphatidylinositol 3-kinase/Akt pathway; 1506-14. 
Zhang W, Zheng X, Meng T, et al (2017) SET protein overexpression contributes to 
paclitaxel resistance in MCF-7/S cells through PI3K/Akt pathway. J Drug Target; 25(3):255-
63. 
Zhao L, Vogt PK (2008) Class I PI3K in oncogenic cellular transformation. Oncogene; 
27(41):5486-96. 
Zhou H, Yu C, Kong L, et al (2019) B591, a novel specific pan-PI3K inhibitor, preferentially 
targets cancer stem cells. Oncogene; 38(18):3371-86. 

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16 
Appendices 
16.1 
Appendix 1: Guidelines for Response, Duration of Overall 
Response, TTF, TTP, Progression-Free Survival, and Overall 
Survival (based on RECIST 1.1) 
Document type: 
TA Specific Guideline 
Document status: 
Version 3.2: February 11, 2016 
Version 3.1: November 29, 2011 
Version 3: October 19, 2009 
Version 2: January 18, 2007 
Version 1: December 13, 2002 
Release date: 
11-Feb-2016  
Authors (Version 3.2): 
 
 
Authors (Version 3.1): 
 
 
 
Authors (Version 3): 
 
 
 
Authors (Version 2): 
 
 
Authors (Version 1): 
 
 
Glossary 
CR 
Complete response 
CSR 
Clinical Study Report 
CT 
Computed tomography 
eCRF 
Electronic Case Report Form 
FPFV 
First patient first visit 
ITT 
Intent-to-treat 
MRI 
Magnetic resonance imaging 
LPLV 
Last patient last visit 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
RAP 
Reporting and Analysis Plan 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SD 
Stable disease 
SOD 
Sum of Diameter 
TTF 
Time to treatment failure 
TTP 
Time to progression 
UNK 
Unknown 

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16.1.1 
Introduction 
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Duffaud and Therasse 2000) and the 
revised RECIST 1.1 guidelines (Eisenhauer et al 2009). 
The efficacy assessments described in Section 16.1.2 and the definition of best response in 
Section 16.1.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 16.1.3.2 is summarizing the “time to 
event” variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 16.1.4 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the SAP (Statistical Analysis Plan) to provide further details needed for programming. 
16.1.2 
Efficacy assessments 
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), and revised 
RECIST guidelines (version 1.1) by (Eisenhauer et al 2009). 
16.1.2.1 Definitions 
16.1.2.1.1 
Disease measurability 
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions. 
• Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. If 
the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
For participants without measurable disease see Section 16.1.3.2.9. 
Measurable lesions (both nodal and non-nodal) 
• Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5 mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm. 
• Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability. 
• Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes ≥ 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring ≥ 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 
baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease. 
• Cystic lesions:  

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• Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same participant, these are preferred 
for selection as target lesions. 
• Non-measurable lesions - all other lesions are considered non-measurable, including 
small lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., 
blastic bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, 
inflammatory breast disease, lymphangitis cutis/pulmonis, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques. 
16.1.2.1.2 
Eligibility based on measurable disease 
If no measurable lesions are identified at baseline, the participant may be allowed to enter the 
study in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, 
it is recommended that participants be excluded from trials where the main focus is on the 
Overall Response Rate (ORR). Guidance on how participants with just non-measurable disease 
at baseline (even if not expected as per eligibility criteria of this protocol) will be evaluated for 
response and also handled in the statistical analyses is given in Section 16.1.3.2.9. 
16.1.2.2 Methods of tumor measurement - general guidelines 
In this document, the term “contrast” refers to intravenous (IV) contrast. 
The following considerations are to be made when evaluating the tumor: 
• All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
• Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
• For optimal evaluation of participants, the same methods of assessment and technique 
should be used to characterize each identified and reported lesion at baseline and during 
follow- up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be 
performed using a 5 mm slice thickness with a contiguous reconstruction algorithm. 
CT/MRI scan slice thickness should not exceed 8 mm cuts using a contiguous 
reconstruction algorithm. If, at baseline, a participant is known to have a medical 
contraindication to CT contrast or develops a contraindication during the trial, the 
following change in imaging modality will be accepted for follow up: a non-contrast CT 
of chest (MRI not recommended due to respiratory artifacts) plus contrast-enhanced MRI 
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• A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a major change in technique (e.g. from CT 
to MRI, or vice-versa), or a change in any other imaging modality. A change from 
conventional to spiral CT or vice versa will not constitute a major “change in method” for 
the purposes of response assessment. A change in methodology will result by default in a 
UNK overall lesion response assessment as per Novartis calculated response. However, 
another response assessment than the Novartis calculated UNK response may be accepted 
from the investigator or the central blinded reviewer if a definitive response 
assessment  can be justified, based on the available information. 
• FDG-PET: can complement CT scans in assessing progression (particularly possible 
for ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm:  
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign 
of PD based on a new lesion. 
• No FDG-PET at baseline with a positive FDG-PET at follow-up:  
• If new disease is indicated by a positive PET scan but is not confirmed by CT (or 
some other conventional technique such as MRI) at the same assessment, then 
follow-up assessments by CT will be needed to determine if there is truly 
progression occurring at that site. In all cases PD will be the date of confirmation 
of new disease by CT (or some other conventional technique such as MRI) rather 
than the date of the positive PET scan. If there is a positive PET scan without any 
confirmed progression at that site by CT, then a PD cannot be assigned. 
• If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is 
not PD. 
• Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
• Physical exams: Evaluation of lesions by physical examination is accepted when lesions 
are superficial, with at least 10mm size, and can be assessed using calipers. 
• Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound should not be used to measure tumor lesions, unless pre-specified by the 
protocol. It is, however, a possible alternative to clinical measurements of superficial 
palpable lymph nodes, subcutaneous lesions and thyroid nodules. Ultrasound might also 
be useful to confirm the complete disappearance of superficial lesions usually assessed by 
clinical examination. 
• Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when biopsies are 
obtained. 

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• Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, 
PSA for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be 
integrated as non-target disease. If markers are initially above the upper normal limit they 
must normalize for a participant to be considered in complete clinical response when all 
lesions have disappeared. 
• Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed). 
• Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
16.1.2.3 Baseline documentation of target and non-target lesions 
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions: 
• Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the eCRF 
(even if it resides in the same organ). 
Minimum target lesion size at baseline 
• Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 16.1.2.1.1 
• Nodal target: See Section 16.1.2.1.1. A sum of diameters (long axis for non-nodal 
lesions, short axis for nodal) for all target lesions will be calculated and reported as the 
baseline sum of diameters (SOD). The baseline sum of diameters will be used as reference 
by which to characterize the objective tumor response. Each target lesion identified at 
baseline must be followed at each subsequent evaluation and documented on eCRF. 
• Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 

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lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 
16.1.2.4 Follow-up evaluation of target and non-target lesions 
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 16-1) and non-target lesions (Table 16-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 16-3) as well as the presence or absence of new lesions. 
16.1.2.4.1 
Follow-up and recording of lesions 
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore, all such data applicable to a particular visit should be associated with the same 
assessment number. 
Non-nodal lesions 
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are participant to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size). 
If the lesion has completely disappeared, the lesion size should be reported as 0 mm. 
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval. 
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated. 
Nodal lesions 
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist. 
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval. 

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However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination. 
16.1.2.4.2 
Determination of target lesion response 
Table 16-1 
Response criteria for target lesions 
Response Criteria 
Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all non-nodal target lesions. In addition, any pathological 
lymph nodes assigned as target lesions must have a reduction in short axis 
to < 10 mm 1 
Partial Response (PR): 
At least a 30% decrease in the sum of diameter of all target lesions, taking 
as reference the baseline sum of diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameter of all measured target 
lesions, taking as reference the smallest sum of diameter of all target 
lesions recorded at or after baseline. In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 
mm 2. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR or CR nor an increase in 
lesions which would qualify for PD. 
Unknown (UNK) 
Progression has not been documented and one or more target lesions 
have not been assessed or have been assessed using a different method 
than baseline.3 
1 SOD for CR may not be zero when nodal lesions are part of target lesions 
2 Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all 
nodal lesions are <10 mm in size. In this case, the target lesion response is CR 
3 In exceptional circumstances an UNK response due to change in method could be over-ruled by the 
investigator or central reviewer using expert judgment based on the available information (see Notes on target 
lesion response and methodology change in Section 16.1.2.2). 
Notes on target lesion response 
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following 
possibilities: 
• The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease 
• The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the eCRF and the tumor assessment will remain 
based on the sum of tumor measurements as presented in Table 16-1 above (i.e., a PD will 
be determined if there is at least 20% increase in the sum of diameters of all measured 
target lesions, taking as reference the smallest sum of diameters of all target lesions 
recorded at or after baseline with at least 5 mm increase in the absolute sum of the 
diameters). Proper documentation should be available to support this decision. This 
applies to participants who have not achieved target response of CR. For participants who 
have achieved CR, please refer to last bullet in this section. 

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• For those participants who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD. 
• Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK. 
• Nodal lesion decrease to normal size: When nodal disease is included in the sum of 
target lesions and the nodes decrease to “normal” size they should still have a 
measurement recorded on scans. This measurement should be reported even when the 
nodes are normal in order not to overstate progression should it be based on increase in the 
size of nodes. 
• Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) 
of the two split lesions should be added together and the sum recorded in the diameter 
field on the eCRF under the original lesion number. This value will be included in the sum 
of diameters when deriving target lesion response. The individual split lesions will not be 
considered as new lesions, and will not automatically trigger a PD designation. 
• Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis - 
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the eCRF, the diameter of the “merged lesion” should be 
recorded for the size of one of the original lesions while a size of “0”mm should be 
entered for the remaining lesion numbers which have coalesced. 
• The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications. 
• Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all non- 
nodal target lesions have disappeared. 
• Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions. 
• Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 mm 
and there is at least 20% increase in sum of the diameters of all nodal target lesions 
relative to nadir with at least 5 mm increase in the absolute sum of the diameters. 
• A change in method for the evaluation of one or more lesions will usually lead to an UNK 
target lesion response unless there is progression indicated by the remaining lesions which 
have been evaluated by the same method. In exceptional circumstances an investigator or 

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central reviewer might over-rule this assignment to put a non-UNK response using expert 
judgment based on the available information. E.g. a change to a more sensitive method 
might indicate some tumor shrinkage of target lesions and definitely rule out progression 
in which case the investigator might assign an SD target lesion response; however, this 
should be done with caution and conservatively as the response categories have well 
defined criteria. 
16.1.2.4.3 
Determination of non-target lesion response 
Table 16-2 
Response criteria for non-target lesions 
Response Criteria 
Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions. In addition, all lymph nodes 
assigned a non-target lesions must be non-pathological in size (< 10 
mm short axis) 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions.1 
Non-CR/Non-PD: 
Neither CR nor PD 
Unknown (UNK) 
Progression has not been documented and one or more non-target 
lesions have not been assessed or have been assessed using a 
different method than baseline2. 
1. The assignment of PD solely based on change in non-target lesions in light of target lesion response of CR, 
PR or SD should be exceptional. In such circumstances, the opinion of the investigator or central reviewer 
prevails. 
2. It is recommended that the investigator and/or central reviewer should use expert judgment to assign a 
Non-UNK response wherever possible (see notes section for more details 
Notes on non-target lesion response 
• The investigator and/or central reviewer can use expert judgment to assign a non-UNK 
response wherever possible, even where lesions have not been fully assessed or a different 
method has been used. In many of these situations it may still be possible to identify 
equivocal progression (PD) or definitively rule this out (non-CR/Non-PD) based on the 
available information. In the specific case where a more sensitive method has been used 
indicating the absence of any non-target lesions, a CR response can also be assigned. 
• The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e. >=10 mm) the response can only be 
‘Non- CR/Non-PD’ unless  there is unequivocal progression of the non-target lesions (in 
which case response is PD) or it is not possible to determine whether there is unequivocal 
progression (in which case response is UNK). 
• Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 

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disease at baseline. If there is unequivocal progression of non-target lesion(s), then at 
least  one of the non-target lesions must be assigned a status of “Worsened”. Where 
possible, similar rules to those described in Section 16.1.2.4.2 for assigning PD following 
a CR for the non-target lesion response in the presence of non-target lesions nodal lesions 
should be applied. 
16.1.2.4.4 
New lesions 
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion eCRF page. 
• If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion 
• If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
participant in which case the response should be UNK, as for any of this participant's 
assessment (Section 16.1.2.5). 
• A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to >= 10 mm for the first time in the study plus 5 
mm absolute increase.  
FDG-PET: can complement CT scans in assessing progression (particularly possible for ‘new’ 
disease). See Section 16.1.2.2 
16.1.2.5 Evaluation of overall lesion response 
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in Table 16-3. 
Table 16-3 
Overall lesion response at each assessment 
Target lesions 
Non-target lesions 
New Lesions 
Overall lesion response 
CR 
CR 
No 
CR1 
CR 
Non-CR/Non-PD3 
No 
PR 
CR, PR, SD 
UNK 
No 
UNK 
PR 
Non-PD and not UNK 
No 
PR1 
SD 
Non-PD and not UNK 
No 
SD1, 2 
UNK 
Non-PD or UNK 
No 
UNK1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1 This overall lesion response also applies when there are no non-target lesions identified at baseline. 
2 Once confirmed PR was achieved, all these assessments are considered PR. 
3 As defined in Section 16.1.2.4 
If  there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK). 

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In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR. 
16.1.3 
Efficacy definitions 
The following definitions primarily relate to participants who have measurable disease at 
baseline. Section 16.1.3.2.9 outlines the special considerations that need to be given to 
participants with no measurable disease at baseline in order to apply the same concepts. 
16.1.3.1 Best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the participant's best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol. 
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met. 
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed. 
• For non-randomized trials where response is the primary endpoint, confirmation is needed. 
• For trials intended to support accelerated approval, confirmation is needed 
• For all other trials, confirmation of response may be considered optional. 
The best overall response for each participant is determined from the sequence of overall 
(lesion) responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required 
• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
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• SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR). 
• PD = progression ≤ 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD). 
• UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks) 
The time durations specified in the SD/PD/UNK definitions above are based on a 6 week tumor 
assessment frequency taking into account assessment windows. However these may be 
modified for specific indications which are more or less aggressive. In addition, it is envisaged 
that the time duration may also take into account assessment windows. E.g. if the assessment 
occurs every 6 weeks with a time window of +/- 7 days, a BOR of SD would require a SD or 
better response longer than 5 weeks after randomization/start of treatment. 
Overall lesion responses of CR must stay the same until progression sets in, with  the exception 
of a UNK status. A participant who had a CR cannot subsequently have a lower status other 
than a PD, e.g. PR or SD, as this would imply a progression based on one or more lesions 
reappearing, in which case the status would become a PD. 
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a participant has a single PR (>=30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not >=20% increase from previous smallest sum), the objective 
status at that assessment should be SD. Once a confirmed PR was seen, the overall lesion 
response should be considered PR (or UNK) until progression is documented or the lesions 
totally disappear in which case a CR assignment is applicable. In studies where confirmation 
of  response  is  not  required  after  a  single  PR  the  overall  lesion  response  should  still  be 
considered PR (or UNK) until progression is documented or the lesion totally disappears in 
which case a CR assignment is applicable. 
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this 
participant. All subsequent assessments are considered  PR  even  if  tumor measurements 
decrease only by 20% compared to baseline (200 mm to 160 mm) at the following assessments. 
If the participant progressed but continues study treatment, further assessments are not 
considered for the determination of best overall response. 
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates. 
The best overall response for a participant is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources: 
• Investigator overall lesion response 

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• Central Blinded Review overall lesion response 
• Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review) 
The primary analysis of the best overall response will be based on the sequence of investigator 
overall lesion responses. 
Based on the participants’ best overall response during the study, the following rates are then 
calculated: 
Overall response rate (ORR) is the proportion of participants with a best overall response of 
CR or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications. 
Disease control rate (DCR) is the proportion of participants with a best overall response of CR 
or PR or SD. The objective of this endpoint is to summarize participants with signs of “activity” 
defined as either shrinkage of tumor (regardless of duration) or slowing  down  of  tumor 
growth. 
Clinical benefit rate (CBR) is the proportion of participants with a best overall response of 
CR or PR , or an overall lesion response of SD or Non-CR/Non-PD which lasts for a minimum 
time duration (with a default of at least 24 weeks in breast cancer studies). This endpoint 
measures signs of activity taking into account duration of disease stabilization. 
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used: 
Early progression rate (EPR) is the proportion of participants with progressive disease within 
8 weeks of the start of treatment. 
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of (Dent et al 2001) and counts 
all participants who at the specified assessment (in this example the assessment would be at 8 
weeks ± window) do not have an overall lesion response of SD, PR, or CR. Participants with 
an unknown (UNK) assessment at that time point and no PD before, will not be counted as early 
progressors in the analysis but may be included in the denominator of the EPR rate, depending 
on the analysis population used. Similarly when examining overall response and disease 
control, participants with a best overall response assessment of unknown (UNK) will not be 
regarded as “responders” but may be included in the denominator for ORR and DCR calculation 
depending on the analysis population (e.g. populations based on an intent-to-treat (ITT) 
approach). 
16.1.3.2 Time to event variables 
16.1.3.2.1 
Progression-free survival 
Usually in all Oncology studies, participants are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint. 

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Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
participant has not had an event, progression-free survival is censored at the date of last 
adequate tumor assessment. 
PFS rate at x weeks is an additional measure used to quantify PFS endpoint. It is recommended 
that a Kaplan Meier estimate is used to assess this endpoint. 
16.1.3.2.2 
Overall survival 
All participants should be followed until death or until participant has had adequate follow-up 
time as specified in the protocol whichever comes first. The follow-up data should contain the 
date the participant was last seen alive / last known date participant alive, the date of death and 
the reason of death (“Study indication” or “Other”). 
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a participant is not known to have died, survival will be 
censored at the date of last known date participant alive. 
16.1.3.2.3 
Time to progression 
Some studies might consider only death related to underlying cancer as an event  which 
indicates progression. In this case the variable “Time to progression” might be used. TTP is 
defined as PFS except for death unrelated to underlying cancer. 
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a participant has not had an event, time to progression is censored at the date of last adequate 
tumor assessment. 
16.1.3.2.4 
PFS2 
A recent EMA guidance (EMA 2012) recommends a substitute end point intermediate to PFS 
and OS called PFS2, a surrogate for OS when OS cannot be measured reliably, which assesses 
the impact of the experimental therapy on next-line treatment. The main purpose of this 
endpoint is to assess long term maintenance strategies, particularly of resensitizing agents and 
where it is necessary to examine the overall “field of influence”. 
PFS2, which could be termed PFS deferred, PFS delayed, tandem PFS, or PFS version 2.0, is 
the time from date of randomization/start of treatment to the date of event defined as the first 
documented progression on next-line treatment or death from any cause. The censoring rules 
for this endpoint will incorporate the same principles as those considered for PFS in this 
document, and in addition may involve other considerations which will need to be detailed in 
the protocol. 
Please note that data collection for the PFS2 is limited to the date of progression and not specific 
read of the tumor assessments. 
It is strongly recommended that the teams consult regulatory agencies for scientific advice given 
the limited experience with the use of this endpoint in regulatory setting in light of 
methodological issues with respect to censoring foreseen. 

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16.1.3.2.5 
Time to treatment failure 
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study drug. In some protocols, time to treatment failure 
(TTF) may be  considered  as  a  sensitivity  analysis  for  time  to  progression.  The  list  of 
discontinuation reasons to be considered or not as treatment failure may be adapted according 
to the specificities of the study or the disease. 
TTF is the time from date of randomization/start of treatment to the earliest of date of 
progression, date of death due to any cause, or date of discontinuation due to reasons other than 
‘Protocol violation’ or ‘Administrative problems’. TTF for participants who did not experience 
treatment failure will be censored at last adequate tumor assessment. 
16.1.3.2.6 
Duration of response 
The analysis of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 
a treatment with a significantly higher response rate had a significantly shorter duration of 
response but where this probably primarily reflected selection bias which is explained as 
follows: It is postulated that there are two groups of participants: a good risk group and a poor 
risk group. Good risk participants tend to get into response readily (and relatively quickly) and 
tend to remain in response after they have a response. Poor risk participants tend to be difficult 
to achieve a response, may have a longer time to respond, and tend to relapse quickly when they 
do respond. Potent agents induce a response in both good risk and poor risk participants. Less 
potent agents induce a response mainly in good risk participants only. This is described in more 
detail by (Morgan et al 1988). 
It is recommended that an analysis of all participants (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates. If an 
inferential comparison between treatments is required this should only be performed on all 
participants (i.e. not restricting to “responders” only) using appropriate statistical methods such 
as the techniques described in (Ellis et al 2008). It should also be stated in the protocol if 
duration of response is to be calculated in addition for unconfirmed response. 
For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-participant analysis of these endpoints are not appropriate since the status 
of participants throughout the study is usually taken into account in the analysis). 
Duration of overall response (CR or PR): For participants with a CR or PR (which may have 
to be confirmed) the start date is the date of first documented response (CR or PR) and the end 
date and censoring is defined the same as that for time to progression. 
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen. 
Duration of overall complete response (CR): For participants with a CR (which may have to 
be confirmed) the start date is the date of first documented CR and the end date and censoring 
is defined the same as that for time to progression. 

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Duration of stable disease (CR/PR/SD): For participants with a CR or PR (which may have 
to be confirmed) or SD the start and end date as well as censoring is defined the same as that 
for time to progression. 
16.1.3.2.7 
Time to response 
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed. 
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 16.1.3.2.6. It is recommended that 
an analysis of all participants (both responders and non-responders) be performed whether or 
not a “responders only” descriptive analysis is presented. Where an inferential statistical 
comparison is required, then all participants should definitely be included in the analysis to 
ensure the statistical test is valid. For analysis including all participants, participants who did 
not achieve a response (which may have to be a confirmed response) will be censored using one 
of the following options. 
• at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for participants who had 
a PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the participant cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV) 
• at last adequate tumor assessment date otherwise.  In this case participants have not yet 
progressed so they theoretically still have a chance of responding 
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint. 
16.1.3.2.8 
Definition of start and end dates for time to event variables 
Assessment date 
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise, if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number. 
In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations. 
Start dates 
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date. 

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For the calculation of duration of response the following start date should be used: 
• Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed. 
End dates 
The end dates which are used to calculate ‘time to event’ variables are defined as follows: 
• Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page). 
• Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease. 
• Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post- 
baseline assessments are available (before an event or a censoring reason occurred), the 
date of randomization/start of treatment is used. 
• Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if backdating is 
considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 16.1.3.2.8). 
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months. 
• Date of discontinuation is the date of the end of treatment visit. 
• Date of last contact is defined as the last date the participant was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date participant alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date. 
• Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery. 
16.1.3.2.9 
Handling of participants with non-measurable disease only at baseline 
It is possible that participants with only non-measurable disease present at baseline are entered 
into the study, because of a protocol violation or by design (e.g. in Phase III studies with PFS 
as the primary endpoint). In such cases the handling of the response data requires special 
consideration with respect to inclusion in any analysis of endpoints based on the overall 
response evaluations. 
It is recommended that any participants with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints. 
Although the text of the definitions described in the previous sections primarily relates to 
participants with measurable disease at baseline, participants without measurable disease should 

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also be incorporated in an appropriate manner. The overall response for participants with non- 
measurable disease is derived slightly differently according to Table 16-4. 
Table 16-4 
Overall lesion response at each assessment: participants with non-
target disease only 
Non-target lesions 
New Lesions 
Overall lesion response 
CR 
No 
CR 
Non-CR/Non-PD1 
No 
Non-CR/non-PD 
UNK 
No 
UNK 
PD 
Yes or No 
PD 
Any 
Yes 
PD 
1 As defined in Section 16.1.2.4 
In general, the non-CR/non-PD response for these participants is considered equivalent to an 
SD response in endpoint determination. In summary tables for best overall response participants 
with only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular 
by displaying the specific numbers with the non-CR/non-PD category. 
In considering how to incorporate data from these participants into the analysis the importance 
to each endpoint of being able to identify a PR and/or to determine the occurrence and timing 
of progression needs to be taken into account. 
For ORR it is recommended that the main (ITT) analysis includes data from participants with 
only non-measurable disease at baseline, handling participants with a best response of CR as 
“responders” with respect to ORR and all other participants as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
participants with only non-measurable disease at baseline, with possible sensitivity analyses 
which exclude these particular participants. Endpoints such as PFS which are reliant on the 
determination and/or timing of progression can incorporate data from participants with only 
non- measurable disease. 
16.1.3.2.10 Sensitivity analyses 
This section outlines the possible event and censoring dates for progression, as well as addresses 
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a participant being lost to follow-up? It is important that the protocol and SAP specify the 
primary analysis in detail with respect to the definition of event and censoring dates and also 
include a description of one or more sensitivity analyses to be performed. 
Based on definitions outlined in Section 16.1.3.2.8, and using the FDA guideline on endpoints 
(Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 2005) 
as 
a 
reference, the following analyses can be considered:  

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Table 16-5 
Options for event dates used in PFS, TTP, duration of response 
Situation 
Options for end-date 
(progression or 
censoring)1 
(1) = default unless 
specified differently in 
the protocol or RAP 
Outcome 
A 
No baseline assessment 
(1) Date of 
randomization/start of 
treatment3 
Censored 
B 
Progression at or before 
next scheduled 
assessment 
(1) Date of progression 
(2) Date of next 
scheduled assessment2 
Progressed 
Progressed 
C1 
Progression or death 
after exactly one missing 
assessment 
(1) Date of progression 
(or death) 
(2) Date of next 
scheduled assessment2 
Progressed 
Progressed 
C2 
Progression or death 
after two or more missing 
assessments 
(1) Date of last adequate 
assessment2 
(2) Date of next 
scheduled assessment2 
(3) Date of progression 
(or death) 
Censored 
Progressed 
Progressed 
D 
No progression 
(1) Date of last adequate 
assessment 
Censored 
E 
Treatment 
discontinuation due to 
‘Disease progression’ 
without documented 
progression, i.e. clinical 
progression based on 
investigator claim 
(1) Ignore clinical 
progression and follow 
situations above 
(2) Date of 
discontinuation (visit date 
at which clinical 
progression was 
determined) 
As per above situations 
Progressed 
F 
New anticancer therapy 
given 
(1) Ignore the new 
anticancer therapy and 
follow situations above 
(ITT approach) 
(2) Date of last adequate 
assessment prior to new 
anticancer therapy 
(3) Date of secondary 
anti-cancer therapy 
(4) Date of secondary 
anti-cancer therapy 
As per above situations 
Censored 
Censored 
Event 
G 
Deaths due to reason 
other than deterioration 
of ‘Study indication’ 
(1) Date of last adequate 
assessment 
Censored (only TTP and 
duration of response) 
1 =Definitions can be found in Section 16.1.3.2.8. 
2 =After the last adequate tumor assessment. “Date of next scheduled assessment” is defined 
in Section 16.1.3.2.8. 
3 =The rare exception to this is if the participant dies no later than the time of the second scheduled 
assessment as defined in the protocol in which case this is a PFS event at the date of death. 

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The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F. 
Situations C (C1 and C2): Progression or death after one or more missing 
assessments: The primary analysis is usually using options (1) for situations C1 and C2, i.e. 
• (C1) taking the actual progression or death date, in the case of only one missing 
assessment. 
• (C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments. 
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2. 
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as participants without documented 
PD should be followed for progression after discontinuation of treatment. However, option (2) 
may be used as sensitivity analysis. If progression is claimed based on clinical deterioration 
instead of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high 
early progression rate or difficulties to assess the tumor due to clinical deterioration. 
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1) (ITT) is the recommended approach; events 
documented after the initiation of new cancer therapy will be considered for the primary 
analysis i.e. progressions and deaths documented after the initiation of new cancer therapy 
would be included as events. This will require continued follow-up for progression after the 
start of the new cancer therapy. In such cases, it is recommended that an additional sensitivity 
analysis be performed by censoring at last adequate assessment prior to initiation of new cancer 
therapy. 
Option (2), i.e. censoring at last adequate assessment may be used as a sensitivity analysis. If a 
high censoring rate due to start of new cancer therapy is expected, a window of approximately 
8 weeks performed after the start of new cancer therapy can be  used  to calculate the date of 
the event or censoring. This should be clearly specified in the analysis plan. 
In some specific settings, local treatments (e.g. radiation/surgery) may not be considered as 
cancer therapies for assessment of event/censoring in PFS/TTP/DoR analysis. For example, 
palliative radiotherapy given in the trial for analgesic purposes or for lytic lesions at risk of 
fracture will not be considered as cancer therapy for the assessment of BOR and  PFS analyses. 
The protocol should clearly state the local treatments which are not considered as antineoplastic 
therapies in the PFS/TTP/DoR analysis. 
The protocol should state that tumor assessments will be performed every x weeks until 
radiological progression irrespective of initiation of new antineoplastic therapy. It is strongly 
recommended that a tumor assessment is performed before the participant is switched to a new 
cancer therapy. 

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Additional suggestions for sensitivity analyses 
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 16-5 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition: 
• Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment. 
 In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation. 
16.1.4 
Data handling and programming rules 
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates). 
16.1.4.1 Study/project specific decisions 
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation. 
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock). 
16.1.4.2 End of treatment phase completion 
Participants may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For participants who are lost to follow- 
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the participant, e.g., dates of telephone calls, registered letters, 
etc. 
The end of treatment visit and its associated assessments should occur within 14 days of the last 
study treatment. 
Participants may discontinue study treatment for any of the following reasons: 
• Adverse event(s) 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 

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• Technical problems 
• Participant/guardian decision 
• Progressive disease 
• Study terminated by the sponsor 
• Non-compliant with study treatment 
• No longer requires treatment 
• Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given) 
Death is a reason which “must” lead to discontinuation of participant from trial. 
16.1.4.3 End of post-treatment follow-up (study phase completion) 
End  of  post-treatment  follow-up  visit  will  be  completed  after  discontinuation  of  study 
treatment and post-treatment evaluations but prior to collecting survival follow-up. 
Participants may provide study phase completion information for one of the following reasons: 
• Adverse event 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Participant/guardian decision 
• Death 
• Progressive disease 
• Study terminated by the sponsor 
16.1.4.4 Medical validation of programmed overall lesion response 
In order to be as objective as possible the RECIST programmed calculated response assessment 
is very strict regarding measurement methods (i.e. any assessment with more or less sensitive 
method than the one used to assess the lesion at baseline is considered UNK) and not available 
evaluations (i.e. if any target or non-target lesion was not evaluated the whole overall lesion 
response is UNK unless remaining lesions qualified for PD). This contrasts with the slightly 
more flexible guidance given to local investigators (and to the central reviewers) to use expert 
judgment in determining response in these type of situations, and therefore as a consequence 
discrepancies between the different sources of response assessment often arise. To ensure the 
quality of response assessments from the local site and/or the central reviewer, the responses 
may be re-evaluated by clinicians (based on local investigator data recorded in eCRF or based 
on central reviewer data entered in the database) at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on RECIST 
criteria. This may be queried for clarification. However, the investigator or central reader’s 
response assessment will never be overruled. 

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If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall  lesion 
response at that specific assessment is to be kept in a dataset. This must be clearly documented 
in the RAP documentation and agreed before database lock. This dataset should be created and 
stored as part of the ‘raw’ data. 
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only participants with documented deterioration 
of symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation. 
16.1.4.5 Programming rules 
The following should be used for programming of efficacy results: 
16.1.4.5.1 
Calculation of 'time to event' variables 
Time to event = end date - start date + 1 (in days) 
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative. 
16.1.4.5.2 
Incomplete assessment dates 
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year. 
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 16.1.3.2.8). If all measurement dates have 
no day recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation. 
16.1.4.5.3 
Incomplete dates for last known date participant alive or death 
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact. 
16.1.4.5.4 
Non-target lesion response 
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’. 
16.1.4.5.5 
Study / project specific programming 
The standard analysis programs need to be adapted for each study/project. 

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16.1.4.5.6 
Censoring reason 
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page. 
For survival the following censoring reasons are possible: 
• Alive 
• Lost to follow-up 
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible: 
• Ongoing without event 
• Lost to follow-up 
• Withdrew consent 
• Adequate assessment no longer available* 
• Event documented after two or more missing tumor assessments (optional, see Table 16-5) 
• Death due to reason other than underlying cancer (only used for TTP and duration of 
response) 
• Initiation of new anti-cancer therapy 
* Adequate assessment is defined in Section 16.1.3.2.8. This reason is applicable when 
adequate evaluations are missing for a specified period prior to data cut-off (or prior to any 
other censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted: 
• This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when participants are 
not followed for progression after treatment completion or when only UNK assessments 
are available just prior to data cut-off). 
• The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent/opposition to use data/biological 
samples, loss to follow-up or alternative anti- cancer therapy) has occurred more than the 
specified period following the last adequate assessment. 
• This reason will also be used to censor in case of no baseline assessment. 
16.1.5 
Reference (available upon request) 
Dent S, Zee B, Dancey J, et al (2001) application of a new multinomial phase II stopping rule 
using response and early progression. J Clin Oncol; 19:785-91. 
Eisenhauer EA, Therasse P, BogaertsJ, et al (2009) New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Euro JCancer; 45:228-47. 
Ellis S, Carroll KJ, Pemberton K, et al (2008) Analysis of duration of response in oncology 
trials. Contemp Clin Trials; 29:456-65. 
EMA Guidance: 2012 Guideline on the evaluation of anticancer medicinal products in man. 

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FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007 
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18 
Therasse P, Arbuck SG, Eisenhauer EA, et al (2000) New Guidelines to Evaluate the 
Response to Treatment in Solid Tumors. J Natl Cancer Inst; 92: 205-16 

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16.2 
Appendix 2: List of concomitant medications 
In general, the use of any concomitant medication deemed necessary for the care of the patient 
is permitted in this study, except as specifically prohibited below. Combination administration 
of study drugs could result in drug-drug interactions (DDI) that could potentially lead to reduced 
activity or enhanced toxicity of the concomitant medication and/or alpelisib. Please note that 
all lists in Appendix 2 are not comprehensive. Please refer to regular updated online sources 
and the label of a concomitant drug to decide whether a drug is permitted (with caution) or 
prohibited based on Section 6.2.2. In doubt please the contact medical monitor with any 
questions. 
16.2.1 
Permitted medication to be used with caution 
This list of CYP substrates and list of inhibitors / inducers was compiled from the University of 
Washington’s Drug Interaction Database (Updated Nov-2020). This list only meant to be used 
as a guide. 
Table 16-6 
List of CYP450 substrates to be used with caution 
Category 
Drug Name 
CYP2C9 substrates 
Narrow Therapeutic index substrates of CYP2C9 
(S)-Warfarin 
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 
Not applicable 
Sensitive substrates of CYP2B6 
Bupropion, Efavirenz 
Selected CYP3A4 substrates 
CYP3A4 substrates which are known or potential 
auto-perpetrators 
Clarithromycin, Conivaptan, Encorafenib, 
Erythromycin, Diltiazem, Mifepriston, Ribociclib, 
Telthromycin, Troleandomycin, Verapamil 
Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-administered with 
a known potent inhibitor. 
Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increases in 
their exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g. 
Torsades de Pointes, QT prolongation).CYP3A4 substrates which are auto-perpetrators: Based on Novartis 
internal assessment 
Table 16-7 
List of inhibitors and inducers of CYP2C8 and strong inhibitors of 
CYP3A to be used with caution 
 Category 
Drug Name 
Strong CYP3A Inhibitors  
Ceritinib, Clarithromycin, Conivaptan, Grapefruit juice2 (citrus 
paradisi fruit juice, 240 mL TID), Idealisib, Itraconazole, 
Ketoconazole, LCL161, Mibefradil, Mifepristone, Nefazodone, 
Posaconazole, Ribociclib, Telithromycin, Troleandomycin, 
Voriconazole 
Strong and moderate CYP2C8 inhibitors 
Clopidogrel (strong), Deferasirox (moderate), Gemfibrozil 
(strong), Letermovir, Teriflunomide (moderate),  
CYP2C8 inducers 
Since all inducers are also inducers of CYP3A4 these are 
prohibited as of Table 16-8 

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 Category 
Drug Name 
This list of CYP inhibitors and inducers was compiled from the University of Washington’s Drug Interaction 
Database (Dated April 2019) 
1 Combination ritonavir-boosted regimens are listed here in the DDI memo as strong CYP3A inhibitors (to avoid 
potential confusion), even though some are considered moderate CYP3A inhibitors in the UW DDI 
Database.2Herbal product 
16.2.2 
Prohibited medication 
Strong inducers of CYP3A4 
This list of CYP inducers was compiled from the University of Washington’s Drug Interaction 
Database (Updated Nov-2020). This list only meant to be used as a guide. 
Table 16-8 
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 
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 16-9 
List of prohibited BCRP inhibitors 
Category 
Drug Name 
BCRP inhibitors - 
Evidence for DDI potential shown in vivo 
Atazanavir/ritonavir1,2, Elvitegravir/cobicistat1,2, 
Lopinavir/ritonavir1,2, Tipranavir/ritonavir1,2 
Curcumin1,2, Cyclosporine1,2, Daclatasvir1,2, Eltrombopag1,2, 
Gefitinib2, Lapatinib1, Ledipasvir2, Pantoprazole1,2, 
Paritepravir2, Tipranavir2 
1 Lee et al, 2015 
2 Novartis PK Sciences DDI List (January, 2018) 

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16.3 
Appendix 3: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements 
Table 16-10 
Liver event and laboratory trigger definitions 
  
Definition/ threshold 
Liver laboratory triggers 
If ALT, AST and total bilirubin normal at baseline: 
• 
ALT or AST > 5 × ULN 
• 
ALP > 2 × ULN (in the absence of known bone 
pathology) 
• 
Total bilirubin > 3 × ULN (in the absence of known 
Gilbert syndrome) 
• 
ALT or AST > 3 × ULN and INR > 1.5 
• 
Potential Hy’s Law cases (defined as ALT or AST 
> 3 × ULN and Total bilirubin > 2 × ULN [mainly 
conjugated fraction] without notable increase in 
ALP to > 2 × ULN) 
• 
Any clinical event of jaundice (or equivalent term) 
• 
ALT or AST > 3 × ULN accompanied by (general) 
malaise, fatigue, abdominal pain, nausea, or 
vomiting, or rash with eosinophilia 
• 
· Any adverse event potentially indicative of a liver 
toxicity 
If ALT or AST abnormal at baseline: 
ALT or AST > 3x baseline or > 300 U/L (whichever 
occurs first) 
Table 16-11 
Follow up requirements for liver laboratory triggers – ALT, AST, TBL 
ALT 
TBL 
Liver Symptoms 
Action 
ALT increase without bilirubin increase: 
  
If normal at baseline: 
ALT > 3 x ULN 
Normal 
For participants with 
Gilbert’s syndrome: No 
change in baseline TBL 
None 
• 
No change to study 
treatment 
• 
Measure ALT, AST, ALP, 
GGT, TBIL, INR, albumin, 
CK, and GLDH in 48-72 
hours. 
• 
· Follow-up for symptoms. 
If elevated at baseline: 
ALT > 2 x baseline 
or > 300 U/L (whichever 
occurs ﬁrst) 
If normal at baseline: 
ALT > 5 x ULN for more 
than two weeks 
Normal 
For participants with 
Gilbert’s syndrome: No 
change in baseline TBL 
None 
• 
Interrupt study drug 
• 
Measure ALT, AST, ALP, 
GGT, TBIL, INR, albumin, 
CK, and GLDH in 48-72 
hours. 
• 
Follow-up for symptoms. 
• 
Initiate close monitoring and 
workup for competing 
etiologies. 
• 
Study drug can be restarted 
only if another etiology is 
identiﬁed and liver enzymes 
return to baseline. 
If elevated at baseline: 
ALT > 3 x baseline 
AND >5x ULNfor more 
than two weeks 
If normal at baseline: 
ALT > 8 x ULN 
Normal 
None 
ALT increase with bilirubin increase: 
If normal at baseline: 
ALT > 3 x ULN 
TBL > 2 x ULN (or INR > 
1.5) 
For participants with 
Gilbert’s syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at baseline: 
ALT > 2 x baseline 
AND >3x ULN 

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ALT 
TBL 
Liver Symptoms 
Action 
If normal at baseline: 
ALT > 3 x ULN 
Normal or elevated 
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain 
If elevated at baseline: 
ALT > 2 x baseline 
AND >3x ULN 
Table 16-12 
Follow up requirements for liver laboratory triggers – Isolated 
Hyperbilirubinemia 
Criteria 
Actions required 
Follow-up monitoring 
Total Biliruin (isolated) 
  
  
>1.5 – 3.0 ULN 
• 
Maintain treatment 
• 
Repeat LFTs within 48-72 
hours 
• 
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline 
> 3 - 10 × ULN (in the absence of 
known Gilbert syndrome) 
• 
Interrupt treatment 
• 
Repeat LFT within 48-72 hours 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate CRF 
• 
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline (ALT, AST, total 
bilirubin, Alb, PT/INR, ALP and 
GGT) 
• 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 10 x ULN 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize the participant 
• 
Establish causality 
• 
Record the AE and contributing 
factors(e.g. conmeds, med hx, 
lab) in the appropriate CRF 
• 
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolution (frequency at 
investigator discretion) 
Any AE potentially indicative of a 
liver toxicity* 
• 
Consider study treatment 
interruption or discontinuation 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g., conmeds, med 
hx, lab) in the appropriate CRF 
• 
Investigator discretion 
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease. 

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16.4 
Appendix 4: Statistical considerations 
Part B1 
The primary endpoint is the overall response rate (ORR). The analysis of the primary endpoint, 
which is Bayesian, uses a binomial sampling and a Beta prior distribution. 
The null value for the ORR was set to 25%. Moreover, a minimum ORR improvement of 10% 
was considered necessary to justify initiation of Protocol part B2 (see Section 12.8 for 
information on published data available to help elicit the 25% and 35% targets). 
The two criteria to assess the proof of preliminary efficacy (PPE) in each treatment group are 
thus: 
• Clinical relevance: posterior mean ≥ 35% 
• Bayesian statistical significance: pr(ORR ≥ 25% | data) ≥ 0.90 
The first criterion is met if the posterior mean ORR is at least 35% which is the minimum ORR 
of clinical interest. The second criterion provides reasonable evidence that the posterior ORR 
is better than the null value of 25%. Both criteria need to be met in order to meet the objective 
of proof of preliminary efficacy. 
Analysis is performed using a Beta-binomial model as follows: 
Assume that y out of n patients have a response as per ORR. 
The likelihood function is y ~ Bin(n, p) where p denotes the ORR. 
Assume p follows a beta prior distribution: [p] ~ Beta(a, b), where a > 0 , b > 0 
The posterior distribution of p is therefore: [p | y] ∼ Beta(a + y, b + n - y) 
A minimally informative prior with unimodal Beta(0.35/(1-0.35),1) distribution is used. The 
prior parameters are chosen so that the prior mean for ORR is equal to 35%. This ensures that 
the clinical relevance criterion is met, if the observed ORR is exactly equal to 35%. 
With the two criteria stated above the minimally required sample size is 32. 
To better understand the design, operating characteristics for various true ORR were assessed 
using simulations as follows: 
• Generate 100,000 trials with ORR results (yes / no) for n participants per treatment group, 
where the ORR follows a binomial distribution y ~ Bin(n, p). 
• Evaluate for each of these simulated trials whether the PPE criteria are met. 
• The probability of declaring preliminary efficacy is the average number of trials meeting 
PPE over the 100,000 sampled trials. 
The operating characteristics presented in Section 12.8 of the protocol consider n=32, with 
varying p from 0.25 to 0.45. Operating characteristics for additional sample sizes of 36 and 40 
participants by treatment group were also assessed and full results are presented in Table 16-11. 

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Table 16-13 
Part B1 Operating characteristics for ORR with 32, 36 or 40 
participants in each arm 
Number of participants 
True ORR 
Probability of declaring 
PPE in each arm 
Probability of missing 
PPE in each arm 
32 
25 % 
0.079 
0.921 
30 % 
0.228 
0.772 
35 % 
0.448 
0.552 
40% 
0.675 
0.325 
45 % 
0.847 
0.153 
36 
25 % 
0.092 
0.908 
30 % 
0.263 
0.737 
35 % 
0.507 
0.493 
40% 
0.738 
0.262 
45 % 
0.893 
0.107 
40 
25 % 
0.102 
0.898 
30 % 
0.296 
0.704 
35 % 
0.559 
0.441 
40% 
0.787 
0.213 
45 % 
0.924 
0.076 
Based on the Operating Characteristics the minimal sample size of 32 participants by treatment 
group was considered as adequate