Clinical trial NCT02437318
Conditions: Breast Cancer
Keywords: BYL719 HR+ HER2-negative advanced breast cancer alpelisib fulvestrant PI3K Phase III ER+ PgR+ men postmenopausal aromatase inhibitor neoplasms
Sponsor: Novartis Pharmaceuticals
Start date: 2015-07-23; Completion date: 2023-06-09
Enrollment: 572 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To determine whether treatment with alpelisib plus fulvestrant prolonged progression-free survival (PFS) compared to fulvestrant and placebo in men and postmenopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor-2 (HER2)-negative advanced breast cancer, who received prior treatment with an aromatase Inhibitor (AI) either as (neo)adjuvant or for advanced disease.

Detailed description:
This was a randomized, double-blind, placebo-controlled, international multicenter Phase III study that evaluated the efficacy and safety of treatment with alpelisib plus fulvestrant versus placebo plus fulvestrant in men and postmenopausal women with HR-positive, HER2-negative advanced breast cancer which had progressed on or after AI treatment.

Subjects were allocated to either the PIK3CA mutant or PIK3CA non-mutant cohort, based on central testing of hotspot-mutations in tumor tissue. Subjects with unknown results were not eligible. Within each cohort, subjects were randomized in a 1:1 ratio to receive either alpelisib 300 mg orally once daily (q.d.), in combination with fulvestrant 500 mg intramuscular (i.m.) on Days 1 and 15 of Cycle 1 and Day 1 of a 28-day cycle thereafter, or placebo daily in combination with fulvestrant 500 mg following the same treatment regimen.

Subjects were treated until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason. All subjects who discontinued study treatment were followed for safety, until 30 days after last study treatment administration, except in the case of death, loss to follow-up, or withdrawal of consent.

Subjects who discontinued study treatment for reasons other than disease progression or withdrawal of consent, were followed until disease progression, death, withdrawal of consent, loss to follow-up, or subject/guardian decision (post-treatment efficacy follow-up).

Finally, all subjects were followed for survival after discontinuation of study treatment and tumor evaluations until the subject's death, loss to follow-up, or withdrawal of consent for survival follow-up (post-treatment survival follow-up)

Arms: arm 1: Subjects treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle) arm 2: Subjects were treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
Interventions: intervention 1: Fulvestrant intervention 2: Alpelisib intervention 3: Placebo
Intervention descriptions: intervention 1: 500 mg of fulvestrant administered via intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle intervention 2: 300 mg of alpelisib tablets for oral use administered once daily intervention 3: 300 mg of placebo tablets for oral use administered once daily

Protocol documents:
Prot_002.pdf: 
Clinical Development
BYL719, Alpelisib
Oncology Clinical Protocol CBYL719C2301 / NCT02437318
SOLAR-1: A phase III randomized double-blind, placebo 
controlled study of alpelisib in combination with fulvestrant 
for men and postmenopausal women with hormone 
receptor positive, HER2-negative advanced breast cancer 
which progressed on or after aromatase inhibitor treatment
Authors
 
Document type
Amended Protocol Version
EUDRACT number
2015-000340-42
Version number
05
Development phase
III
Document status
Final
Release date
11-Feb-2020
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Template version 17-Nov-2014


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................8
List of tables ........................................................................................................................8
List of abbreviations..........................................................................................................10
Glossary of terms...............................................................................................................14
Protocol summary..............................................................................................................16
Amendment 5 (11-Feb-2020)............................................................................................19
Amendment 4 (22-Nov2017) ............................................................................................23
Amendment 3 (14-Dec-2016)............................................................................................24
Amendment 2 (30-Aug-2016)...........................................................................................27
Amendment 1 ....................................................................................................................32
1
Background........................................................................................................................38
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............38
1.1.1
Hormone receptor-positive breast cancer..............................................38
1.1.2
The PI3K pathway.................................................................................38
1.1.3
PI3K pathway in HR+ breast cancer.....................................................40
1.2
Introduction to investigational treatment(s) and other study treatment(s).............41
1.2.1
Overview of fulvestrant.........................................................................41
1.2.2
Overview of alpelisib............................................................................43
1.2.3
Overview of the combination of alpelisib and endocrine treatments....49
1.2.4
Potential for drug interactions...............................................................52
2
Rationale............................................................................................................................53
2.1
Study rationale and purpose...................................................................................53
2.2
Rationale for the study design ...............................................................................54
2.3
Rationale for dose and regimen selection..............................................................55
2.4
Rationale for choice of combination drugs............................................................55
2.5
Rationale for choice of comparators drugs............................................................56
2.6
Risks and benefits..................................................................................................56
2.6.1
Potential benefit for participants...........................................................56
2.6.2
Potential risks to clinical trial participants............................................57
2.6.3
Risks related to study procedures..........................................................57
2.6.4
Risk management strategies..................................................................57
3
Objectives and endpoints...................................................................................................57
4
Study design ......................................................................................................................60
4.1
Description of study design ...................................................................................60


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4.1.1
Screening phase.....................................................................................61
4.1.2
Treatment phase ....................................................................................62
4.1.3
Safety follow-up....................................................................................62
4.1.4
Efficacy follow-up ................................................................................62
4.1.5
Survival follow-up ................................................................................62
4.2
Timing of interim analyses and design adaptations...............................................63
4.3
Definition of end of the study................................................................................63
4.4
Early study termination..........................................................................................64
5
Population..........................................................................................................................64
5.1
Patient population..................................................................................................64
5.2
Inclusion criteria ....................................................................................................64
5.3
Exclusion criteria...................................................................................................66
6
Treatment...........................................................................................................................69
6.1
Study treatment......................................................................................................69
6.1.1
Dosing regimen.....................................................................................69
6.1.2
Guidelines for continuation of treatment ..............................................72
6.1.3
Ancillary treatments..............................................................................72
6.1.4
Rescue medication ................................................................................72
6.1.5
Treatment duration................................................................................72
6.2
Dose escalation guidelines.....................................................................................72
6.3
Dose modifications................................................................................................72
6.3.1
Dose modification and dose delay ........................................................72
6.3.2
Follow-up for toxicities.........................................................................82
6.3.3
Anticipated risks and safety concerns of the study drug.......................87
87
87
88
89
6.5
Patient numbering, treatment assignment or randomization .................................90
6.5.1
Patient numbering .................................................................................90
6.5.2
Treatment assignment or randomization...............................................90
6.5.3
Treatment blinding................................................................................91
6.6
Study drug preparation and dispensation...............................................................91
6.6.1
Study drug packaging and labeling.......................................................91
6.6.2
Drug supply and storage........................................................................92
6.6.3
Study drug compliance and accountability ...........................................92


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Disposal and destruction .......................................................................93
7
Visit schedule and assessments .........................................................................................93
7.1
Study flow and visit schedule................................................................................93
7.1.1
Screening.............................................................................................101
7.1.2
Treatment period.................................................................................103
7.1.3
Discontinuation of study treatment .....................................................103
7.1.4
Withdrawal of consent ........................................................................104
7.1.5
Follow-up for safety evaluations.........................................................105
7.1.6
Efficacy follow-up ..............................................................................105
7.1.7
Survival follow-up ..............................................................................105
7.1.8
Lost to follow-up.................................................................................105
7.1.9
End of post-treatment follow-up.........................................................106
7.2
Assessment types.................................................................................................106
7.2.1
Efficacy assessments...........................................................................106
7.2.2
Safety and tolerability assessments.....................................................110
7.2.3
Pharmacokinetics ................................................................................115
119
123
7.2.6
Patient reported outcomes...................................................................124
8
Safety monitoring and reporting......................................................................................126
8.1
Adverse events.....................................................................................................126
8.1.1
Definitions and reporting ....................................................................126
8.1.2
Laboratory test abnormalities..............................................................128
8.1.3
Adverse events of special interest.......................................................128
8.2
Serious adverse events.........................................................................................128
8.2.1
Definitions...........................................................................................128
8.2.2
Reporting.............................................................................................129
8.3
Emergency unblinding of treatment assignment .................................................130
8.4
Pregnancies..........................................................................................................130
8.5
Warnings and precautions....................................................................................130
8.6
Data Monitoring Committee................................................................................131
8.7
Steering Committee .............................................................................................131
9
Data collection and management.....................................................................................131
9.1
Data confidentiality .............................................................................................131
9.2
Site monitoring ....................................................................................................132
9.3
Data collection.....................................................................................................132


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9.4
Database management and quality control..........................................................133
10 Statistical methods and data analysis ..............................................................................134
10.1
Analysis sets ........................................................................................................134
10.1.1
Full Analysis Set .................................................................................134
10.1.2
Safety Set ............................................................................................134
10.1.3
Per-Protocol Set ..................................................................................134
10.1.4
Dose-determining analysis set.............................................................134
10.1.5
Pharmacokinetic analysis set...............................................................134
10.2
Patient demographics/other baseline characteristics ...........................................134
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................135
10.4
Primary objective.................................................................................................135
10.4.1
Variable...............................................................................................135
10.4.2
Statistical hypothesis, model, and method of analysis........................135
10.4.3
Handling of missing values/censoring/discontinuations.....................136
10.4.4
Supportive and sensitivity analyses ....................................................136
10.5
Secondary objectives ...........................................................................................137
10.5.1
Key secondary objective(s).................................................................137
10.5.2
Other secondary efficacy objectives ...................................................138
10.5.3
Safety objectives .................................................................................141
10.5.4
Patient-reported outcomes...................................................................142
10.5.5
Pharmacokinetics ................................................................................144
145
145
145
145
146
146
147
10.7
Interim analysis....................................................................................................148
10.7.1
Primary endpoint: Progression-free survival in the PIK3CA mutant 
cohort...................................................................................................148
10.7.2
Key secondary endpoint: Overall survival in the PIK3CA mutant 
cohort...................................................................................................150
10.7.3
Secondary endpoint: Overall survival in the PIK3CA non-mutant 
cohort: .................................................................................................151
10.8
Sample size calculation........................................................................................152


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10.9
Power for analysis of key secondary variable .....................................................154
10.9.1
Patients with PIK3CA non-mutant status (secondary endpoint):........155
11 Ethical considerations and administrative procedures ....................................................156
11.1
Regulatory and ethical compliance......................................................................156
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................156
11.3
Informed consent procedures...............................................................................156
157
11.4
Discontinuation of the study................................................................................157
11.5
Publication of study protocol and results.............................................................157
11.6
Study documentation, record keeping and retention of documents.....................158
11.7
Confidentiality of study documents and patient records .....................................158
11.8
Audits and inspections.........................................................................................159
11.9
Financial disclosures............................................................................................159
12 Protocol adherence ..........................................................................................................159
12.1
Amendments to the protocol................................................................................159
13 References (available upon request)................................................................................160
14 Appendices ......................................................................................................................166
166
166
167
172
14.2
Appendix 2 – Patient Patient reported outcomes.................................................173
14.3
Appendix 3 - Guidelines for response, duration of overall response, TTF, 
TTP, progression-free survival and overall survival (based on RECIST 1.1).....180
14.3.1
Introduction.........................................................................................182
14.3.2
Efficacy assessments...........................................................................182
14.3.3
Definitions...........................................................................................182
14.3.4
Disease measurability..........................................................................182
14.3.5
Eligibility based on measurable disease..............................................183
14.3.6
Methods of tumor measurement - general guidelines.........................183
14.3.7
Baseline documentation of target and non-target lesions ...................185
14.3.8
Follow-up evaluation of target and non-target lesions........................186
14.3.9
Follow-up and recording of lesions.....................................................186
14.3.10
Non-nodal lesions................................................................................186
14.3.11
Nodal lesions.......................................................................................186
14.3.12
Determination of target lesion response..............................................187


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14.3.13
Determination of non-target lesion response ......................................189
14.3.14
New lesions .........................................................................................190
14.3.15
Evaluation of overall lesion response .................................................190
14.3.16
Efficacy definitions .............................................................................191
14.3.17
Best overall response...........................................................................191
14.3.18
Time to event variables .......................................................................194
14.3.19
Progression-free survival ....................................................................194
14.3.20
Overall survival...................................................................................194
14.3.21
Time to progression.............................................................................194
14.3.22
Time to treatment failure.....................................................................195
195
195
196
14.3.26
Definition of start and end dates for time to event variables ..............197
14.3.27
Handling of patients with non-measurable disease only at baseline...198
14.3.28
Sensitivity analyses .............................................................................199
14.3.29
Data handling and programming rules................................................202
14.3.30
Study/project specific decisions..........................................................202
14.3.31
End of treatment phase completion.....................................................202
14.3.32
End of post-treatment follow-up (study phase completion)................202
14.3.33
Medical validation of programmed overall lesion response ...............203
14.3.34
Programming rules..............................................................................203
14.3.35
Calculation of ‘time to event’ variables..............................................203
14.3.36
Incomplete assessment dates...............................................................204
14.3.37
Incomplete dates for last known date patient alive or death ...............204
14.3.38
Non-target lesion response..................................................................204
14.3.39
Study/project specific programming...................................................204
14.3.40
Censoring reason.................................................................................204
14.3.41
References (available upon request) ...................................................206
14.4
Appendix 4 - Guidelines for the treatment of study drug combination induced 
diarrhea ................................................................................................................207
14.5
Appendix 5 - Guidelines for the treatment of study drug induced 
stomatitis/oral mucositis......................................................................................211
14.6
Appendix 6 - Statistical methodology .................................................................212
14.6.1
Statistical methodology and operating characteristics – PFS futility 
criteria in the PIK3CA mutant cohort..................................................212


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14.6.2
Statistical design and operating characteristics – PFS in the 
PIK3CA non-mutant cohort.................................................................213
14.7
Appendix 7: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.......................................................................................................214
List of figures
Figure 1-1
Schematic representation of the PI3K pathway ....................................39
Figure 1-2
Effect of alpelisib and fulvestrant alone or in combination on ER 
transcriptional activity and tumor growth in MCF7 PIK3CA mutant 
ER+ breast cancer model ......................................................................49
Figure 1-3
Effect of fulvestrant with or without alpelisib (BYL719) on tumor 
growth in patient derived xenograft models..........................................50
Figure 4-1
Study design..........................................................................................61
Figure 14-1
EORTC QLQ-C30 ..............................................................................173
175
178
List of tables
Table 1-1
PI3K signaling pathway mutations and alterations in breast cancer.....40
Table 1-2
Study [CBYL719X2101]: AEs (greater than or equal to10%) 
suspected to be related to study treatment.............................................52
Table 3-1
Objectives and related endpoints ..........................................................58
Table 6-1
Alpelisib/placebo and fulvestrant dose and treatment schedule ...........70
Table 6-2
Dose reduction sequential steps for alpelisib/placebo ..........................73
Table 6-3
Criteria for interruption and re-initiation of alpelisib/placebo 
treatment................................................................................................74
Table 6-4
Alternative causes of liver disease ........................................................86
Table 6-5
Packaging and labeling .........................................................................92
Table 6-6
Supply and storage of study treatments ................................................92
Table 7-1
Visit evaluation schedule ......................................................................95
Table 7-2
Imaging assessment collection plan....................................................109
Table 7-3
ECOG performance status...................................................................111
Table 7-4
Central clinical laboratory parameters collection plan........................113
Table 7-5
Local ECG collection plan..................................................................115
Table 7-6
Pharmacokinetic blood collection log for trough sampling................118
Table 7-7
Pharmacokinetic blood collection log for sparse sampling.................118
120


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Table 7-10
Patient reported outcomes collection plan ..........................................125
Table 10-1
Simulated probabilities to stop for futility or efficacy at the interim 
or final analysis in the PIK3CA mutant cohort ...................................149
Table 10-2
Simulated probabilities to stop for efficacy at 1st interim, 2nd 
interim, or final OS analysis in the PIK3CA mutant cohort................151
Table 10-3
Simulated probabilities to stop for efficacy at 1st interim, 2nd 
interim, or final OS analysis in the PIK3CA non-mutant cohort ........152
Table 10-4
Estimated timelines for interim and final PFS analyses in the 
PIK3CA mutant cohort........................................................................153
Table 10-5
Operating characteristics for PoC criteria in PIK3CA non-mutant 
cohort...................................................................................................154
Table 10-6
Estimated timelines for interim and final OS analyses in the 
PIK3CA mutant cohort........................................................................155
Table 10-7
Estimated timelines for interim and final OS analyses in the 
PIK3CA non-mutant cohort.................................................................156
 
 
 
 
 
166
168
169
172
Table 14-5
Response criteria for target lesions .....................................................187
Table 14-6
Response criteria for non-target lesions..............................................189
Table 14-7
Overall lesion response at each assessment ........................................191
Table 14-8
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................198
Table 14-9
Options for event dates used in PFS, TTP, 
........200
Table 14-10
NCI CTCAE version 4.03 grading of diarrhea for patients without 
colostomy............................................................................................207
Table 14-11
Operating characteristics for PFS futility criteria in the PIK3CA
mutant cohort ......................................................................................212
Table 14-12
Operating characteristics for PoC criteria in PIK3CA non-mutant 
cohort...................................................................................................214
Table 14-13
Liver event and laboratory trigger definitions ....................................214


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List of abbreviations
ADA
American Diabetes Association
ADME
Absorption Distribution Metabolism and Excretion
AE
Adverse Event
AI
Aromatase Inhibitor
AESI
Adverse Events of Special Interest
AKT
Protein Kinase B
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase/Glutamic Pyruvic Transaminase/GPT
ARA
Acid Reducing Agents 
aPTT
Activated partial thromboplastin time
Arizona CERT
Arizona Center for Research and Education on Therapeutics
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase/Glutamic Oxaloacetic Transaminase/GOT
ATC
Anatomical Therapeutic Chemical Classification System
AUC0-6h
Area Under the Curve 0-6h
b.i.d.
bis in diem (twice a day)
BAL
Broncho-alveolar Lavage
BC
Breast Cancer
BCRP
Breast Cancer Resistance Protein
BIRC
Blinded Independent Review Committee
BOV
Between-Occasion-Variability
BSA
Body Surface Area
BSV
Between-Subject-Variability
BUN
Blood Urea Nitrogen
CABG
coronary artery bypass graft
CAR
Constitutive Androstane Receptor
CDK4/6
Cyclin-Dependent Kinases 4 and 6
CFR
Code of Federal Regulations
CISH
Chromogenic In Situ Hybridization
CK
Creatine Kinase
Cmin
Minimum Concentration
CNS
Central Nervous System
CR
Complete Response
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of Variation
CYP
Cytochrome P
DDI
Drug-Drug Interaction
DLT
Dose Limiting Toxicity
DBP
Diastolic Blood Pressure


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DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
DRESS
Drug Reaction with Eosinophilia and Systemic Symptoms
DS&E
Drug Safety and Epidemiology
EC
Ethics Committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EGFR
Epidermal Growth Factor Receptor
EM
Erythema Multiforme
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire
EOT
End of Treatment
ER
Estrogen Receptor
FAS
Full Analysis Set
eSAE
Electronic Serious Adverse Event
FDA
Food and Drug Administration
FDG-PET
Fluorodeoxyglucose Positron Emission Tomography
FISH
Fluorescence In Situ Hybridization
FPG
Fasting Plasma Glucose
FSH
Follicle-stimulating Hormone
GGT
Gamma-glutamyltranspeptidase
GI
Gastrointestinal
GLP
Good Laboratory Practice
 
HbA1c
Glycosylated Hemoglobulin
HDL
High Density Lipoprotein
HER2
Human Epidermal Growth Factor Receptor 2
HFHC
High-fat high-calorie 
HIV
Human Immunodeficiency Virus
HLA
Human Leukocytes Antigen 
HR
Hormone Receptor
HR.
Hazard Ratio
HR+
Hormone Receptor Positive
i.v.
intravenous(ly)
IB
Investigator Brochure
IC50
Half maximal Inhibitory Concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IIT
Investigator Initiated Trial
IN
Investigator Notification
INR
International Normalized Ratio


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IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
IWRS
Interactive Web Response System
LDH
Lactate dehydrogenase
LDL
Low Density Lipoprotein
LFT
Liver Function Tests
LLOQ
Lower Limits of Quantitation
LFLC
Low-fat low-calorie 
LH-RHa
Luteinizing hormone-releasing hormone agonist
LVEF
Left Ventricular Ejection Fraction
MBC
Metastatic Breast Cancer
MCF7
Michigan Cancer Foundation-7
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MDR1
Multi Drug Resistance
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
MRP2
Multi-drug Resistance Protein-2
MTD
Maximum Tolerated Dose
mTOR
Mammalian Target of Rapamycin
MUGA
Multiple Gated Acquisition
NCCN
National Comprehensive Cancer Network
NCDS
Novartis Clinical Data Standards
NCI-CTCAE
National Cancer Institute Common Terminology Criteria Adverse Event
NGS
Next Generation Sequencing
NSAI
Non-Steroidal Aromatase Inhibitors
NTCP
Sodium Taurocholate Co-transporting Polypeptide
o.d.
omnia die (once a day)
OAT
Organic Anion Transporter
OATP
Organic Anion-transporting Polypeptide
OCT
Organic Cation Transporter
ORR
Overall Response Rate
OS
Overall Survival
p.o.
per os (by mouth/orally)
PD
Progressive Disease
PET/CT
Positron Emission Tomography/Computed Tomography
PFS
Progression-Free Survival
PgR
Progesterone Receptor
PHI
Protected Health Information
PhRMA
Pharmaceutical Research and Manufacturers in America
PI3K
Phosphatidylinositol-3-kinase
PIK3CA
Gene which encodes the p110alpha catalytic subunit of PI3K
PK
Pharmacokinetics
PoC
Proof of Concept
PPS
Per-Protocol Set


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PR
Partial Response
PRO
Patient Reported Outcomes
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
PTEN
Phosphatase and Tensin Homolog
PXR
Pregnane X receptor
q.d.
Quaque Die (every day)
QOL
Quality of Life
QTcF
Q-T interval in the ECG (corrected according to the formula of Fridericia)
RBC
Red Blood Cells
REB
Research Ethics Board
R Value
ALT/ALP in x ULN
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SAP
Statistical Analysis Plan
SC
Steering Committee
SD
Stable Disease
SEC
Specific safety event categories
SERD
Selective Estrogen Receptor Down regulator
SERM
Selective Estrogen Receptor modulator
SISH
Silver in situ Hybridization
SJS
Stevens-Johnson Syndrome
SmPC
Summary of Product Characteristics
SSC
Study Steering Committee
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBIL
Total Bilirubin
t.i.d.
Ter in die (3 times a day)
Tc99
Technetium-99
TdP
Torsade de Pointes
TTP
Time to Progression
UGT1A9
UDP-glucuronosyltransferase 1 family, polypeptide A9
ULN
Upper Limit of Normal
WBC
White Blood Cell
WHO
World Health Organization


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Glossary of terms
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 subject
Control drug
A study treatment 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
Cohort
A group of newly enrolled patients based on the PIK3CA status defined as mutant 
or non-mutant
Cycles
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g.: q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
Enrollment
Point/time of patient entry into the study; the point at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with “investigational 
new drug”
Investigational treatment
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes 
approved drugs used outside of their indication/approved dosage, or that are tested 
in a fixed combination. Investigational treatment generally does not include other 
study treatments administered as concomitant background therapy required or 
allowed by the protocol when used in within approved indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is linked to 
one of the treatment arms of a study
Other study treatment
Any drug administered to the patient as part of the required study procedures that 
was not included in the investigational treatment
Subject Number (Subject 
No. NCDS)
A unique identifying number assigned to each patient/subject/healthy volunteer who 
enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller functional segments 
such as screening, baseline, titration, washout, etc.
Randomization number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Stage related to study 
timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
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
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins.
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this case 
refers to the investigational and non-investigational treatments in combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for any reason
Supportive treatment
Refers to any treatment required by the exposure to a study treatment, e.g. 
premedication of vitamin supplementation and corticosteroid for pemetrexed 
disodium.
Variable
Identifier used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified timepoints


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Withdrawal of consent
Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not 
want any further study related contact


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Protocol summary
Title
SOLAR-1: A phase III randomized double-blind, placebo controlled study of alpelisib in 
combination with fulvestrant for men and postmenopausal women with hormone receptor 
positive, HER2-negative advanced breast cancer which progressed on or after 
aromatase inhibitor (AI) treatment
Brief title
Study assessing the efficacy and safety of alpelisib plus fulvestrant in men and 
postmenopausal women with advanced breast cancer which progressed on or after AI 
treatment.
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 plus fulvestrant 
prolongs progression-free survival (PFS) compared to fulvestrant and placebo in men 
and postmenopausal women with hormone receptor positive (HR+), HER2-negative 
advanced breast cancer, who received prior treatment with an AI either as (neo)adjuvant 
or for advanced disease.
Pre-clinical data showing potential for cell death in addition to decreased proliferation 
have been observed when PI3K inhibitors are given in combination with hormonal 
therapy, in particular fulvestrant. Furthermore promising clinical activity has been 
observed with single agent alpelisib in heavily pre-treated ER+ Metastatic Breast Cancer 
(MBC) patients and when alpelisib was given in combination with fulvestrant or AI to HR+ 
HER2-negative metastatic breast cancer patients.
Primary 
Objective(s) and 
Key Secondary
Objective
The primary objective is to determine whether treatment with alpelisib in combination 
with fulvestrant prolongs PFS compared to treatment with placebo in combination with 
fulvestrant based on local radiological assessment for patients with PIK3CA mutant 
status
The key secondary objective is to determine whether treatment with alpelisib in 
combination with fulvestrant prolongs overall survival (OS) compared to treatment with 
placebo in combination with fulvestrant for patients with PIK3CA mutant status
Secondary 
Objectives
● To establish proof of concept of treatment benefit with alpelisib in combination with 
fulvestrant with respect to PFS for patients with PIK3CA non-mutant status
● To evaluate the two treatment arms with respect to OS for patients with PIK3CA non-
mutant status
● To evaluate the two treatment arms and cohorts of interest with respect to overall 
response rate (ORR), clinical benefit rate.
● To evaluate the two treatment arms and cohorts of interest with respect to time to 
deterioration of Eastern Cooperative Oncology Group (ECOG) performance status
● To evaluate the safety and tolerability of alpelisib in combination with fulvestrant
● To evaluate change in global health status/Quality of Life (QOL) in the two treatment 
arms and cohorts of interest
● To characterize the pharmacokinetics (PK) of fulvestrant and alpelisib when given in 
combination with fulvestrant.
● To evaluate the association between PIK3CA mutation status as measured in ctDNA 
at baseline with PFS upon treatment with alpelisib.


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Study design
This is a randomized, phase III, double-blind, placebo controlled global trial comparing 
the combination of fulvestrant + alpelisib to fulvestrant + placebo in men and 
postmenopausal women with HR+, HER2-negative advanced breast cancer. The study 
will consist of 35-days screening phase, of a treatment phase, and of a post-treatment 
phase which includes safety, efficacy, and survival follow-up.
After molecular assessment of PIK3CA mutation status, patients will be assigned to one 
of the following cohorts:
● Cohort I; PIK3CA mutant: Patients with a confirmed PIK3CA mutation as per protocol 
definition.
● Cohort II; PIK3CA non-mutant: Patients without evidence of PIK3CA mutation as per 
protocol definition.
In each cohort, patient will be randomly assigned to either fulvestrant+alpelisib or 
fulvestrant+placebo in a 1:1 ratio. Randomization will be stratified by the following 
factors:
● Lung and/or liver metastases (yes versus no)
● Previous treatment with any CDK4/6 inhibitor (yes versus no)
(note: the total number of patients pre-treated with any CDK4/6 inhibitor will be limited to 
30% of the overall study population)
Population
The study will include approximately 560 men and postmenopausal women with HR+, 
HER2-negative advanced breast cancer which progressed on or after AI treatment. The 
investigator or designee must ensure that only patients who meet all of the inclusion and 
none of the exclusion criteria are offered treatment in the study.
Key Inclusion 
criteria
● Patient is man or postmenopausal woman
● Patient has adequate tumor tissue for the analysis of PIK3CA mutational status by a 
Novartis designated laboratory. One new or recent biopsy (collected at screening if 
feasible) or archival tumor block or slides (15 slides minimum from a surgical specimen, 
20 slides minimum from a biopsy) must be provided. It is recommended to provide a 
tumor sample collected after the most recent progression or recurrence
● Patient has identified PIK3CA status (mutant or non-mutant; determined by a Novartis 
designated laboratory)
● Patient has advanced (loco regionally recurrent not amenable to curative therapy or 
metastatic) breast cancer.
● Patients may be:
● relapsed with documented evidence of progression while on (neo) adjuvant 
endocrine therapy or within 12 months from completion of (neo)adjuvant endocrine 
therapy with no treatment for metastatic disease
● relapsed with documented evidence of progression more than 12 months from 
completion of (neo)adjuvant endocrine therapy and then subsequently progressed with 
documented evidence of progression while on or after only one line of endocrine therapy 
for metastatic disease
● newly diagnosed advanced breast cancer, then relapsed with documented 
evidence of progression while on or after only one line of endocrine therapy
● Patient has recurrence or progression of disease during or after AI therapy (i.e. 
letrozole, anastrozole, exemestane).
● Patient has a histologically and/or cytologically confirmed diagnosis of ER+ and/or 
PgR+ breast cancer by local laboratory
● Patient has HER2-negative breast cancer defined as a negative in situ hybridization 
test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, 
CISH, or SISH) test is required by local laboratory testing
● Patient has either measurable disease, i.e., at least one measurable lesion as per 
RECIST 1.1 criteria OR if no measurable disease is present, then at least one 
predominantly lytic bone lesion must be present
● Patient has ECOG performance status 0 or 1
● Patient has adequate bone marrow function


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Key Exclusion 
criteria
● Patient who relapsed with documented evidence of progression more than 12 months 
from completion of (neo)adjuvant endocrine therapy with no treatment for metastatic 
disease
● Patient with symptomatic visceral disease or any disease burden that makes the 
patient ineligible for endocrine therapy per the investigator’s best judgment
● Patient has received prior treatment with chemotherapy (except for neoadjuvant/ 
adjuvant chemotherapy), fulvestrant, any PI3K, mTOR or AKT inhibitor
● Patient has a concurrent malignancy or malignancy within 3 years of randomization, 
with the exception of adequately treated, basal or squamous cell carcinoma, non-
melanomatous skin cancer or curatively resected cervical cancer
● Patient 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) and/or from whom ≥ 
25% of the bone marrow was irradiated
● Patients with an established diagnosis of diabetes mellitus type I or not controlled type 
II
● Patient has impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of the study drugs
● Patient has any other concurrent severe and/or uncontrolled medical condition that 
would, in the investigator’s judgment, contraindicate patient participation in the clinical 
study
● Patient has currently documented pneumonitis
● Patient has active cardiac disease or a history of cardiac dysfunction (more details in 
Section 5.3)
● Patient has a history of acute pancreatitis within 1 year of screening or a past medical 
history of chronic pancreatitis
Investigational 
and reference 
therapy
Within each cohort, patients will be randomized 1:1 to receive either alpelisib in 
combination with Fulvestrant (treatment arm B) or placebo in combination with 
Fulvestrant (treatment arm A)
For this study, the term “investigational drug” refers to Novartis study drug alpelisib. 
Fulvestrant is also being used in this study. Study treatment in this study refers to the 
combination of drugs in each of the study arms and includes alpelisib/placebo and 
fulvestrant.
Patients will be randomly assigned to one of the below treatment arms in a 1:1 ratio:
● Control arm (Arm A): fulvestrant + alpelisib placebo
OR
● Experimental arm (Arm B): fulvestrant + alpelisib
Study treatment
Pharmaceutical form and 
route of administration
Frequency and/or Regimen
Fulvestrant
Two 5ml injections for i.m. 
administration
Dosed every 28 days (Cycle n 
Day 1) with 1 additional dose 
on Day 15 of Cycle 1
Alpelisib/ Placebo
Tablet for oral use
Once daily
Efficacy 
assessments
● CT/ MRI every 8 weeks for the first 18 months, then every 12 weeks until 36 months, 
then change to as clinically indicated thereafter until disease progression, death, 
withdrawal of consent, loss to follow-up, or subject/guardian decision
● Brain CT or MRI as clinically indicated if brain lesion at screening
● Whole body scan as clinically indicated
● Bone X-ray, CT or MRI (if bone lesion at screening) every 8 weeks for the first 18 
months and then every 12 weeks until 36 months, then change to as clinically indicated
● Skin color photography (if skin lesions at screening) every 8 weeks during the first 18 
months and then every 12 weeks until 36 months, then change to as clinically indicated
● CT/ MRI for any disease outside of the chest, abdomen, pelvis (if lesion identified at 
screening) every 8 weeks for the first 18 months and then every 12 weeks until 36 
months, then change to as clinically indicated
● Survival status every 12 weeks (or earlier if required) regardless of treatment 
discontinuation reason


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Safety 
assessments
● Physical examination
● ECOG performance status
● Height, weight, and vital signs
● 12 lead ECGs
● ECHO, MUGA scan
● Laboratory assessments including hematology, biochemistry, lipid panel, FPG and 
HbA1c, fasting lipase, fasting amylase, coagulation (via aPTT, PTT and INR) and 
urinalysis
Other 
assessments
Pharmacokinetic: blood samples will be obtained from approximately 200 patients 
(25%) in the study for sparse PK for alpelisib. In all other patients, pre-dose samples will 
be taken for alpelisib and fulvestrant trough plasma concentrations.
Biomarker: tumor and blood samples will be collected for biomarker analysis
All
assessments will be performed by a Novartis designated laboratory. The 
assessments on
samples will include a multiplex 
approach.
Patient-reported outcomes: Patient questionnaires (EORTC-QLQ-C30, 
 
) will be collected to assess health-related quality-of-life, health status, 
functioning, disease symptoms, side effects, and cancer-related pain.
Healthcare resource utilization: Potential differences in hospital resource utilization will 
be explored by assessing the number of patients hospitalized, the total number and 
length of hospitalizations
Data analysis
The primary efficacy endpoint, PFS, will be determined based on local tumor 
assessment following RECIST 1.1 guidelines. The primary efficacy analysis will be the 
comparison of the distribution of PFS between the two treatment groups using a stratified 
log-rank test at a one-sided 2.0% level of significance in the PIK3CA mutant cohort.
Interim analyses that allow to stop for futility and efficacy in the PIK3CA mutant cohort 
with the primary endpoint are included.
A stratified Cox regression model will be used to estimate the hazard ratio of PFS, along 
with 95% confidence interval. Subgroup analyses will be performed on each level of 
stratification factors if the primary analysis is significant.
If the primary endpoint PFS is statistically significant in the PIK3CA mutant cohort, the 
key secondary efficacy analysis will be the comparison of the distribution of OS between 
the two treatment groups using a stratified log-rank test at a one-sided 2.0% level of 
significance.
Interim analyses that allow to stop for efficacy with the key secondary endpoint are 
included.
A stratified Cox regression will be used to estimate the hazard ratio of OS, along with 
95% confidence interval.
The assessment of safety will be based mainly on the frequency of adverse events and 
on the number of laboratory values that fall outside of pre-determined ranges.
Key words
HR+, HER2-negative, advanced breast cancer, alpelisib, fulvestrant,PI3K, Phase III, 
ER+, PgR+, men, postmenopausal, aromatase inhibitor.
Amendment 5 (11-Feb-2020)
Study CBYL719C2301 was initiated in 2015 with first patient screened on 23 July 2015 and 
completed enrollment on 21 July 2017 with 572 patients
randomized (341 in 
the PIK3CA mutant cohort and 231 in the PIK3CA non-mutant cohort). Results of this trial led 
to the registration of PIQRAY (Alpelisib, BYL719) in combination with fulvestrant for the 
treatment of HR-positive, HER-2 negative, PIK3CA-mutated, advanced or metastatic breast 


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cancer, with approvals already received in some countries including the United States. Patients 
are still being followed up for survival and long-term safety.
The purpose of this amendment is to provide a protocol update on the following based on the 
recently released IB Edition 13:
Update on 
 and the use of 
Update on guidance of dose interruption/modifications, management of AEs associated with 
the use of alpelisib, and guidance for follow-up on toxicities
Added AST/ALT/Total Bilirubin dose modifications in Table 6-3 (based on a feedback from 
FDA to match PIQRAY USPI). Accordingly, Table 6-4 was replaced with a table on alternative 
causes of liver diseases; and section on follow-up of potential drug-induced liver injury (DILI) 
was updated
Minor update for the guidelines of skin rash (based on feedback from KOL Dermatologist)
Added DRESS as one of possible manifestations of severe cutaneous skin reactions
Update of the VES for PRO, ECG, ECHO/MUGA assessments
Amendment 5 Rationale
Safety update 
Patients are still being followed up for survival and long-term safety. The Investigator’s 
Brochure (IB) Edition 13, dated 15-Oct-2019, included comprehensive assessments of SOLAR-
1 safety data (with cutoff date: 13-May-2019) and all other available safety data which led to 
further defining alpelisib safety profile and risks associated with alpelisib.
Additionally, this amendment covers the updates:
VES update for PRO assessment
The PRO section of the VES (table 7-1) was reformatted to clarify the PRO schedule during the 
post-treatment follow-up phase and to align with section 7.2.6
Change to efficacy, ECG, ECHO/MUGA and PRO assessmentsSince the study met its 
primary endpoint,the visit schedule for efficacy, ECG, ECHO/MUGA and PRO assessments 
will be performed at C3D1 and then every 2 cycles until 36 months, then it will change to as 
clinically indicated to reflect more closely clinical practice.
Update to the treatment blinding
Protocol text regarding timing of unblinding clarified.
Changes to the protocol
The changes are outlined as follows in order of appearance:

Section 1 : Background: Update on health authority approval and the current status of 
the study treatment in clinical research

Section 4.1.4: efficacy follow-up: Update to the frequency of assessments for patients 
in longer-term efficacy follow-up


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
Section 6.1.1.1: Alpelisib/placebo dosing: Clarification on instructions for a missed 
dose

Section 6.3: Dose modifications: Updates based on IB-12 and IB-13

Section 6.3.1: Dose modification and dose delay

Table 6-3: Criteria for interruption and re-initiation of alpelisib/placebo 
treatment: Minor updates on the management of AEs of special interest

Section 6.3.2: Follow up on toxicities: Updates based on IB-12 and IB-13

Section 6.3.2.1.1: Management of Pneumonitis/ILD: included ILD as a selected 
toxicity

Section 6.3.2.1.2: Guidelines for the treatment of study drug induced skin toxicity: 
included DRESS as a skin toxicity and guidelines for follow up on skin toxicity further 
clarified

Section 6.3.2.1.3: Guidelines for the treatment of alpelisib induced hyperglycemia: 
Update on guidance for glucose lowering medications after discontinuation of alpelisib

Section 6.3.2.1.5: Follow up on potential drug-induced liver injury (DILI) cases: 
Additional information on the diagnosis of DILI and clarification on the approach if DILI 
is confirmed or unlikely

Table 6-4: Alternative causes of liver disease: Table added

Section 6.3.2.1.6: Guidelines for hypersensitivity: Section added
 

Section 6.5.3: Treatment blinding: Timing of unblinding clarified 

Section 7.1: Study flow and visit schedule: Frequency of assessments reduced for 
patients in longer-term efficacy follow-up

Table 7-1: Visit evaluation schedule: Efficacy assessment schedule updated

Section 7.1.6: Efficacy follow-up Frequency of assessments changed for patients in 
longer-term efficacy follow-up

Section 7.2.1: Efficacy assessment Frequency of assessments changed for patients in 
longer-term efficacy follow-up

Table 7-2: Imaging assessment collection plan Frequency of imaging 
assessments changed for patients in longer-term efficacy follow-up

Section 7.2.2.7.1: Electrocardiogram (ECG)

Table 7-5: Local ECG collection plan

Section 7.2.2.7.2: Cardiac imaging – MUGA scan or ECHO 

Section 7.2.6: Patient reported outcomes Frequency of PROs changed for patients in 
longer-term efficacy follow-up

Table 7-10: Patient reported outcomes collection plan

Section 14: Appendix 7: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements Section/Table added


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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 4 (22-Nov2017)
The first patient was screened on 23 July 2015 and enrollment was completed on 21 July 2017, 
with a total of 572 patients randomized (341 in the PIK3CA mutant cohort and 231 in the 
PIK3CA non-mutant cohort).
The purpose of this amendment is to provide updated guidance on the management of skin and 
subcutaneous reactions.
Additional change in the protocol amendment: 
To correct the sentence in section 8.1.1 regarding the timeline of the safety follow up visit. 
Since fulvestrant is a marketed product, and is being used according to locally approved labeling, 
the safety follow-up visit for adverse event monitoring after fulvestrant 5 half-lives (i.e. 40-50 
days) is not applicable.
This visit will take place within 30 days following the last dose of study treatment, which is 
longer than 5 half-lives of alpelisib.
Amendment 4 rationale
Update in Skin Toxicity Management Guidance
Skin toxicity is a known class effect of PI3K/mTOR pathway inhibition. In addition to the 
previously reported case of Stevens-Johnson Syndrome (SJS) from study CMEK162X2109, a 
new suspected case of SJS related to alpelisib treatment was reported from study 
CBYL719C2301 (SOLAR-1) (see IB Ed 10 for details on both cases). An overall assessment 
of the risk of alpelisib for severe cutaneous reactions such as SJS but also Erythema Multiforme 
(EM) has been conducted in April 2017 across the development program. In the Novartis safety 
database for severe adverse events, there were overall 2 cases of SJS and 2 cases of EM reported 
for 1710 patients exposed to alpelisib across all studies (cut-off May 2017). This assessment 
indicated that a causal role of alpelisib in development of SJS and EM cannot be excluded. 
Therefore, in the current protocol and across the alpelisib development program, the existing 
guidance for the management of skin and subcutaneous reaction have been updated to include 
further detailed dose modification and follow-up management guidelines in case of severe 
cutaneous reactions. 
Changes to the protocol
The changes are outlined as follows in order of appearance:

Table 6-3 Criteria for interruption and re-initiation of alpelisib/placebo treatment

Section 6.3.2.1.2 Guidelines for the treatment of study drug induced skin toxicity

Table 7.1 Visit evaluation schedule

Section 8.1.1 Safety monitoring and reporting 
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.


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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.
Amendment 3 (14-Dec-2016)
The first patient was screened on 23 July 2015 and as of 14 December 2016, 443 patients (214
in the PIK3CA mutant cohort and 229 in the PIK3CA non-mutant cohort) have been 
randomized in the study CBYL719C2301.  Enrollment into the PIK3CA non-mutant cohort 
ended on 29 September 2016.  
No efficacy analyses have been performed in this study as of the date of this amendment.
The purpose of this amendment is to:

Modify the interim PFS analysis efficacy stopping boundary from Lan-DeMets (O’Brien-
Fleming) to Haybittle-Peto boundary in the PIK3CA mutant cohort

Ensure that the Novartis clinical team will remain blinded to the treatment allocation in both 
cohorts until the time point when PIK3CA mutant cohort can be unblinded. The
responsibility for performing the final PFS analysis (and first interim OS analysis) in the 
PIK3CA non-mutant cohort is modified from the Novartis Clinical Team to an independent 
statistical group. The results from this analysis will be provided by the independent 
statistical group to the DMC for decision making on the outcome of the PIK3CA non-mutant 
cohort
Additional changes in the protocol amendment

Add a blood sample collection to
 

Revision of window regarding whole body bone scan: change from within 28 days to 
within 42 days prior to randomization

Table 6-3-“Criteria for interruption and re-initiation of alpelisib/placebo treatment”: 
clarification has been added, to indicate that metformin is a preferred option, but that other 
insulin sensitizers such as thiazolidinediones or dipeptidyl peptidase-4 Inhibitors can also 
be used, per investigator judgement

Clarify that the data from the audit-based BIRC assessment summarized using the method 
proposed by Amit et al. 2011 is not considered as exploratory
Amendment 3 rationale
Rationale to change the interim PFS analysis efficacy stopping boundary in the 
PIK3CA mutant cohort
The interim PFS analysis efficacy stopping boundary is changed from Lan-DeMets (O’Brien-
Fleming) to a Haybittle-Peto boundary in the PIK3CA mutant cohort. At the interim efficacy 
analysis for PFS, the observed p-value has to be less than or equal to 0.0001 based on Haybittle-
Peto boundary in order to conclude superior efficacy.


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The main advantage of the Haybittle–Peto boundary is that very little alpha is spent at the early 
interim look which allows stopping the trial early only in case of compelling and overwhelming 
evidence against the null hypothesis. Hence, stopping the trial early for PFS benefit based on a 
Haybittle-Peto boundary is likely to confirm the robustness of the interim analysis results.
Rationale to modify the responsibility for performing the final PFS analysis in 
the PIK3CA non-mutant cohort
In the Protocol Amendment 2 the responsibility for performing the final PFS analysis in the 
PIK3CA non-mutant cohort (and the first IA for OS, if applicable at that time), both of which 
are secondary objectives, was attributed to the Novartis clinical team. The Novartis clinical 
team would unblind the treatment allocations in this cohort to perform this analysis.
In order to avoid any potential for impacting the integrity of the trial in relation to the PIK3CA 
mutant cohort whilst this cohort is still blinded and ongoing, the responsibility for performing 
the final PFS analysis in the PIK3CA non-mutant cohort (and the first IA for OS) will now 
belong to an independent statistical group and this analysis will be provided to DMC.  The 
Novartis clinical team will remain blinded to the treatment allocations in both cohorts up until 
such point the PIK3CA mutant cohort can be unblinded.
The DMC will inform the sponsor only on the outcome of the Proof of Concept result (along 
with the formal testing outcome if Proof of Concept is met).
Rationale to collect an additional blood sample 
To further 
 
 
 
 
Changes to the protocol
The changes are outlined as follows in order of appearance:

List of abbreviations is updated 
 

Section 6.3.1.2, Table 6-3 has been updated to clarify that metformin is a preferred option, 
but that other insulin sensitizers such as thiazolidinediones or dipeptidyl peptidase-4 
Inhibitors can also be used, per investigator judgement

Section 7.1 and 7.1.1 have been updated to clarify that the whole body bone scan required 
at screening can be performed within 42 days prior to randomization

Table 7-1 has been updated to clarify that the whole body bone scan required at screening
can be performed within 42 days prior to randomization
 

Section 7.2.1.1 and Table 7.2, have been updated to clarify the whole body bone scan
required at screening can be performed within 42 days prior to randomization


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
Section 10.4.4: has been updated to clarify that a sample based BIRC audit strategy will be 
used to assess PFS by BIRC.
 
 

Section 10.7.1: has been updated to correct typographical errors to clarify that at the time 
of the futility analysis, the PIK3CA mutant cohort may be stopped for futility if one or both 
of the criteria are met.

Sections 10.7.1 and 10.7.2: have been updated to modify the interim PFS analysis efficacy 
stopping boundary from Lan-DeMets (O’Brien-Fleming) to a Haybittle-Peto boundary in 
the PIK3CA mutant cohort. Table 10-1 is updated accordingly.  

Section 10.7.1: PFS futility boundary based on gamma-family beta spending function has 
been modified due to the slight change in power resulting from change in efficacy stopping 
boundary from a Lan-DeMets (O’Brien-Fleming) to a Haybittle-Peto boundary whilst 
maintaining the same number of PFS events as the original design. 

Section 10.7.2 has been updated to clarify that the responsibility for performing the final 
PFS analysis in the PIK3CA mutant cohort (and the first IA for OS, if applicable at that 
time),  belongs to the Novartis clinical team

Section 10.7.3 has been updated to clarify that the responsibility for performing the final 
PFS analysis in the PIK3CA non-mutant cohort (and the first IA for OS, if applicable at that 
time), belongs to an independent statistical group and this analysis will be provided to DMC.

Section 10.8 has been updated to amend the interim PFS analysis efficacy stopping 
boundary to a Haybittle-Peto boundary and update the statistical power for the primary 
endpoint in the PIK3CA mutant cohort.

Section 14.6.1 has been updated to amend Table 14-11 with the revised interim futility  
stopping probabilities.

In addition to above, changes to typographical errors where applicable have been made
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.
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 2 (30-Aug-2016)
The first patient was screened on 23 July 2015 and as of 19 August 2016, 317 patients have 
been randomized in the study CBYL719C2301.
The purpose of this amendment is to:

Modify the patient population to be enrolled in the study. Patients who relapsed more than 
12 months from completion of (neo)adjuvant endocrine therapy with no treatment for 
metastatic disease will no longer be enrolled in the study

Modify the criteria to define futility at the interim analysis in the PIK3CA mutant cohort

Update inclusion criteria and provide more detailed treatment guidance for AE of 
hyperglycemia and update on AE management for skin toxicity following an advisory-board 
meeting recommendation

Update the general administration guidelines for alpelisib/placebo based on a food effect 
and ARA DDI study: alpelisib must be taken with a meal regardless of composition or 
overall calorie intake. A staggered approach for co-administration of alpelisib with acid 
reducing agents is no longer required

Change the approach for Blinded Independent Review Committee (BIRC) assessment of 
PFS from a full read to an audit (sample) based approach. As PFS in the PIK3CA non-
mutant cohort is a secondary endpoint, no BIRC assessment will be made for these patients.
 
 

Update the estimated timing of interim and final PFS and OS analyses taking into account 
current and expected enrolment rates.
Additional Changes in the protocol amendment:

The protocol appendix 2 has been updated to reflect the new Novartis guidance on the 
implementation of RECIST 1.1

Clarify dose adjustment recommendation in case of isolated AST/ALT grade 3 increase, for 
patients with a baseline AST/ALT between 3 and 5 x ULN

Exclude female patients with a QTcF>460 msec for alignment to the standard language

Add a recommendation to ensure that the central PIK3CA testing result is available before 
conducting other screening assessments, when possible

Removal of the requirement for a central radiology assessment by medical oncologist: 
medical oncologist review has been replaced by a standard blinded independent review 
committee (BIRC) assessment 

Clarify possibility to perform unscheduled laboratory assessments locally if medically 
indicated

Update section 11.5  “Publication of study protocols and results”
Amendment 2 Rationale
Rationale to modify patient population and exclude patients sensitive to prior 
endocrine therapy


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The original protocol allows for patients with documented evidence of progression more than 
12 months from completion of (neo-) adjuvant endocrine therapy with no treatment for 
metastatic disease to participate in the study. The number of patients in this category was 
assumed to be around 15% of the total study population. Based on Howell 2004 and Robertson 
2014, the median PFS for fulvestrant of this group was considered to be 18 months (Section 
10.8). Based on the expected median PFS, a low number of events at interim analysis is 
anticipated to occur in this subgroup. Due to potential difficulties in the interpretation of the 
results for this subgroup, it was decided to exclude endocrine sensitive patients from the study. 
Thus, the proposed patient population will become more homogenous, focusing on patients 
that are refractory to prior hormonal therapy. Accordingly, Section 5.2, Inclusion criterion 9 
and Section 10.8, sample size assumptions, have been modified. The endocrine sensitive 
patients enrolled before the current protocol amendment will be included in the full analysis 
set. The initial assumption for the non-mutant cohort (i.e. 15% of patients being sensitive to 
prior endocrine therapy) is not impacted as enrollment in this cohort is expected to be 
completed at the time of the implementation of the current protocol amendment.
Rationale to modify futility criteria in PIK3CA mutant cohort
In light of the emerging changing treatment landscape, the futility criteria for the PIK3CA
mutant cohort have been modified.
In addition to the stopping boundary for futility based on a beta-spending function defined in 
Section 10.7.1, the DMC will now be asked to consider the conditional probability of observing 
a clinically relevant PFS result of a HR≤0.6 at the final PFS analysis of this cohort, given the 
data observed at the time of the interim analysis. The PIK3CA mutant cohort sample size and 
futility analysis timing remain unchanged.
Update of Inclusion Criteria and detailed guidance for AE management of 
hyperglycemia and updated AE management for skin toxicity
In 2016, a program-wide assessment of available data on alpelisib-induced hyperglycemia and 
skin toxicity was conducted and results were shared and discussed by an advisory board 
consisting of oncologists, endocrinologists and a dermatopathologist. The inclusion/exclusion 
criteria as well as management guidelines were reviewed and more detailed guidance for the 
management of alpelisib induced hyperglycemia and skin toxicity has been developed. The 
inclusion criteria have been modified to exclude patients with HbA1c ≥ 6.5%, as patients with 
fasting plasma glucose ≥ 126 mg/dl (eligible by protocol) and HbA1c ≥6.5% are considered to 
be diabetic according to American Diabetes Association (ADA) guidelines. In addition, patients
with baseline FPG ≥100 mg/dl(5.6 mmol/L) and/or HbA1c ≥5.7% should be instructed on 
lifestyle changes at screening and a consultation with a diabetologist is highly recommended.
For skin toxicity of any grade, treatment with topical steroids 3-4 times daily is recommended. 
Oral anti-histamines are indicated in case of skin toxicity accompanied with burning, stinging
or pruritus or prophylactic in case of hypersensitivity in patients’ medical history, e.g. seasonal 
allergy, allergic asthma, drug-induced exanthema in the past. Consultation with a dermatologist 
is highly recommended for better assessment and management of alpelisib-induced skin toxicity.
Table 6.3, Criteria for interruption and re-initiation of alpelisib/placebo treatment, has been 
updated to provide more detailed guidance than the previous version of the protocol.  


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Update of general administration guidelines for alpelisib/placebo 
The impact of food on the absorption of alpelisib was investigated in a clinical trial in healthy 
volunteers (Study CBYL719A2103) after a single 300 mg oral dose of alpelisib. Compared to 
the fasted state a high-fat high-calorie (HFHC) meal increased – on average – AUCinf by 73% 
and Cmax by 84%, and a low-fat low-calorie (LFLC) meal increased AUCinf by 77% and Cmax 
by 145%, confirming a positive food effect on absorption of alpelisib. No significant difference 
was found for AUCinf between LFLC and HFLC meals. Overall, data from study 
CBYL719A2103 confirmed that alpelisib must continue to be given with a meal. However as 
neither composition nor overall calorie intake have shown an effect, the light meal restriction 
can be lifted, allowing also some further flexibility with regards to alpelisib intake during the 
day if dose administration has been forgotten in the morning.  
Co-administration of an acid-reducing agent (ARA) was investigated in the same clinical trial. 
The co-administration of the H2 receptor antagonist ranitidine in combination with a single 300 
mg oral dose of alpelisib slightly reduced the bioavailability of alpelisib and decreased overall 
exposure of alpelisib. In the presence of a LFLC meal, AUCinf was decreased – on average –
by 21% and Cmax by 36% with ranitidine. In the absence of food, the effect was more 
pronounced with a 30% decrease in AUCinf and a 51% decrease in Cmax with ranitidine 
compared to the fasted state without co-administration of ranitidine. As the study showed a non-
clinically relevant 21% decrease in exposure of alpelisib in combination with ranitidine when 
given with a LFLC meal, ARAs can be administered concomitantly and do not have to be 
administered in a staggered manner. Hence, the restriction about the staggered administration 
of H2-receptor antagonists as well as the avoidance of proton-pump inhibitors has been 
removed.
For more information, please refer to the [Alpelisib (BYL719) Investigators Brochure Edition 
9].
Rationale to change the approach for Blinded Independent Review Committee 
(BIRC) assessment: 
For studies with local PFS as the primary endpoint, central PFS has generally been used as a 
secondary analysis in support of the treatment effect observed in the primary efficacy analysis. 
Although, 100% central review of scans has been performed in many studies, there is a growing 
body of evidence that an audit based approach for central evaluation is sufficient (Zhang et al, 
2012, FDA ODAC 2012). Therefore, the study is being amended to change the central 
assessment of PFS from a full read to an audit based approach. Consequently, blinded 
independent review committee (BIRC) based PFS will no longer be a secondary endpoint but 
will be considered supportive of the primary endpoint analysis in the PIK3CA mutant cohort 
only. As PFS in the PIK3CA non-mutant cohort is a secondary endpoint, no BIRC assessment 
will be made for these patients.
Changes to the protocol
The changes are outlined as follows in order of appearance:

List of abbreviations and Glossary of terms are updated

Protocol summary has been revised to reflect changes made in other protocol sections


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
Section 3, Table 3-1 - secondary 
 objectives and endpoints have been 
updated to remove the PFS assessed by BIRC as secondary objective 
 

Section 4.1.1 recommendation has been added to ensure that the central PIK3CA testing 
result is available before conducting other screening assessments, when possible
 

Section 5.2 has been updated to include only patients resistant to prior endocrine therapy 
and patients with HbA1c ≤ 6.4%

Section 5.2 has been updated to exclude female patients with a QTcF>460 msec

Section 5.2 has been updated to exclude patients who relapsed with documented evidence 
of progression more than 12 months from completion of (neo)adjuvant endocrine therapy 
with no treatment for metastatic disease

Section 6.1.1.1 on alpelisib/placebo dosing instructions and recommendations have been 
updated based on the results of a food effect and ARA DDI study for alpelisib

Section 6.3.1.2, Table 6-3 has been updated to provide more guidance for hyperglycemia 
and skin toxicity management and to update guidance on AST/ALT increase and in case of 
acute pancreatitis

Section 6.3.2.1.3 has been updated per update of Table 6-3

Section 6.4.1.4 has been updated to reflect the changes with respect to the co-administration 
of acid reducing agents, lifting the restriction for the use of proton-pump-inhibitors and 
staggered dosing of other gastric protection agents
 
 
 

Section 7.2.1.1 has been updated to reflect the addition of the audit based strategy for the 
BIRC assessment in the PIK3CA mutant cohort

Section 7.2.1.3 has been added to describe the audit-based central assessment in the PIK3CA
mutant cohort

Section 7.2.3.3 has been updated based on the results of a food effect and ARA DDI study 
for alpelisib

Section 7.2.2.5 has been updated to allow possibility to perform unscheduled laboratory 
assessments locally if medically indicated

Section 10.4.4 has been updated to describe the supportive analysis of PFS using an audit 
based BIRC assessment in the PIK3CA mutant cohort

Section 10.5.1 has been updated to describe the amended interim analysis timings for OS in 
the PIK3CA mutant cohort


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
Section 10.5.2.2 has been updated to describe the amended interim analysis timings for OS 
in the PIK3CA non-mutant cohort

Section 10.5.2.6 has been removed to reflect the removal as a secondary endpoint of  PFS 
as assessed by the BIRC, for both cohorts

Section 10.7.1 has been updated to describe:

the amended interim analysis timings for PFS and revised operating characteristics in 
the PIK3CA mutant cohort

The revised interim futility criteria for PFS in the PIK3CA mutant cohort

Section 10.7.2 has been updated to describe the amended interim analysis timings for OS 
and revised operating characteristics in the PIK3CA mutant cohort

Section 10.7.3 has been updated to describe the amended interim analysis timings for OS 
and revised operating characteristics in the PIK3CA non-mutant cohort

Section 10.8 has been updated to amend the power calculation in the PIK3CA mutant cohort 
resulting from the addition of the revised futility criteria

Section 10.8 has been updated to add revised assumptions regarding the patient population, 
expected PIK3CA mutation rate and revised current and expected accrual rates

Section 10.8 has been updated to add a sample size calculation for the audit size of 
sample-based BIRC assessment of PFS in the PIK3CA mutant cohort

Section 10.9 has been updated to add amended interim and final analysis timings for OS in 
the PIK3CA mutant cohort as a result of the revised assumptions in Section 10.8

Section 10.9.1 has been updated to add amended interim and final analysis timings for OS 
in the PIK3CA non-mutant cohort aligning these timings with the revised interim analysis 
timings for OS in the PIK3CA mutant cohort as described in Section 10.9

Section 11.5 has been modified to reflect update in publication of study protocol and results 

Section 14.3 Appendix 3 has been updated to reflect the new Novartis guidance on the 
implementation of RECIST 1.1

Section 14.6 Appendix 6 has been updated to provide the statistical methodology and 
operating characteristics for the revised interim futility criteria for PFS in the PIK3CA
mutant cohort

In addition to above, changes to typographical errors where applicable have been made
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.
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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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.
Amendment 1
Amendment rationale
The first patient was screened on 23 July 2015 and as of 10 February 2016, 92 patients have 
been randomized in the study CBYL719C2301.
The main purpose of this protocol amendment is to modify the study design for the PIK3CA
non-mutant cohort from pivotal to a proof-of-concept. The PIK3CA mutant cohort will remain 
unchanged. Consequently the primary and key secondary objectives of the study will be to 
compare the two treatment groups, based on PFS and OS respectively, for patients in the 
PIK3CA mutant cohort. Comparison of PFS and OS for patients in the PIK3CA non-mutant 
cohort will be part of the secondary objectives.
The additional purposes of this amendment are:

To update inclusion/exclusion criteria, monitoring and guidance for hyperglycemia and 
skin toxicity management following recent overall safety assessment of alpelisib across 
the development program

To update inclusion/exclusion criteria and to add management guidelines for acute 
pancreatitis; as a life-threatening case of acute pancreatitis has been reported in this study

To add collection of a post-dose ECG assessment around the expected Tmax (2h) for all 
patients

To extend the time window by one week for providing the tumor sample for molecular 
testing from day -28 to day -35 of the screening period; this will allow more time for re-
sending of tumor material/re-biopsy if necessary, or perform a new tumor biopsy

To clarify that a 
 is recommended, when feasible, over 
archival sample for 
 to minimize
at time of study entry

To add the collection of an additional whole blood sample to be used as non-tumor control 
for those patients where a newly obtained tumor biopsy is collected at progression

To update the language of some protocol sections as part of a general update implemented 
across the development program (e.g. safety language for liver toxicity, pancreatitis and 
QT prolongation; language for Adverse Events reporting)
In addition, editorial changes and text corrections were made for clarification in sections of the 
protocol, as appropriate/required.
Rationale to modify the study design for PIK3CA non-mutant cohort from a 
pivotal to a proof-of-concept:
PIK3CA mutations have been established to be associated with a higher sensitivity to alpelisib 
both in vivo and in vitro (Fritsch 2014). In accordance with pre-clinical data, more mature 
clinical data from study [CBYL719X2101] demonstrate that patients with HR+ HER2-negative 


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PIK3CA mutant mBC may derive a greater benefit from alpelisib either as monotherapy or in 
combination with fulvestrant as opposed to patients with PIK3CA non-mutant tumors (Janku 
2014; Novartis internal data). In addition, this finding has been suggested for the combination 
of alpelisib with letrozole or exemestane in a more recently reported study (Dickler 2015). 
Furthermore, a large phase III study assessing the safety and efficacy of the pan-PI3K inhibitor 
buparlisib in combination with fulvestrant showed a trend towards better efficacy in patients 
carrying PIK3CA mutant tumors assessed by ctDNA compared to patients with PIK3CA non-
mutant tumor (Baselga 2015). These data are considered hypothesis generating and at this time, 
the relatively limited activity of pan-PI3K inhibitor and alpelisib in patients with PIK3CA non-
mutant HR+ HER2-negative mBC is not considered conclusive.
Therefore, the primary and key secondary objectives of this study are amended to determine 
whether treatment with alpelisib in combination with fulvestrant prolongs PFS and OS 
respectively, compared to treatment with placebo in combination with fulvestrant for patients 
with PIK3CA mutant status only.
 
 
Analysis of 
PFS for the PIK3CA non-mutant cohort will be conducted as a secondary endpoint and will be 
carried out once 102 PFS events in that cohort have been reported. Considering that analysis 
for the PIK3CA non-mutant cohort will be conducted independently of the primary analysis in 
the PIK3CA mutant cohort, an alpha of 0.5% will be assigned to this comparison. The primary 
efficacy analysis of PFS based on the population of patients with PIK3CA mutation status will 
be performed at a 2.0% level of significance. This approach guarantees the protection of the 
overall type I error (α = 2.5%).
The updated design will allow a reasonable estimate of the effect of the combination of alpelisib 
and fulvestrant in the PIK3CA non-mutant cohort with a decrease in the number of patients to 
be randomized (220 instead of 478). An interim futility analysis based on PFS in the non-mutant 
cohort will no longer be conducted due to the reduced sample size; the planned OS analyses 
have been updated accordingly.
Rationale for updating the inclusion/exclusion criteria and management of 
hyperglycemia
An overall assessment of occurrence and risk factors for alpelisib induced hyperglycemia has 
recently been conducted across the development program in more than 1000 patients treated 
with alpelisib at different dose levels, tumor types and regimens. A higher risk of developing 
grade 3/4 hyperglycemia was observed in patients with HbA1c between 6.5 and 8.0% (Novartis 
Internal Data). In addition, and according to the American Diabetes Association (ADA) 
guidelines with regards to glycemic targets in patients with diabetes mellitus, a value of HbA1c 
>6.5% represents a status of not-optimally controlled diabetes. The equivalent FPG values for 
an HbA1c of 6.5% are around 140 mg/dl. Therefore, in an attempt to reduce the risk of alpelisib-
induced hyperglycemia and in alignment with ADA guidelines, the inclusion criterion #12 for 
FPG and HbA1c has been modified as follows: FPG ≤ 140 mg/dl and HbA1c ≤ 6.5%.
Further recommendations for management of hyperglycemia have also been added in the 
additional follow-up for selected toxicities section.


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Rationale for update on skin toxicity management
A second on-target effect of alpelisib treatment is skin toxicity. As for hyperglycemia, an overall 
assessment of skin toxicity occurrence and possible preventive actions has also been conducted 
recently across the alpelisib development program. Although some improvement in the severity 
of rash has been reported with the prophylactic use of non-sedating oral anti-histamines (Dickler 
2015, Mayer 2015), no conclusive data are available with the combination of alpelisib at 300 
mg/day and fulvestrant 500 mg. Nevertheless, the study is amended to recommend the use of 
prophylactic oral non-sedating anti-histamines (e.g. cetirizine or equivalent), as per the 
discretion of the investigator.
Skin toxicity also typically occurs within the first few weeks of treatment. Therefore, the visit 
on day 8 at cycle 1 is amended to include a clinical assessment of the skin for rash or other 
toxicities.
Rationale for updating the inclusion and exclusion criteria, and the 
management of pancreatitis
One case of life threatening acute pancreatitis has recently been reported in the study 
CBYL719A2301 (SOLAR-1), where postmenopausal women with advanced breast cancer are 
randomized to receive BYL719 (300 mg, once daily) and fulvestrant or BYL719 and placebo. 
No preclinical evidence for this risk has been observed. An overall assessment of the risk of 
alpelisib to induce acute pancreatitis has been conducted at the end of November 2015 across 
the development program (details reported in the IN PHHO2015IL018569). The key findings 
of such evaluation indicate that asymptomatic elevations of pancreatic enzymes may occur in 
some patients treated with alpelisib. Clinical data suggest that a small percentage (< 1%) of 
patients treated with alpelisib may develop acute clinical pancreatitis (Tenner et al 2013).
Therefore, in the current protocol and across the alpelisib development program, the following 
changes have been implemented to allow for diagnosis of acute pancreatitis based on the 
American College of Gastroenterology Guidelines (Tenner et al 2013): modification of 
inclusion criteria; now including fasting amylase and lipase added to the panel of investigations 
at screening; frequent monitoring of amylase and lipase; detailed dose modification guidelines 
in case of increase of amylase and/or lipase or clinical signs of pancreatitis included.
Rationale for the modification of the potassium inclusion criterion
A concentration-effect-analysis for BYL719 (single agent) showed a limited but positive trend 
of increase in QT. While no clinical significant QT prolongation (> 10 ms) is expected at a 300
mg dose, potassium levels should be within normal range at study entry to limit the risk of 
cardiac adverse events, as hypokalemia has been shown to increase QT prolongation and 
hyperkalemia can lead to faster repolarization of the cardiac action potential. During study 
conduct, any potassium related adverse event will be monitored.
Rationale for ECG PK:
Based on a concentration-effect-analysis for alpelisib single agent and in combination with 
fulvestrant (based on [CBYL719X2101]), no clinically significant QT prolongation (> 10ms) 
is expected. Following FDA consultation, to gather additional data, a post-dose ECG 


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assessment, around the expected Tmax (2h), was added for all patients. The expected Tmax 
(2h) is matched to the C1 D15 PK sample for the sparse population (approximately 200 patients 
overall).
Rationale for the update of the management of liver toxicity
Management of liver toxicity has been incorporated as guidance for Investigators and criteria 
for alpelisib dose modification have been updated to better characterize liver toxicities and 
provide more details on their management and follow up.
Changes to the protocol
The changes are outlined as follows in order of appearance:

List of abbreviations and Glossary of terms are updated

Protocol summary has been revised to reflect changes made in other protocol sections

Section 2 Rationale has been updated to reflect the change in study design for PIK3CA
non-mutant cohort

Table 3-1 Objectives and Related Endpoints have been updated to reflect the change in
study design for PIK3CA non-mutant cohort(errors have also been corrected)

Section 4.1 Description of study design has been updated to reflect the change in study 
design for PIK3CA non-mutant cohort

Section 4.1.1 Screening phase has been extended to 35 days prior to randomization/C1D1 
to increase flexibility for sites to send a second biopsy sample in case the first screening 
biopsy sample does not yield a PIK3CA result

Section 4.2 Timing of interim analysis and design adaptions has been modified to reflect 
change in study design change for the PIK3CA non-mutant cohort

Section 4.3 Definition of end of the study has been modified to reflect the change of study 
design for the PIK3CA non-mutant cohort

Section 5.2 Inclusion criteria and Section 5.3 Exclusion criteria have been updated to 
reflect the redefined patient population, to provide further clarity, and to reflect the new 
standard language

Section 6.1.1.1.2 has been revised to include dosing of amylase and lipase

Section 6.3.1.2 has been revised to provide more clarity for treatment dosing 
( recommendation for dose reduction or interruption, and to clarify that treatment must be 
discontinued per Table 6-3)

Table 6-3. Criteria for alpelisib/placebo dose modifications has been revised to introduce 
new guidance to investigators to better characterized liver and pancreatic toxicities and to 
reflect the new standard language

Section 6.3.2 Standard protocol language for the management of liver toxicity and 
amylase/lipase elevation has been incorporated as guidance for Investigators. In addition, 
the management of skin toxicity is revised following recent overall safety assessment of 
alpelisib

Section 6.4.3 Prohibited concomitant therapy has been revised to provide further guidance 
with regards to administration of QT prolonging drugs


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
Section 6.5.2 Treatment assignment or randomization has been updated in accordance 
with study design modification of the PIK3CA non-mutant cohort

Table 7-1 Visit evaluation schedule has been modified:

to extend the screening phase to 35 days prior to randomization/C1D1

to reflect the addition of ECG reading at C1D15 for all patients

to add a physical examination at C1D8

to add FPG assessment at C1D8

to add fasting amylase and lipase at C1D8 and revise the assessment schedule of those 
2 parameters to monthly monitoring instead of every second cycle

Section 7.1.1 Screening has been updated to extend period of screening for molecular 
testing

Section 7.1.1.3 has been updated to reflect collection of amylase

Section 7.2.2.1 Physical examination has been updated to include physical examination at 
C1D8 and has been clarified to allow flexibility of when the exam can be done prior to 
randomization

Section 7.2.2.5 Laboratory evaluations have been updated to reflect collection of fasting 
amylase and to recommend local assessment of FPG at C1D8 and C1D15

Table 7-4 Central clinical laboratory parameters collection plan has been modified to 
incorporate new lab parameters for chemistry (creatine kinase, lactate dehydrogenase) and 
coagulation (activated partial thromboplastin time), and to add fasting amylase as 
additional test.

Sections 7.2.2.5.2; 7.2.2.5.3 and 7.2.2.5.4 have been updated to reflect collection of new 
lab parameters as per Table 7-4, and to update FPG assessment schedule

Section 7.2.2.7.1 Electrocardiogram added at C1D15 for all patients and clarification 
provided for triplicate ECG required at screening – As a consequence, Table 7-5 has been 
updated accordingly

Section 7.2.3.3 Pharmacokinetic blood sample collection plan has been clarified with 
recommendation for unscheduled PK

Section 7.2.4.1.1 Assessments in tumor tissues has been clarified to recommend provision 
of newly obtained tumor biopsy if possible
 

Section 8. Safety monitoring and reporting has been updated to reflect implementation of 
new SAE reporting instruction


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
Section 10. Statistical methods and data analysis: updates to reflect changes to study 
design (from a pivotal to proof-of-concept design for PIK3CA non-mutant cohort)

Section 10.1.2 Definition of the Safety Set updated to reflect standard text per new 
protocol template

Section 10.1.3 Situations where Per Protocol Set may be used is updated to reflect changes 
to study design objectives

Section 10.4 Primary objective amended to be PFS in PIK3CA mutant cohort

Section 10.4.2 Statistical hypothesis, model, and method of analysis amended for PFS in 
PIK3CA non-mutant cohort

Section 10.4.4. Clarification on situation where subgroup analysis of primary endpoint 
will be conducted

Section 10.5.1 Key secondary objective amended to be OS in PIK3CA mutant cohort only.

Section 10.5.2 Secondary objectives of PFS and OS in PIK3CA non-mutant cohorts added.

Section 10.5.3.1 Clarification on reporting of safety data added

Section 10.5.3.2 : Language for Adverse Event (AE) reporting has been updated to reflect 
new protocol template

Section 10.7 Changes to the Interim Analysis scheme reflecting changes to study design 
(from a pivotal to proof-of-concept design for PIK3CA non-mutant cohort)

Section 10.8 Specification of the new sample size derivation for PFS in the PIK3CA non-
mutant cohort.

Section 10.9 Changes to the timing and assessment of statistical power for Overall 
Survival in the PIK3CA non-mutant cohort
 

Section 14.6 Appendix 6 – Statistical methodology has been added
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 underlined for insertions.
IRB/IEC
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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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
1.1.1
Hormone receptor-positive breast cancer
Breast cancer (BC) is the most common cancer in women, with about 900,000 new cases 
annually. It is estimated that worldwide over 508,000 women died in 2011 due to breast cancer 
(Global Health Estimates, WHO 2013). Breast cancer in men is a more rare disease and makes 
up < 1% of all cases of breast cancers, but its treatment is based on the guidelines for female 
breast cancer (Foerster et al 2014, Agrawal et al 2007, Patten et al 2013, Giordano et al 
2002).Subtypes of breast cancer are distinguished by expression of estrogen receptors (ER), 
progesterone receptors (PgR) and human epidermal growth factor receptor-2 (HER2), as well 
as by distinct gene expression profiles (Perou et al 2000; Sotiriou and Pusztai 2009). Within 
these subtypes 60-70% of breast tumors are HR+HER2-negative. Expression of the ER and/or 
PgR is one of the most important prognostic factors in invasive breast cancer. Estrogen 
deprivation therapy is the core treatment modality in patients with HR+ advanced breast cancer. 
Endocrine therapy options for postmenopausal women with ER+ advanced breast cancer 
(locally advanced, recurrent, or metastatic breast cancer (MBC)) include selective ER 
modulators (SERM; tamoxifen), ER antagonists (fulvestrant), selective nonsteroidal AIs (NSAI; 
anastrozole and letrozole) and steroidal AIs (exemestane). Blocking estrogen signaling with 
tamoxifen has been the main approach in treatment for ER+ breast cancer for over 35 years. In 
postmenopausal women, AIs reduce peripheral estrogen synthesis by blocking the conversion 
of androgens to estrogens in non-ovarian tissues; synthesis in these tissues is the primary source 
of estrogens in postmenopausal women. AIs are generally used as the first line of therapy for 
women with HR+ breast cancer (Beslija et al 2009; NCCN 2.2015). The combination of targeted 
and endocrine therapies has also been evaluated: everolimus, an mTOR inhibitor, combined 
with exemestane showed synergistic inhibition of the tumor proliferation and is approved for 
postmenopausal women with advanced HR+, HER2- negative breast cancer (advanced HR+ 
BC) in combination with exemestane after failure of treatment with letrozole or anastrozole 
(Baselga et al 2012, Yardley et al 2014); recently, palbociclib, a Cyclin-Dependent Kinases 4 
and 6 inhibitor (CDK4/6i), has been approved in United States in combination with letrozole 
for the treatment of postmenopausal women with ER+, HER2-negative advanced breast cancer 
as initial endocrine-based therapy for their metastatic disease based on the results of the phase 
2 Paloma-1 study. The addition of palbociclib to letrozole significantly prolonged PFS as 
compared to letrozole alone (median PFS 20.2 months versus 10.2 months (HR 0.49; 95% 
CI:0.32, 0.75; p=0.0004) (Finn et al 2015).
1.1.2
The PI3K pathway
The phosphatidylinositol-3-kinase (PI3K) signaling regulates diverse cellular functions, 
including cell proliferation, survival, translational regulation of protein synthesis, glucose 
metabolism, cell migration, and angiogenesis (Katso et al 2001). PI3K signaling also serves a 
central role in the pathogenesis of numerous forms of neoplasia. Constitutive activation of PI3K 
signaling is known to be a critical step in mediating the transforming potential of oncogenes 
and tumor suppressors and in many tumor types (Liu et al 2009). Resistance to a variety of 


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therapeutic interventions, including chemotherapy, hormonal therapy and anti-HER2 therapies, 
can also be linked to constitutive activation of the PI3K pathway (McCubrey et al 2006).
Molecular changes leading to constitutive activation of the PI3K pathway are diverse and 
include, but are not limited to:

Gain-of-function mutations of PI3K subunits (PIK3CA encoding the PI3K catalytic 
subunit p110α; genes encoding the p85 regulatory subunit) or oncogenes encoding 
positive regulators of PI3K (e.g. HER2, EGFR, RAS, Src-family proteins) or

Loss-of-function mutations or epigenetic alterations affecting negative regulators of PI3K 
signaling (e.g. loss of Phosphatase and Tensin Homolog (PTEN) expression or function) 
(Chow et al 2006, Cully et al 2006).
A schematic representation of these PI3K components is shown in Figure 1-1.
Figure 1-1
Schematic representation of the PI3K pathway
Somatic missense mutations of PIK3CA that increase the kinase activity of PIK3α protein have 
been identified in tumor tissues and have been linked to cellular transformation in many 
different human cancers (Samuels et al 2004). The majority of somatic mutations were 
identified in mutational hotspots affecting the helical (exon 9) and kinase (exon 20) domains of 
the protein (Karakas et al 2006). However, some mutations were also identified in other 
domains of PI3K, such as the C2 domain (Bader et al 2005; Samuels et al 2004). Mutations 
affecting the helical or kinase domains were shown to enhance PI3K lipid kinase activity, to 
up-regulate the pathway downstream (increasing intracellular levels of phospho-AKT and 
phospho-S6), to drive cellular transformation in vitro and in vivo, and to enhance cell survival 
(Zhao et al 2008, Mankoo et al 2009). Mutations in the C2 domain were shown to induce or 
facilitate conformational changes leading to an increased activity of PI3Kα (Burke et al 2012, 
Hon et al 2012). Overall, the majority of gain-of function mutations identified in the PIK3CA


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gene were reported to occur in the mutational hotspots from exons 7, 9 and 20 which affect the 
C2, helical and kinase domains of PI3Kα respectively (Mankoo et al 2009).
1.1.3
PI3K pathway in HR+ breast cancer
PI3K pathway is frequently altered in HR+ breast cancer. Gain-of-function mutations in 
PIK3CA have been observed in about up to 45% of HR+ breast cancer patients using next 
generation sequencing (NGS) approach (Table 1-1). Inactivation of the tumor suppressor gene 
PTEN via loss-of-function mutations, gene deletion or transcriptional down-regulation also 
leads to PI3K pathway activation and has been reported in approximately 13% of HR+ breast 
cancer patients (Table 1-1).
The overlap between PIK3CA and PTEN alteration appears relatively rare (Cancer Genome 
Atlas Network 2012).
Table 1-1
PI3K signaling pathway mutations and alterations in breast cancer
PIK3CA Mutation
PTEN mutation/loss
All breast tumors
36%
NR
HR+ HER2- negative
45%
13%
Triple Negative
9%
35%
HER2- positive
39%
4%
(Cancer Genome Atlas Network 2012)
Furthermore, pre-clinical data have shown that the ER pathway interacts with the PI3K pathway. 
Extensive crosstalk has been shown between ER and growth factor pathway (Miller et al 2011a; 
Osborne and Schiff 2011).
For example estrogen deprivation leads to hyperactivation of the PI3K/mTOR pathway, which 
induces in turn an increase in cell proliferation and survival (Bjornsti et al 2004; Crespo et al 
2002; Huang et al 2004; Mita et al 2003; Wullschleger et al 2006). This mechanism is linked to 
de novo or acquired resistance to endocrine therapy (Campbell 2001), including AI resistance 
(Shoman et al 2005; Crowder et al 2009; Miller 2011a). Treatment with PI3K inhibitors in 
absence of estrogen can inhibit proliferation of long term estrogen deprived cell lines supporting 
the concept of using combination of a PI3K inhibitor with an endocrine therapy in breast cancer.
More specifically, inhibition of the PI3K pathway has been shown to induce a unique synthetic 
lethality in the context of estrogen deprivation (Crowder et al 2009).
The FERGIE phase II trial was the first randomized Phase II trial investigating the combination 
of the pan-PI3K inhibitor pictilisib with fulvestrant 500 mg vs matching placebo with 
fulvestrant in patients with ER+, HER2-negative, AI-resistant advanced or metastatic breast 
cancer either PI3K mutant or not. One hundred sixty eight patients were randomized. The 
observed mPFS in the combination arm was 6.2 months vs. 3.8 months in the placebo arm (HR 
0.77; 95% CI 0.50-1.19). For patients with PIK3CA mutation mPFS was 6.2 months in the 
combination compared to 5.1 months in the placebo arm (HR 0.92; 95% CI 0.48-1.76), (Krop 
et al 2014). Exploratory post-hoc subgroup analysis suggested a statistically significant 
improvement in mPFS in patients with ER+ and PgR+ tumors treated with pictilisib plus 
fulvestrant 7.2 vs 3.7 months (HR 0.46; 95% CI, 0.27 to 0.78). Multivariate analysis suggests 


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that this treatment effect in patients with ER+/PgR+ tumors is maintained after adjusting for 
possible baseline imbalances.
In the pictilisib arm an increased number of GI toxicities (mainly diarrhea, nausea, vomiting 
and stomatitis), rash and fatigue were observed. All hyperglycemia grades (considered also as 
a potential pharmacodynamic marker for PI3K pathway inhibition) were observed only in 17% 
of patients treated with pictilisib.
Taken together, these observations suggest that the combination of an endocrine treatment, like 
fulvestrant, a selective ER downregulator, and PI3K-inhibitors could be an interesting 
therapeutic option for patients with HR+ breast cancer.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of fulvestrant
Fulvestrant (Faslodex®) is the first-in-class unique ER down regulator with no known agonist 
effects (Addo et al 2002). In fact, fulvestrant mechanism of action is distinct from other 
endocrine agents (Wakeling et al 2000); it binds, blocks and, unlike tamoxifen or other SERMs, 
degrades the ER, completely inhibiting ER signaling. As a result, there is less chance of the ER 
being activated by alternative pathways that are believed to cause resistance (e.g. growth factor–
mediated mechanisms) (Nicholson et al 2005).
Fulvestrant is approved for the treatment of HR+ metastatic breast cancer in postmenopausal 
women with disease progression following anti-estrogen therapy (USA, Europe). However, also 
in postmenopausal women without symptomatic visceral disease also after recurrence or 
progression to an AI, current clinical practice and treatment guidelines include fulvestrant as 
treatment option (NCCN 2.2015).
Fulvestrant 250 mg monthly and exemestane were compared in the EFECT study, a double 
blind placebo controlled phase III trial in 693 postmenopausal women with HR+ breast cancer 
after recurrence or progression on a NSAI (Chia et al 2008). No difference in PFS (median 3.7 
months in both arms), response rate (7.4% vs. 6.7%, respectively) or clinical benefit rate (32.2% 
vs. 31.5%) were observed. A recently completed phase III trial (SOFeA study) compared 
fulvestrant (induction with 500 mg and then 250 mg monthly), to exemestane, and to the 
combination of fulvestrant and anastrozole in ER+ breast cancer patients, following progression 
on non-steroidal AI (Johnston et al 2013). There was no evidence of difference in median PFS 
4.8 months (95%CI 3.6-5.5); 3.4 months (95%CI 3.0-4.6) and 4.4 months (95%CI 3.4-5.4) 
respectively for the fulvestrant, exemestane and fulvestrant plus anastrozole arms.
In postmenopausal patients who experienced progression after prior endocrine therapy (either 
AI or tamoxifen), fulvestrant 500 mg emerged as the optimal dose based on the results of the 
CONFIRM study, which showed that the higher dose (500 mg monthly) significantly prolonged 
PFS compared to the 250 mg dose (mPFS 6.5 vs. 5.5 months; HR= 0.80; p = 0.006) (Di Leo et 
al 2010). More specifically, in that trial, subgroup analysis showed that PFS was prolonged in 
patients who had recurred or relapsed during anti-estrogen therapy (median PFS 8.6 vs. 5.8 
months; HR 0.76; p = 0.013) or during AI therapy although not reaching statistical significance 
for the latter (median PFS 5.4 vs. 4.1 months; HR 0.85; p = 0.195) (Summary of Product 


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Characteristics (SmPC) Faslodex®). Median OS (not a predefined endpoint) was 26.4 months 
for fulvestrant 500 mg and 22.3 months for 250 mg (HR 0.81; p = 0.02, at 75% maturity), 
irrespective of type of prior endocrine treatment (Di Leo et al 2013).
Recently, data have been presented for the phase II randomized study (FIRST) of fulvestrant 
500 mg compared to anastrozole as a first-line therapy in postmenopausal women with HR+ 
advanced breast cancer who received no prior endocrine therapy for advanced disease 
(Robertson et al 2014). Among the 205 patients randomized, 75% of them were naïve from any 
endocrine treatment and 25% had received tamoxifen as adjuvant treatment. The observed 
clinical benefit rate (primary endpoint of the study) was 72.5% for fulvestrant vs 67% for 
anastrozole (HR 1.30; p = 0.386). No significant difference was observed in ORR (36% vs 
35.5%). The median Time to Progression (TTP) was significantly longer for fulvestrant than 
anastrozole (23.4 vs 13.1 months, HR 0.66; p = 0.01). Median OS was 54.1 months for 
fulvestrant and 48.4 months for anastrozole (HR 0.7; p=0.041). OS was not a predefined
endpoint of FIRST in the initial protocol; OS analysis was performed at 66.8% maturity. 
Incidence of Serious Adverse Events were similar between the arms (23.8% fulvestrant vs 21.4% 
anastrozole).
Fulvestrant at the dose of 250 mg did not show superior efficacy compared to tamoxifen in the 
same first-line setting of HR+ metastatic breast cancer where median TTP of 8.2 months was 
observed with fulvestrant and 8.3 months with tamoxifen (HR 1.10; p = 0.39) (Howell et al 
2004). The difference in these TTPs for fulvestrant may be attributed to the higher dose of 500 
mg since findings from clinical, biological studies and PK modeling suggested that fulvestrant 
at an increased dose could further increase the clinical efficacy (Robertson et al 2004). A caveat 
may be found in the small sample size of FIRST study (n= 102 for fulvestrant arm). FALCON 
(ClinicalTrials.gov identifier: NCT01602380), a randomized phase III study comparing 
fulvestrant 500 mg with anastrozole as first-line treatment for postmenopausal women with 
HR+ MBC, completed enrollment in September 2014; results are still pending.
The most common clinically significant adverse reactions occurring in ≥5% of patients 
receiving fulvestrant 500 mg were: injection site reactions, nausea, bone pain, arthralgia, 
headache, back pain, fatigue, pain in extremity, hot flash, vomiting, anorexia, asthenia, 
musculoskeletal pain, cough, dyspnea and constipation. Pooled safety analysis (SmPC) 
identified Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) or alkaline 
phosphatase increases in approximately 15% of the treatment population with grade 3 increases 
seen in 1-2%. There was no difference in rates of AST, ALT and AP elevations between groups 
treated with 250 mg and 500 mg doses. Please refer to the SmPC for further pooled safety data 
for multiple fulvestrant 500 mg trials data.
1.2.1.1
Clinical pharmacokinetics of fulvestrant
The recommended dose (intramuscular injection) is 500 mg at intervals of one month, with an 
additional 500 mg dose given two weeks after the initial dose. Fulvestrant is slowly absorbed 
reaching maximum plasma concentrations after about 5 days. Steady-state is achieved within 
the first month of dosing. At steady-state there is more than a 2-fold difference between mean 
Cmax and Cmin. After intramuscular administration, the exposure is approximately dose-
proportional in the dose range of 50 to 500 mg. Fulvestrant is subject to extensive and rapid 
distribution. Fulvestrant is eliminated mainly by metabolism. The major route of excretion is 


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via the feces with less than 1% being excreted in the urine. Fulvestrant has a high clearance, 
suggesting that it is a drug with a high extraction ratio. The terminal half-life after intramuscular 
administration is governed by the absorption rate and was estimated to be 40-50 days. An in 
vitro inhibition study showed no relevant inhibition of CYP1A2, 2C9, 2C19, 2D6 or 3A4 by 
fulvestrant. The lack of inhibition of CYP3A4 was confirmed in an in vivo interaction study 
with midazolam. Studies using human liver preparations and recombinant human enzymes 
indicate that CYP3A4 is the only P450 isoenzyme involved in the oxidation of fulvestrant; 
however, non-P450 routes appear to be more predominant in vivo as interaction studies with 
rifampicin (CYP3A4 inducer) and ketoconazole (CYP3A4 inhibitor) demonstrated no effect on 
fulvestrant pharmacokinetics. The relative contribution of P-450 and non-P-450 routes in vivo
is unknown [Faslodex® Prescribing Information].The potential for interaction with fulvestrant 
therefore appears to be low.
Increased exposure to fulvestrant was observed in patients with moderate hepatic impairment 
(Child-Pugh class B); therefore a dose of 250 mg is recommended in these cases. Fulvestrant 
has not been administered to patients with severe hepatic impairment (Child-Pugh class C) 
[Faslodex® Prescribing Information].
1.2.2
Overview of alpelisib
Alpelisib is an oral class I α-specific PI3K inhibitor belonging to the 2-aminothiazole class of 
compounds. Alpelisib strongly inhibits the PI3Kα isoform (both p110α wild-type and p110α 
mutation+) and much less strongly the β, δ and γ isoforms. It is inactive against the majority of 
other kinases (Fritsch et al 2014).
Alpelisib has demonstrated anti-tumor activity in preclinical in vitro and in vivo tumor models.
In vitro, alpelisib has been shown to preferentially inhibit the proliferation of cell lines 
harboring PIK3CA mutations (Fritsch et al 2014). In vivo, alpelisib has demonstrated 
dose-dependent tumor growth inhibition in various subcutaneous tumor transplant models. Both 
in vitro and in vivo tumor models (other than breast cancer) provided evidence that PTEN driven 
model might display a lesser sensitivity to alpelisib, in particular if the PTEN alteration is 
concomitant with PIK3CA mutation. This feature, however might not be relevant in HR+ breast 
cancer patients considering how rarely overlap between these alterations has been seen (see 
Section 1.1.3). Alpelisib is currently being investigated in Phase I dose escalation trials and in 
Phase Ib combination trials. Doses up to 450 mg once daily (q.d.) have been administered to 
patients suffering from cancer. The Maximum Tolerated Dose (MTD) of single-agent oral 
alpelisib has been declared at 400 mg q.d. and the recommended phase II single agent dose 
declared at 350 mg.
For further details on clinical and non-clinical experience, please refer to the latest version of 
[Alpelisib (BYL719) Investigators Brochure].
1.2.2.1
Non-clinical experience
1.2.2.1.1 Pharmacodynamics of alpelisib
In biochemical assays, alpelisib inhibits specifically p110α (IC50 = 4.6 nM,) more potently than 
the p110δ and γ isoforms. Alpelisib is equipotent against the most common somatic mutations 
of p110α (H1047R, E545K) compared to wild type p110α. The alpelisib biological activity 


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correlates with inhibition of various PI3K/AKT downstream signaling pathway components 
commonly used as indicators of pharmacodynamics. Please refer to the [Alpelisib (BYL719) 
Investigators Brochure] for further details.
In vivo, alpelisib shows dose and time-dependent inhibition of the PI3K/AKT pathway in 
relevant tumor xenograft models (p110α-mechanistic model and p110α-mutant xenograft 
models) in nude mice and rats. In vivo analyses of tumor tissues, upon acute dose or after 
repeated dosing, show a good correlation between compound exposure and PI3K pathway 
blockade (Fritsch et al 2014).
Finally, in breast cancer xenograft models, treatment with alpelisib led to significant decrease 
in AKT phosphorylation, further supporting the observation of effective inhibition of PI3K 
signaling (see Section 1.1.2).
1.2.2.1.2 Nonclinical PK and metabolism of alpelisib
Alpelisib demonstrates low plasma clearance, a moderate volume of distribution (Vss) at steady 
state and a good absolute oral bioavailability in all preclinical species tested. The compound is 
moderately bound to plasma proteins with no major species difference and this binding is 
independent of the concentration (free fraction in human plasma ~ 10.8%). Alpelisib showed a 
rapid distribution to almost all rat tissues, except the brain (rat Absorption Distribution 
Metabolism and Excretion (ADME) study). Results from 4-week Good Laboratory Practice
(GLP) toxicology studies in dogs showed a roughly dose-proportional increase in exposure, 
while in rats the exposure increased up to a dose of 30 mg/kg beyond which no further increase 
was noted following single dose administration. The toxicology studies provided no clear 
evidence of increase in exposure following multiple dosing. No gender differences in exposure 
were observed in rats or dogs.
In vitro metabolism and transport
The overall metabolic turnover of alpelisib was very low in dog and human hepatocytes (as well 
as microsomes) and slightly higher in the rat. CYP3A4 was found to be the major P450 enzyme 
involved in hepatic oxidative metabolism in vitro with small contribution by other enzymes. 
While UGT phenotyping showed that UGT1A9 could be involved in the glucuronidation of 
alpelisib in human liver microsomes, the turnover rate of phase II metabolism in vitro was very 
low. No covalent drug protein adduct formation was noted in human microsomes or hepatocytes. 
The main biotransformation pathway that was observed consistently in vitro and in vivo (see 
below) across species was amide hydrolysis to BZG791, a pharmacologically inactive product 
which – based on vitro experiments – can be produced both chemically and enzymatically by 
ubiquitously expressed, high-capacity enzymes (esterases, amidases, choline esterase) unlikely 
to become fully inhibited by drug interactions.
 
 
 
 
 
 


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Disposition of alpelisib
Elimination of alpelisib in vivo - at the current stage of knowledge - appears to be a three-parted 
pathway consisting of CYP450-mediated oxidative metabolism, hydrolysis to BZG791 
(enzymatic or chemical, currently unknown) and biliary elimination. Recent results from human 
ADME trial [CBYL719X2107] have shown that the contribution of oxidative metabolism to 
the overall clearance of alpelisib can be considered minor, in line with in vitro metabolism 
results. The main circulating metabolite in human plasma was BZG791 which represented on 
average 21.4% of the Area Under the Curve 0-6h (AUC0-6h) (proportionately higher than in 
rat and dog). Other circulating metabolites (oxidative metabolite M3 and N-glucoronide M12) 
were considered minor, as they represented only 0.03% and 1.89% of total radioactivity in the 
plasma of one out of four subjects but were below the limit of quantification in the other subjects. 
Alpelisib and identified metabolites represented on average 94% of the plasma AUC0-6h. In 
terms of excretion the bulk of the dose was excreted in feces (78.8% of the dose) and urine 


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(13.1 % of the dose) with only ~2% of unchanged alpelisib in urine indicating the renal 
clearance is negligible. In excreta (urine and feces combined), alpelisib represented 37.8% of 
the administered dose, BZG791 represented 39.1%. Biliary excretion has been also previously 
been demonstrated in a rat excretion study showing that 25% of the dose of [14C]-alpelisib was 
excreted in feces with 40% of the dose being found unchanged in bile. As alpelisib is a substrate 
for human BCRP in vitro there is strong evidence for a hepatobiliary excretion, which is also 
supported by rat and human sandwich-cultured hepatocyte experiments.
1.2.2.1.3 Safety pharmacology and toxicology of alpelisib
PI3 kinase is involved in various cellular processes such as proliferation, metastasis, or energy 
metabolism. Therefore, it is not unexpected to observe toxic effects when cellular test systems 
or animals are exposed to an inhibitor of this pathway.
In accordance with current guidance, repeated-dose toxicity studies were conducted up to 13 
weeks of duration, using a daily oral treatment in rats and dogs. In the 4- and 13-week studies, 
reversibility of toxicity findings was assessed for a 4-week treatment-free recovery period (8 
weeks in the 13-week rat study). This package was complemented by in vitro and in vivo safety 
pharmacology studies to investigate effects on respiratory, neuronal and cardiovascular 
functions, an ICH-compliant genotoxicity battery and the evaluation of a phototoxic potential 
in vitro. In addition, for exploratory studies, such as insulin/glucose tolerance tests, mice were 
used.
Alpelisib was relatively well tolerated in the 4- and 13-week repeated-dose toxicity studies at 
exposure levels at which tumor growth control was achieved in mouse or rat tumor models. 
Alpelisib affected rapidly dividing tissues which only resulted in pharmacologically relevant 
observations in the animals exposed to an alpelisib dose close to or at MTD. The most 
frequently affected organs were the bone marrow and lymphoid tissue (spleen, thymus), the 
epithelia of the alimentary tract, while other tissues like the vagina and uterus in rats, or prostate 
in dogs were also affected at higher doses. Bone/cartilage and tooth-forming structures were 
only affected in rats. In dogs, epithelial effects were seen in the cornea; however, the dose-
dependency of this cornea observation was not evident. No other ophthalmologic abnormalities, 
associated with alpelisib treatment, were observed in rats or in dogs.
Abnormal clinical chemistry and histopathology (pancreatic islets) findings indicated an altered 
glucose metabolism, correlating with a clear effect towards insulin insensitivity. In both rats 
and dogs, histopathology and clinical pathology findings were generally observed at higher 
doses that were also associated with reduced body weight development (in the growing animals) 
and reduced food intake. All toxic events were reversible or showed a tendency to reversibility
after a 4-week or 8-week treatment-free recovery period.
Cardiac safety studies, conducted in vitro and in vivo, did not indicate an electrophysiological 
risk. Furthermore, alpelisib in the rat safety pharmacology studies showed no effect on neuronal 
or pulmonary function, and no evidence of a phototoxic potential was found in a 3T3 neutral 
red uptake test in vitro.
In conclusion, the majority of the observed toxicological effects of alpelisib were related to the 
pharmacological activity of alpelisib as a p110α specific inhibitor of PI3K pathway, such as an 
influence on insulin (and potentially glucose) homeostasis and the risk of increased blood 


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pressure. The pharmacologically relevant toxicity was mainly observed at dosages close to or 
at MTD with the bone marrow and lymphoid tissue, pancreas, and some reproductive organs of 
both genders being the main target organs of the toxic effects (refer to the [Alpelisib (BYL719) 
Investigators Brochure] for further details).
1.2.2.1.4 Genotoxicity status of alpelisib and metabolites
In an in vitro genotoxicity package consisting of a 2-strain miniscreen Ames and a TK6 
micronucleus screen, as well as International Conference on Harmonization (ICH) S2 guidance-
compliant GLP tests for Salmonella reverse mutations in five strains, and chromosome 
aberrations in primary human lymphocytes, no evidence of a potential to induce reverse gene 
mutations or numerical or structural chromosome aberrations was seen for alpelisib. No 
elevated micronucleus frequencies were found in peripheral blood reticulocytes sampled in 
week 4 of the 13-week rat study. In addition, metabolite BZG791 was tested in a Salmonella 
reverse mutation and a micronucleus test in vitro and found to be free of a genotoxic potential.
1.2.2.2
Clinical experience
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 25 clinical 
studies and as of 13-May-2019, 17 studies have been completed and 9 studies are ongoing. The 
safety profile of alpelisib is well characterized and manageable with generally reversible AEs. 
The alpelisib Investigator’s Brochure (IB) provides a more detailed review of the preclinical 
and clinical information. 
The most common adverse events observed with treatment of alpelisib alone or in various 
combinations are hyperglycemia, rash or GI disorder (nausea, vomiting, diarrhea).
In summary, the current data indicate a favorable clinical safety profile for alpelisib.
The trial [CBYL719X2101] was a Phase IA, multicenter, open-label, dose-escalation study with 
a dose expansion arm of single-agent alpelisib in patients with PIK3CA-altered advanced solid 
tumors, PIK3CA-altered or wildtype ER+ breast cancer. Alpelisib was administered orally as a 
tablet using doses ranging from 30 to 450 mg q.d., and 120 to 200 mg b.i.d. The trial enrolled 
132 patients with advanced solid tumors and the single agent MTD has been declared at 400 
mg q.d., and RP2D at 350 mg q.d. The most frequent observed AEs were hyperglycemia (47%), 
nausea (46%), diarrhea (38%), decreased appetite (37%), fatigue (29%) and vomiting (27%). 
The most common drug-related Grade 3 or 4 adverse event was hyperglycemia (24%). Other 
Grade 3 or 4 AEs occurred in three patients, in all cases maculopapular rash. Among the 131 
evaluable patients, confirmed partial response (PR) was observed in 7 patients (5.3%), with 8 
(6.0%) that achieved an unconfirmed PR. Stable disease (SD) was observed in 68 patients (52%) 
with a disease control rate (CR/PR/SD) of 53%. All tumor responses were observed at alpelisib 
doses of 270 mg or higher (Juric 2014, Juric manuscript in preparation).


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Overall, 20 patients with ER+, PIK3CA-altered, metastatic breast cancer received alpelisib as 
part of the Phase I study (Juric et al 2012). Sixteen out of 20 patients had received some form 
of chemotherapy and most patients had received multiple prior lines of therapy, including AIs, 
tamoxifen and fulvestrant. Hyperglycemia was observed in 13/20 patients (65%), with Grade 3 
or 4 in 25% of patients. Rash was observed in 11/20 patients (55%), with Grade 3 or 4 in 15% 
of patients. GI events and fatigue/asthenia were also among the most commonly reported AE. 
Overall the safety profile of alpelisib in patients with advanced breast cancer was comparable 
to that seen in patients with other solid tumors. Eighteen of the 20 patients received potentially 
effective doses of ≥270 mg/day. Among 18 patients evaluable for radiologic response, 6 patients 
achieved tumor shrinkage >20%, with 2 patients demonstrating a PR (1 confirmed, 1 
unconfirmed). Among the 11 patients who received study treatment for ≥16 weeks, 2 patients 
had PR and 9 had stable SD. Median PFS for the 20 breast cancer patients was 166 days (5.5 
months; 95% CI: 110–286 days), compared with 107 days (3.5 months; 95% CI: 63–148 days) 
for 56 patients with other advanced solid tumors.
For further details on clinical experience, please refer to the latest version of [Alpelisib 
(BYL719) Investigators Brochure].
In vivo metabolism and transport
Alpelisib is primarily metabolized by chemical and enzymatic hydrolysis to form its metabolite 
BZG791 and to a lesser extent by CYP3A4 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 BCRP, its elimination may be 
affected when co-administered with BCRP inhibitors.
1.2.2.3
Clinical pharmacokinetics
The pharmacokinetics of alpelisib has been studied in healthy patients and adult patients with 
solid tumors. Steady-state alpelisib maximum plasma concentration (Cmax) and 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 SOLAR-1 trial, 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 PK approach. 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 


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alpelisib AUC by 77% and Cmax by 145% following a single dose of alpelisib. No clinically 
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 after food, since food exhibited a more pronounced effect on the solubility of alpelisib 
than the effect of gastric pH.
1.2.3
Overview of the combination of alpelisib and endocrine treatments
1.2.3.1
Preclinical experience
Pre-clinical data showing potential for cell death in addition to decreased proliferation have 
been observed when PI3K inhibitors are given in combination with hormonal therapy. In vitro
combination of letrozole or fulvestrant with alpelisib in a PIK3CA mutant cell line of ER+ breast 
cancer (MCF7) displays synergy (O’Brien et al 2014) in line with the concept of synthetic 
lethality seen previously when PI3K was inhibited in an estrogen deprived cell line (Crowder 
et al 2009).
In addition it has been recently demonstrated that PI3Kα inhibition through alpelisib induces a 
transcriptome switch toward a more luminal (ER-driven) phenotype (Bosh et al 2013). The 
trend towards the more luminal signature is related to an increase in ER transcriptional (left 
panel of Figure 1-2) and adding a selective ER down regulator (SERD) like fulvestrant to 
alpelisib prevents the increase in ERα transcriptional activity effectively shutting down both 
ER and PI3K pathways. This can explain the tumor regression observed by the combination of 
fulvestrant and alpelisib and position fulvestrant as a preferred partner to alpelisib in HR+ breast 
cancer in vivo models (Figure 1-2, right panel) (Baselga in press; Bosh et al 2013).
Figure 1-2
Effect of alpelisib and fulvestrant alone or in combination on ER 
transcriptional activity and tumor growth in MCF7 PIK3CA mutant ER+ 
breast cancer model
Although initial analysis demonstrated an increased sensitivity in cells carrying a PIK3CA
mutation, further investigation using patient derived xenografts reveal a potential for the 


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combination in models presenting no mutations as well. This is illustrated in
where 
both
derive a
form the
 
1.2.3.2
Clinical experience with alpelisib and aromatase inhibitors in MBC
An investigator initiated trial (IIT), phase Ib (n=26), is currently ongoing, assessing the 
combination of alpelisib + letrozole in previously treated HR+ HER2-negative metastatic breast 
cancer patients. All the patients were pretreated with AI, with 24 and 8 of them that received 
endocrine therapy and chemotherapy in metastatic setting, respectively. The RP2D of alpelisib 
in combination with letrozole was established at 300 mg q.d. Favorable safety profile was 
reported. Most common Grade 3 AEs at 300 mg were hyperglycemia, diarrhea (12% each), and 
transaminitis (6%). Overall, 5 PRs (19%) have been reported, with SD in 12 (46%). Six out 9 
patients on treatment for ≥ 6 months had a PIK3CA mutant breast cancer, however so far the 
clinical activity was not restricted to patients with PIK3CA mutant tumors only (Mayer et al
2014).
Another IIT phase Ib trial of alpelisib plus letrozole or exemestane in HR+ HER2-negative 
metastatic breast cancer patients has been recently presented. Starting dose for alpelisib was 
selected at 300 mg q.d. MTD has not been determined for continuous dosing schedule (2/7 Dose 
Limiting Toxicities (DLTs) grade 3 rash observed). Common Grade 1 or 2 AEs included rash, 
hyperglycemia, mucositis, diarrhea, anorexia and abdominal pain. Grade 3 or 4 AEs included 
rash and hyperglycemia. With 10 patients evaluable for response (7 PIK3CA mutant and 3 wild-
type), 1 confirmed PR (in a mutant patient) and 7 SD were observed (5 mutant and 2 wild-type) 
(Dickler et al 2014).
[CLEE011X2107] is a phase Ib/II study investigating in three arms the combination of LEE011 
(CDK4/6 inhibitor) and letrozole, alpelisib and letrozole, and LEE011 plus alpelisib and 
letrozole in adult patients with advanced HR+ HER2-negative MBC. Data from 17 patients 
have been reported, 7 of whom received alpelisib 300 mg q.d. (starting dose) + letrozole 2.5 
mg. In alpelisib plus letrozole arm 2 DLTs (Grade 2 hyperglycemia) were observed and the 
most common of all grade AEs were hyperglycemia (57%), nausea (43%), decreased appetite 
(43%) and diarrhea (43%) (Munster et al 2014).
[CBYL719A2201] is a phase II randomized, double-blind, placebo-controlled, study of 
letrozole with or without alpelisib or buparlisib (pan-PI3K inhibitor), for the neoadjuvant 


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treatment of postmenopausal women with HR+ HER2-negative early BC. Patients are 
randomized in a 1:1:1 ratio within two cohorts (PIK3CA mutant tumors, and PIK3CA non-
mutant). The primary objective of this study is pCR rate in each cohort. The alpelisib dose being 
used in this study is also 300 mg q.d.
1.2.3.3
Experience with alpelisib and fulvestrant in MBC
The combination of alpelisib with fulvestrant 500 mg q28 days was investigated as part of 
[CBYL719X2101] study in heavily pre-treated patients with HR+ metastatic breast cancer 
(median number of prior therapies = 5 [1-16] in two groups: PIK3CA mutant and non- mutant 
patients. Eighty-four patients have been enrolled (50 with PIK3CA mutant tumors, 31 wild-type, 
3 unknown) and updated data have been recently presented (Janku et al 2014). Overall, for all 
dose levels, the most common all-grade AEs were diarrhea (57% of patients), hyperglycemia 
(45%), decreased appetite and nausea (37% each). The most frequent Grade 3 or 4 AEs were 
hyperglycemia (18%) and maculopapular rash (13%) (see Table 1-2). The MTD for alpelisib 
was declared at 400 mg, with DLTs in 4 patients (diarrhea, vomiting, decreased appetite, 
abdominal distension and fatigue). Also alpelisib doses of 350 mg and 300 mg q.d. were 
investigated and 300 mg q.d. emerged as the recommended dose in this combination for the 
following reasons:

Similar level of pharmacodynamic and clinical activity were observed among the dose 
levels explored (300, 350 and 400 mg);

Among the patients starting alpelisib treatment at 400 mg, 70% and 13% experienced AEs 
leading to dose reduction or drug discontinuation, respectively, compared to 33% and 0% 
respectively, among those patients treated at 300 mg

Despite different dose levels and dose linearity shown in the single agent arm of 
[CBYL719X2101] study, exposure of alpelisib in the combination arm with fulvestrant 
was similar between 300 mg and 400 mg.
In fact, for comparison with the single agent arm, full PK profiles of alpelisib were collected on 
Day 1 and Day 8 of Cycle 1 and on Day 1 of Cycle 2. While median values were within the 
ranges observed for the 300 to 400 mg single agent cohorts, median Cmax was lower in 
combination with fulvestrant (~30%). Exposure (AUC0-24) at steady state was comparable at 
300 mg (30500 vs. 33200 ng*h/ml) and 350 mg (30600 vs. 29500 ng*h/ml) but lower for the 
400 mg cohort (28900 vs. 39600 ng*h/ml). Median Tmax remained largely unchanged (ranging 
between 1.8 and 3.1 hours) but median terminal T1/2 was also slightly increased (approximately 
9-10 hours compared to 7 to 8 hours for single agent) at 400 mg.
Preliminary clinical efficacy of alpelisib + fulvestrant was demonstrated across all dose levels. 
Best overall response achieved was confirmed PR for 12 (24%) patients and SD for 28 (56%) 
patients with PIK3CA mutant tumors vs PR for 0 (0%) patient and SD for 14 (45%) patients 
with PIK3CA non-mutant tumors. Disease control rate was 80% (95% CI: 66.3–90.0) and 45% 
(95% CI: 27.3–64.0) in the PIK3CA mutant and PIK3CA non-mutant groups, respectively. 
Estimated median PFS was longer in the PIK3CA mutant group vs PIK3CA non-mutant group 
(8.3 months vs 4.7 months) (Janku et al 2014).


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Table 1-2
Study [CBYL719X2101]: AEs (greater than or equal to10%) suspected 
to be related to study treatment
Drug related 
Adverse Event
n (%)
Grade
Alpelisib Dose
All 
Patients 
(N=84)*
300 mg/day
n=9
350 mg/day
n=8
400 mg/day
n=66
Diarrhea
All
3/4
5 (55.6)
0
5 (62.5)
0
36 (54.5)
2 (3.0)
48 (57.1)*
2 (2.4)
Hyperglycemia
All
3/4
4 (44.4)
0
5 (62.5)
2 (25.0)
29 (43.9)
13 (19.7)
38 (45.2)
15 (17.9)
Decreased 
appetite
All
3/4
1 (11.1)
0
4 (50.0)
0
26 (39.4)
1 (1.5)
31 (36.9)
1 (1.2)
Nausea
All
3/4
4 (44.4)
0
5 (62.5)
0
22 (33.3)
0
31 (36.9)
0
Fatigue
All
3/4
3 (33.3)
0
6 (75.0)
0
15 (22.7)
3 (4.5)
26 (31.0)*
3 (3.6)
Stomatitis
All
3/4
2 (22.2)
0
3 (37.5)
0
18 (27.3)
1 (1.5)
23 (27.4)
1 (1.2)
Vomiting
All
3/4
3 (33.3)
0
1 (12.5)
0
17 (25.8)
1 (1.5)
21 (25.0)
1 (1.2)
Rash
All
3/4
3 (33.3)
0
4 (50.0)
1 (12.5)
8 (12.1)
5 (7.6)
15 (17.9)
6 (7.1)
Rash
(maculopapular)
All
3/4
0
0
2 (25.0)
2 (25.0)
13 (19.7)
9 (13.6)
15 (17.9)
11 (13.1)
Dysgeusia
All
3/4
3 (33.3)
0
1 (12.5)
0
10 (15.2)
0
14 (16.7)
0
Asthenia
All
3/4
1 (11.1)
0
3 (37.5)
0
7 (10.6)
0
11 (13.1)
0
Dry skin
All
3/4
1 (11.1)
0
2 (25.0)
0
7 (10.6)
0
10 (11.9)
0
Pruritus
All
3/4
1 (11.1)
0
3 (37.5)
0
6 (9.1)
2 (3.0)
10 (11.9)
2 (2.4)
1.2.4
Potential for drug interactions
1.2.4.1
Potential overlapping toxicities
Based on the fulvestrant prescribing information and current compound and class related risks 
identified for alpelisib, the following overlapping toxicities might occur:

Nausea, vomiting, diarrhea

Skin alterations/rash.
For further details on clinical safety, please refer to the latest version of [Alpelisib (BYL719) 
Investigators Brochure].
1.2.4.2
Potential for drug-drug interactions with fulvestrant
The potential for a drug-drug interaction between fulvestrant and co-administered drugs is 
considered low. There are no known drug interactions with fulvestrant. In vitro studies showed 
no relevant inhibition of the major CYP enzymes, including CYP1A2, 2C9, 2C19, 2D6 or 3A4 
by fulvestrant. The lack of inhibition of CYP3A4 was confirmed in an in vivo interaction study 
with midazolam. In addition, interaction studies with rifampicin (strong CYP3A4 inducer) and 


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ketoconazole (strong 
CYP3A4 inhibitor) demonstrated no effect on fulvestrant 
pharmacokinetics. Therefore, a DDI involving fulvestrant and alpelisib are unlikely to occur 
[Faslodex® Prescribing Information].
However, due to the slightly reduced exposure of alpelisib observed in [CBYL719X2101] in 
combination with fulvestrant compared to single agent (see Section 1.2.3.3), pharmacokinetics 
of alpelisib in combination with fulvestrant will be explored in this study in a larger population 
using a population PK approach to assess whether fulvestrant affects the pharmacokinetics of 
alpelisib. The effect of alpelisib on fulvestrant will also be assessed by comparative trough 
analysis in the treatment arms.
2
Rationale
2.1
Study rationale and purpose
The purpose of this study is to determine whether treatment with alpelisib plus fulvestrant 
prolongs PFS compared to fulvestrant and placebo in men and postmenopausal women with 
HR+, HER2-negative advanced breast cancer which progressed on or after AI treatment.
As described in Section 1.2.3.1, promising pre-clinical data showing potential for cell death in 
addition to decreased proliferation have been observed when PI3K inhibitors are given in 
combination with hormonal therapy, in particular fulvestrant (O’Brien et al 2014). Furthermore 
clinical activity has been observed with single agent alpelisib in heavily pre-treated ER+ breast 
cancer patients and when alpelisib was given in combination with fulvestrant AI to HR+ HER2-
negative metastatic breast cancer patients (Janku et al 2014; Mayer et al 2014).
Rationale for enrolling all patients (PIK3CA mutant and non-mutant)
Up to 45% of HR+ breast cancers present with a mutation in the PIK3CA gene, and thus these 
tumors may be particularly suited to treatment with the alpha specific PI3K inhibitor alpelisib. 
More specifically, about 30% of patients’ tumors display a PIK3CA mutation identified as one 
of the most frequently reported hotspots. While PIK3CA mutant cell lines display an increased 
sensitivity to alpelisib treatment (Fritsch et al 2014), sensitivity to alpelisib in combination with 
fulvestrant was observed in both PIK3CA mutant and wild-type ER+ in vivo models (see Figure 
1-3, Section 1.2.3.1). Indeed, HR+ breast cancer – particularly if previously treated with 
endocrine agents - may display a dependency on the PI3K pathway that is independent of a 
PIK3CA mutation and hence confer a level of sensitivity to alpelisib in non-PIK3CA mutant 
breast cancer tumors as well.
In addition, although preliminary phase I data suggest a better outcome (i.e. response rate, 
clinical benefit rate, PFS) in PIK3CA mutant breast tumors when treated with alpelisib (either 
in monotherapy or combination with an endocrine agent), some patients without identified 
mutations benefitted as well (Mayer et al 2014; Dickler et al 2014, Janku et al 2014). Overall 
the current pre-clinical and clinical findings show an increased efficacy of the combination of 
alpelisib and fulvestrant in PIK3CA mutant HR+ BC patients, while suggesting that this 
combination may also have some activity in PIK3CA non-mutant HR+ BC patients.
To assess the treatment effect of alpelisib specifically in PIK3CA mutant and non-mutant 
patients, two cohorts are considered:


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
One pivotal cohort aiming at confirming the activity of the combination of alpelisib and 
fulvestrant in PIK3CA mutant HR+ BC patients

One “proof-of concept” cohort aiming at further evaluating the anti-tumor activity of the 
combination of alpelisib and fulvestrant in PIK3CA non-mutant HR+ BC patients
Within each of these cohorts patients will be randomized and treated in a 1:1 fashion between 
alpelisib plus fulvestrant and placebo plus fulvestrant.
2.2
Rationale for the study design
This study is a multicenter, randomized, double-blind, placebo controlled phase III trial. 
Patients will be randomized to receive alpelisib in combination with fulvestrant or placebo in 
combination with fulvestrant. After molecular assessment of PIK3CA mutation status, patients 
will be assigned to one of the following two cohorts:

Cohort I; PIK3CA mutant: Patients with a confirmed PIK3CA mutation as per protocol 
definition

Cohort II; PIK3CA non-mutant: Patients without evidence of PIK3CA mutation as per 
protocol definition.
PIK3CA mutant status will be defined as follows: PIK3CA mutation will be identified by 
analyzing the PIK3CA gene for hotspots known to impact the PI3K function in exons 7, 9 and 
20 (see Section 7.2.4.1). 
 
PIK3CA non-mutant status will be defined as follows: all analysis for PIK3CA mutation are 
interpretable and do not show evidence of a mutation in the PIK3CA gene for the defined 
hotspots on Exons 7, 9 and 20.
If the analysis for PIK3CA gene was not fully interpretable, i.e. at least one hot-spot is providing 
a non-interpretable read out, the patient is not eligible for the trial.
To avoid any bias, sites will be kept blinded to PIK3CA mutation status provided by the 
Novartis designated laboratory.
Based on Novartis Internal Data obtained on a similar population, frequency of PIK3CA
mutation status as defined above in HR+ breast cancer is expected to be approximately 30% for 
this study.
Randomization will be stratified by the following factors (see Section 4.1 for further details):
1. Lung and/or liver metastases (yes versus no)
2. Previous treatment with any CDK4/6 inhibitor (yes versus no).
It is well known that visceral involvement is a prognostic factor in the clinical outcome of breast 
cancer patients. Patients with visceral involvement like lung and/or liver metastases have a 
shorter PFS compared to patients with no visceral involvement (Clark et al 1987).
Currently no data are available if and how pretreatment with a CDK4/6 inhibitors may impact 
the outcome of any subsequent treatment with fulvestrant and/or PI3K inhibitors, or may have 
any prognostic value. However, recently the CDK4/6 inhibitor palbociclib in combination with 


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letrozole showed a strong PFS advantage over single agent letrozole (that led to palbociclib 
approval in USA). Therefore, CDK4/6 inhibitor pretreatment may have an important impact on 
any subsequent treatment and may lead to different outcome compared to what currently 
estimated according to published data (based on CDK4/6 inhibitors naïve patients). 
Stratification of randomization based on previous CDK4/6 inhibitors treatment in the current 
study will prevent imbalance between the two treatment arms in each cohort.
To avoid any unforeseen impact on the overall study results, for the reasons stated above and 
the lack of data, the total number of patients pre-treated with any CDK4/6 inhibitor will be 
limited to 30% of the overall study population.
2.3
Rationale for dose and regimen selection
In study [CBYL719X2101] single agent MTD has been declared at 400 mg q.d., and RP2D at 
350 mg q.d.
As described in Section 1.2.3.3, the recommended dose for alpelisib in combination with 
fulvestrant in the same clinical trial was 300 mg q.d. Pharmacokinetic data and longitudinal 
tumor size measurements from [CBYL719X2101] were used for population pharmacokinetic 
(PopPK) and pharmacodynamic modelling of tumor growth to describe the time course of tumor 
response (anti-tumor efficacy) in relation to drug systemic exposure and simulate the anti-tumor 
activity of different doses and regimens of alpelisib for the single agent arm (De Buck et al 
2014). The pharmacodynamic model consisted of a sigmoid Emax tumor growth model with a 
zero order rate tumor growth constant (Kgrowth), a first order tumor death rate constant (Kdeg), 
the maximum pharmacodynamic effect (Emax) and IC50 as the plasma drug concentration at 
50% of the maximal inhibitory effect. The IC50 for tumor growth inhibition was estimated to 
be 101 ng/ml (95% CI:40.6-179), corresponding to a free drug estimate of about 10 ng/ml 
(fraction unbound 0.108) which is in close agreement to the in vitro-based inhibitory potential 
against the kinase activity of recombinant PI3Kα (IC50 of ~4.6 ng/ml) and in Rat1-myr-p110α 
cells (IC50 = 74 nM or 32.7 ng/ml; free drug IC50 of ~18 ng/ml, free fraction in cellular assay 
~0.55) (Fritsch et al 2014). The calculated IC80 by the Hill equation was 404 ng/ml. In 
[CBYL719X2101] median trough levels (Cmin) at steady state were found to be > 101 ng/ml 
at doses greater than 180 mg QD (Novartis Internal Data). Based on this model simulation were 
conducted showing that the minimum dose to achieve tumor regression was between 135 and 
136 mg QD, therefore doses of 250 mg and 200 mg (in case dose reductions are required per 
protocol) can be considered as effective doses.
In addition, alpelisib 300 mg q.d. was also the selected starting dose or emerged to be the best 
tolerated dose in combination with AIs (Mayer et al 2014; Dickler et al 2014; Munster et al
2014; CBYL719A2201 study) (see Section 1.2.3.2 and Section 1.2.3.3).
Therefore, in this clinical trial alpelisib will be given at the dose of 300 mg q.d. together with 
fulvestrant administered as per the product labeling (Faslodex® EU SmPC and US PI): 500 mg 
given intra-muscularly (i.m.) at Day 1, 15 of Cycle (month) 1 and Day 1 of every cycle (month) 
thereafter. In this study, a cycle is defined as 28 days ± 3 days.
2.4
Rationale for choice of combination drugs
The rationale to combine alpelisib with fulvestrant is based on the following:


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
The demonstrated efficacy of fulvestrant in this patient population (Section 1.2.1)

Synergism between PI3K inhibition with alpelisib and the effect of fulvestrant seen in 
preclinical experiments the combination being significantly more effective than each drug 
taken separately (Section 1.2.3)

No drug-drug interaction between alpelisib and fulvestrant and same pharmacokinetic 
results for alpelisib in the combination with fulvestrant compared to single agent alpelisib 
[CBYL719X2101 study] (Section 1.2.4.2)

Preliminary preclinical and clinical data suggesting acceptable safety profile of the 
combination [CBYL719X2101 study] (Section 1.2.3.3)

Preliminary promising clinical activity [CBYL719X2101 study].
2.5
Rationale for choice of comparators drugs
Patients enrolled in the study will either be in first line or in second line for the treatment of 
their metastatic disease.
In first line setting, currently approved treatment options include tamoxifen, AI or palbociclib
in combination with letrozole.
The recently presented data from the FIRST study, conducted in HR+ HER2-negative advanced 
breast cancer patients with no prior endocrine therapy or with long DFS after adjuvant endocrine 
therapy, showed superiority of fulvestrant 500 mg compared to anastrozole (Robertson 2014). 
Despite methodological limitations linked to indirect comparisons, the benefit brought by 
fulvestrant over anastrozole appears to be of the same extent than the one brought by the 
addition of palbociclib to letrozole. FALCON (ClinicalTrials.gov identifier: NCT01602380), a 
randomized phase III study comparing fulvestrant 500 mg with anastrozole as first-line 
treatment for postmenopausal women with HR+ MBC, completed enrollment in September 
2014; results are still pending.
Taken together, these data support fulvestrant 500 mg as an acceptable therapy in the first-line 
metastatic setting.
In second line setting, several acceptable options are available (NCCN 2.2015) and include 
Fulvestrant. In addition, Fulvestrant is currently approved for the treatment of HR+ metastatic 
breast cancer in postmenopausal women with disease progression following anti-estrogen 
therapy. Hence, fulvestrant is considered a standard therapy for patients who have progressed 
on or after treatment with other endocrine agents and who require a well-tolerated alternative 
therapy (Ciruelos et al 2014).
In conclusion, fulvestrant at the selected dose of 500 mg given intramuscularly at one month 
intervals, with an additional 500 mg dose given 2 weeks after the initial dose, is considered an 
appropriate comparator arm for this study (see also Section 1.2.1).
2.6
Risks and benefits
2.6.1
Potential benefit for participants
Treatment with alpelisib in combination with fulvestrant may result in an improved clinical 
benefit compared to fulvestrant alone in men and postmenopausal women with HR+, HER2-


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negative advanced breast cancer, which progressed on or after AI treatment. All patients 
enrolled in this trial will receive an active endocrine therapy for their disease (see Section 2.5). 
Based on preclinical and preliminary clinical data (see Section 1.2.3), treatment with alpelisib 
in combination with fulvestrant is expected to be well tolerated and it is hypothesized that it 
will result in delayed disease progression by inhibiting proliferation of endocrine-resistant 
breast cancer cells.
For further details on clinical safety, please refer to Section 1.2.2 and the latest version of 
[Alpelisib (BYL719) Investigators Brochure].
2.6.2
Potential risks to clinical trial participants
Patients in this study will be carefully monitored for key toxicities that have been observed with 
alpelisib (see Section 1.2.2), fulvestrant (see Section 1.2.1) or the combination of both (see 
Section 1.2.3) with the following assessments (see Section 7): periodic laboratory, renal and 
liver function, urinalysis and ECG.
Risk will be further minimized by adherence to inclusion/exclusion selection criteria (see 
Section 5), avoidance of prohibited medication (see Section 6.4.3), close safety monitoring (see 
Section 8) and dose adjustment guidelines (see Section 6.3 and current fulvestrant prescribing 
information [Faslodex® prescribing information]. PK sampling will be conducted in patients to 
assess plasma concentration of the study drug to evaluate any potential drug interaction. An 
independent data monitoring committee (DMC) (see Section 8.6) will be constituted and will 
monitor safety, efficacy and available PK data as outlined in the protocol. A Steering Committee 
(SC) (see Section 8.7) will be established comprising of investigators and Novartis personnel 
participating in the trial to 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.
2.6.3
Risks related to study procedures
Study related risks include, but are not limited to collection of fresh tumor samples, blood 
collections, the different imaging methods incl. Echocardiogram (ECHO) or multiple gated 
acquisition (MUGA) scan, bone scans and electrocardiograms (ECGs). Please refer to the 
Consent Form for more information.
2.6.4
Risk management strategies
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria 
and study procedures, close clinical monitoring, recommendations for concomitant medications, 
guidance for prohibited medications and dose adjustments as outlined in Section 6.3. There may 
be unforeseen risks with alpelisib.
Based on key anticipated benefits and potential risks, the benefit-risk balance is anticipated to 
be positive for the target population of this trial.
3
Objectives and endpoints
Objectives and related selected endpoints are described in Table 3-1 below. More details are 
described in Section 10 as referred in the Table 3-1.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
● To determine whether treatment with alpelisib in combination 
with fulvestrant prolongs PFS compared to treatment with 
placebo in combination with fulvestrant for patients with PIK3CA
mutant status
PFS based on local radiology assessments and using RECIST 1.1 
criteria in the PIK3CA mutant cohort
Key secondary
Refer to Section 10.5.1
To determine whether treatment with alpelisib in combination 
with fulvestrant prolongs overall survival (OS) compared to 
treatment with placebo in combination with fulvestrant for 
patients with PIK3CA mutant status
OS in the PIK3CA mutant cohort
Other secondary
Refer to Section 10.5.2
● To establish proof of concept of treatment benefit with alpelisib 
in combination with fulvestrant with respect to PFS for patients 
with PIK3CA non-mutant status
PFS based on local radiology assessments and using RECIST 1.1 
criteria in the PIK3CA non-mutant cohort
● To evaluate the two treatment arms with respect to OS for 
patients with PIK3CA non-mutant status
OS in the PIK3CA non-mutant cohort
● To evaluate the two treatment arms and cohorts of interest 
with respect to overall response rate (ORR), clinical benefit rate.
ORR and CBR in each of the PIK3CA mutant and non-mutant cohorts
● To evaluate the two treatment arms and cohorts of interest 
with respect to time to deterioration of ECOG performance 
status.
Time to definitive deterioration of the ECOG performance status of the 
score from baseline in each of the PIK3CA mutant and non-mutant 
cohorts
● To evaluate the safety and tolerability of alpelisib in 
combination with fulvestrant
● Type, frequency and severity of adverse events per CTCAEv4.03
● Type, frequency and severity of laboratory toxicities per 
CTCAEv4.03
Refer to Section 10.5.3
● To evaluate change in global health status/QOL in the two 
treatment arms and cohorts of interest
●Time to 10% deterioration in the global health status/QOL scale 
score of the EORTC QLQ-C30
● Change from baseline in the global health status/QOL scale score of 
the EORTC QLQ-C30
in each of the PIK3CA mutant and non-mutant cohorts
Refer to Section 10.5.4


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Objective
Endpoint
Analysis
● To characterize the pharmacokinetics (PK) of fulvestrant and 
alpelisib when given in combination with fulvestrant.
Summary statistics for PK: plasma concentration-time profiles of 
alpelisib given in combination with fulvestrant and appropriate 
individual PK parameters based on population PK model
Summary statistics of fulvestrant trough plasma concentrations in each 
treatment arm (alpelisib/placebo)
Refer to Section 10.5.5
● 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 and using RECIST 1.1 
criteria for each of (i) patients with PIK3CA mutant status and (ii) 
patients with PIK3CA non-mutant status as measured in ctDNA at 
baseline.
Refer to Section 10.6
 
 
 
 
 
Refer to Section 10.5.4
 
 
 
 
 
 


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4
Study design
4.1
Description of study design
This is a randomized, double blind, placebo controlled, international multi-center Phase III trial 
to determine the efficacy and safety of treatment with fulvestrant + alpelisib versus fulvestrant 
+ placebo in men and postmenopausal women with HR+ HER2-negative advanced breast 
cancer which progressed on or after AI treatment.
PFS, as assessed by the local radiologists/investigators and using RECIST 1.1 criteria will be 
the primary endpoint. PFS as assessed through Blinded Independent Review Committee (BIRC) 
will be used for supportive evidence of the primary efficacy endpoint.
This study will consist of 4 phases: screening (35 days), randomized treatment, post-treatment 
disease progression follow-up, and post-treatment survival follow-up. Patients will be treated 
until disease progression, unacceptable toxicity, or discontinuation from the study treatment for 
any other reason.
In the randomized treatment phase, patients will be randomized 1:1 to receive:

Control arm (Arm A): fulvestrant (500 mg intramuscular [as two 5 ml injections] on Day 1 
and 15 of Cycle 1 and on Day 1 ± 3 days of every Cycle thereafter + Placebo (by mouth 
once daily, in a 28-day cycle)
OR

Experimental arm (Arm B): fulvestrant (500 mg intramuscular [as two 5 ml injections] on 
Day 1 and 15 of Cycle 1 and on Day 1 ± 3 days of every Cycle thereafter + Alpelisib (300 
mg by mouth once daily, in a 28-day cycle)
A total of approximately 560 patients will be enrolled; in which approximately 340 and 220 
patients will be enrolled respectively to each of two cohorts: PIK3CA mutant and PIK3CA non-
mutant. Within each of these two cohorts, randomization will be stratified by:
1. Lung and/or liver metastases (yes versus no)
2. Previous treatment with any CDK4/6 inhibitor (yes versus no)
The total number of patients pre-treated with any CDK4/6 inhibitor will be limited to 30% of 
the total number of patients.
One futility interim analysis is planned for the primary efficacy endpoint (PFS) in the PIK3CA
mutant cohort at the expected time given in Section 10.8. There is no intention to stop for 
superiority at this interim analysis. Another interim analysis that allows the study to stop for 
superior efficacy is planned in the PIK3CA mutant cohort, after all patients have been 
randomized and approximately 75% of the total PFS events have been documented, as per local 
assessments. If PFS is statistically significant, interim analyses for OS will also be conducted 
as detailed in Section 10.5.1 and Section 10.7.


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Figure 4-1
Study design
An independent data monitoring committee (DMC) will be constituted and will monitor safety 
and efficacy as outlined in Section 8.6 and Section 10.7. A Study Steering Committee (SSC) 
will be established comprising investigators participating in the trial to ensure transparent 
management of the study according to the protocol through recommending and approving 
modifications as outlined in Section 8.7.
Patients will receive treatment until disease progression, unacceptable toxicity, death, or 
discontinuation from the study treatment for any other reason. Patients will still be followed for 
efficacy when discontinuing study treatment for any reason other than disease progression or 
death. Patients will be followed for survival regardless of treatment discontinuation reason 
(except if consent is withdrawn or patient is lost to follow-up). Treatment crossover from 
placebo to alpelisib will not be permitted in this study.
This study will use an Interactive Response Technology (IRT) for patient screening, enrollment, 
randomization, discontinuation, stratification and alpelisib/placebo study medication 
management. In addition the IRT will manage the limitation of the number of patients with prior 
CDK4/6 inhibitors treatment up to 30% of the total number of the patients (see Section 2.2). If 
the study will continue in both cohorts to the final analyses, the maximum total number of 
CDK4/6 inhibitors pretreated patients will be 168.
4.1.1
Screening phase
At screening, the patient will provide a signed informed consent form prior to any study related 
activities. Signed informed consent will be obtained as early as Day−35. Collection and 
shipment of tumor sample (archived tissue or new biopsy) to Novartis designated laboratory 
should occur as soon as possible as early as Day-35 and no later than Day−21. The tumor sample 
will serve to establish the PIK3CA mutation status for randomization. It is recommended to wait 
for the central PIK3CA testing results before conducting other screening assessments.
Additional screening evaluations must be performed within 28 days before treatment start; 
physical examinations and laboratory assessments will be performed within 14 days before 
treatment start (see Section 7 for more details).
Patients will be screened in IRT only once patient has provided signed informed consent form.


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4.1.2
Treatment phase
Patient eligibility will be checked once all screening procedures are completed. An eligibility 
review and confirmation will be embedded to the IRT system. Please refer to and comply with 
detailed guidelines in the IRT manual. Once the PIK3CA mutation status is identified by the 
Novartis designated laboratory, the IRT system will confirm the inclusion of eligible patients 
and randomize them in a 1:1 ratio to one of the two treatment groups described in Section 4.1.
Sites will be kept blinded to PIK3CA mutation status provided by the Novartis designated 
laboratory.
In order to assess any potential impact of fulvestrant on the pharmacokinetics of alpelisib, sparse 
and trough PK samples for alpelisib and fulvestrant will be collected in approximately 200 
patients from selected centers; trough PK samples will be collected for alpelisib and fulvestrant 
in all other patients as detailed in Section 7.2.3.
Patients will receive treatment until disease progression (assessed by RECIST 1.1), 
unacceptable toxicity, death or discontinuation from treatment for any other reason. Efficacy 
and safety monitoring will continue as per visit schedule (Table 7-1).
All antineoplastic therapies given after the last dose of the study drug unless patient is lost to 
follow-up, or withdraws consent will be recorded in the electronic Case Report Forms (eCRFs).
4.1.3
Safety follow-up
After discontinuation of study treatment, all patients will be followed for safety, AEs and patient 
reported outcomes (PROs) which will be collected until 30 days after last study therapy 
administration, except in case of death, loss to follow-up or withdrawal of consent. For details 
please refer to Section 7.1.5.
4.1.4
Efficacy follow-up
Patients who discontinue treatment for reasons other than disease progression or withdrawal of 
consent for efficacy follow-up, will continue to be followed every 8 weeks ± 1 week for efficacy 
(i.e., tumor assessments and PROs) during the first 18 months and every 12 weeks ± 1 week 
until 36 months, then change to as clinically indicated until disease progression, death, 
withdrawal of consent, loss to follow-up, subject/guardian decision. All scans will be acquired 
and analyzed for primary endpoint locally and will be sent to the Contract Research 
Organization (CRO) designated by Novartis for central imaging interpretation. If a patient starts 
a new antineoplastic treatment without withdrawing consent, the patient will continue to be 
followed for efficacy according to above specified protocol schedule until disease progression, 
death, withdrawal of consent, loss to follow-up, or subject/guardian decision. For further details 
please refer to Table 7-1 and Section 7.1.6.
4.1.5
Survival follow-up
All patients will be followed for survival once they discontinue study treatment and tumor 
evaluations until the final number of OS events have been reached or the study is stopped for 
other reasons. Survival follow-up will be done every 12 weeks ± 1 week or earlier if a survival 
update is required to meet safety or regulatory needs. Survival information can be obtained by 


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clinical visits or telephone calls (Section 7.1.8) until death, the patient is lost to follow-up, or 
the patient withdraws consent for survival follow-up.
During the survival follow-up, in addition, subsequent 
 
 will be collected along with the 
on subsequent therapies to assess 
4.2
Timing of interim analyses and design adaptations
Interim analyses for both the primary endpoint (PFS) and key secondary endpoint (OS) are 
planned for this study, in the PIK3CA mutant cohort. Interim analyses for the secondary 
endpoint, OS, in the PIK3CA non-mutant cohort are also planned.
An interim analysis that allows the cohort to stop for futility (non-binding) is planned after 
approximately 40% PFS events in the PIK3CA mutant cohort have been documented per local 
assessments. Another interim analysis that allows the cohort to stop for superior efficacy is 
planned after all patients in the PIK3CA mutant cohort have been randomized and 
approximately 75% PFS events have been documented, as per local assessments.
If PFS is statistically significant in either cohort, interim analyses for OS in that cohort will also 
be conducted. The interim analyses for OS will allow early stopping of the study for evidence 
of overwhelming efficacy of the alpelisib combination treatment compared to placebo. A 
maximum of three analyses are planned for OS in each cohort as detailed in Section 10.5.1 and 
Section 10.7.
4.3
Definition of end of the study
The end of the study for a given patient is defined as when the patient permanently discontinues 
study treatment with alpelisib + fulvestrant or placebo + fulvestrant and all the end of trial 
procedures are completed. The end of the overall study is defined as the time point when data 
collection will stop in both cohorts and the final analysis of the study will occur.
The primary analysis will occur when approximately the required number of PFS events is 
reached (refer to Section 10.8). The primary clinical study report (CSR) will be produced once 
the required number of PFS events is reached.
If the enrollment in the PIK3CA mutant cohort is stopped due to futility at the interim analysis 
or if the primary PFS analysis in the PIK3CA mutant cohort does not demonstrate a statistically 
significant treatment effect, then all subjects in each cohort will be followed for safety until 30 
days post last dose and data collection will stop after all patients have discontinued study 
treatment and completed the safety follow-up period.
In the PIK3CA mutant cohort, if the primary endpoint of PFS is statistically significant the study 
will remain open, then patients still being followed, including patients in the PIK3CA non-
mutant cohort, continue as per the schedule of assessments.
The study will end once the final OS analysis in the PIK3CA mutant cohort is performed 
approximately when the required number of deaths is observed or when statistical significance 
is reached for OS analysis (see Section 10) and the final analysis of study data is conducted. All 
available data from all patients in each cohort up to this cut-off date will be analyzed.


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Patients continuing to derive benefit from study treatment in the opinion of the investigator at 
the end of the study will be able to continue receiving trial therapy on an individual basis (e.g. 
separate protocol or Novartis providing study treatment to the investigator as per local 
regulations).
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the assessments described in Section 7 for a 
discontinued or withdrawn patient should be performed. 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 patient’s interests. The investigator will be responsible for informing IRBs 
and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
The study will include men and postmenopausal women with HR+, HER2-negative advanced 
(loco regionally recurrent not amenable to curative therapy or metastatic) breast cancer which 
progressed on or after AI treatment.
Patients with symptomatic visceral disease or any disease burden that makes the patient 
ineligible for endocrine therapy per the investigator’s best judgment will not be included in this 
study.
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.
The patients are not permitted to participate in additional parallel investigational drug or device 
studies.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
Written informed consent must be obtained prior to any screening procedures
1. Patient is an adult ≥ 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. Patient has adequate tumor tissue for the analysis of PIK3CA mutational status by a 
Novartis designated laboratory. One new or recent biopsy (collected at screening if 
feasible) or archival tumor block or slides (15 slides minimum from a surgical specimen, 
20 slides minimum from a biopsy) must be provided. It is recommended to provide a 
tumor sample collected after the most recent progression or recurrence.
3. Patient has identified PIK3CA status (mutant or non-mutant; determined by a Novartis 
designated laboratory).
4. If female, then the patient is postmenopausal. Postmenopausal status is defined either by:

Prior bilateral oophorectomy


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
Age ≥60

Age <60 and amenorrheic for 12 or more months in the absence of chemotherapy, 
tamoxifen, toremifene, or ovarian suppression and Follicle-stimulating Hormone
(FSH) and estradiol in the postmenopausal range per local normal range
Note: For women with therapy-induced amenorrhea, serial measurements of FSH and/or 
estradiol are needed to ensure postmenopausal status (NCCN.2.2015). Ovarian radiation or 
treatment with a luteinizing hormone-releasing hormone agonist (LH-RHa) (goserelin acetate 
or leuprolide acetate) is not permitted for induction of ovarian suppression in this trial.
5. Patient has radiological or objective evidence of recurrence or progression.
6. Patient has a histologically and/or cytologically confirmed diagnosis of ER+ and/or PgR+ 
breast cancer by local laboratory.
7. Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or 
an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or 
SISH) test is required by local laboratory testing.
8. Patient has either:

Measurable disease, i.e., at least one measurable lesion as 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

If no measurable disease is present, then at least one predominantly lytic bone lesion 
must be present (patients 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).
9. Patient has advanced (loco regionally recurrent not amenable to curative therapy or 
metastatic) breast cancer.
Patients may be:

relapsed with documented evidence of progression while on (neo) adjuvant endocrine 
therapy or within 12 months from completion of (neo)adjuvant endocrine therapy 
with no treatment for metastatic disease

relapsed with documented evidence of progression more than 12 months from 
completion of (neo)adjuvant endocrine therapy and then subsequently progressed with 
documented evidence of progression while on or after only one line of endocrine 
therapy for metastatic disease

newly diagnosed advanced breast cancer, then relapsed with documented evidence of 
progression while on or after only one line of endocrine therapy
Note: i) Patients with newly diagnosed endocrine treatment naïve advanced breast cancer, ii) ii) 
Patient who relapsed with documented evidence of progression on/or within 12 months from 
completion of adjuvant endocrine therapy and then subsequently relapsed with documented 
evidence of progression after one line of endocrine therapy (with either an antiestrogen or an 
AI) for metastatic disease will NOT be included in the study.
10. Patient has recurrence or progression of disease during or after AI therapy (i.e. letrozole, 
anastrozole, exemestane). AI therapy does not need to be the latest treatment regimen.
11. Patient has an ECOG performance status 0 or 1


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12. Patient has adequate bone marrow and organ function as defined by the following 
laboratory values (as assessed by central laboratory for eligibility):

Absolute neutrophil count ≥ 1.5 × 109/L

Platelets ≥ 100 × 109/L

Hemoglobin ≥ 9.0 g/dL

Calcium (corrected for serum albumin) and magnesium within normal limits or ≤ 
grade 1 according to NCI-CTCAE version 4.03 if judged clinically not significant by 
the investigator

Potassium within normal limits, or corrected with supplements

International Noramlized Ratio (INR) ≤1.5

Creatinine Clearance ≥ 35 mL/min using Cockcroft-Gault formula

In absence of liver metastases, ALT and AST ≤ 2.5 × ULN. If the patient has liver 
metastases, ALT and AST ≤ 5 × ULN

Total bilirubin < ULN except for patients with Gilbert’s syndrome who may only be 
included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN

Fasting plasma glucose (FPG) ≤ 140 mg/dL (7.7 mmol/L)* and Glycosylated 
Hemoglobin (HbA1c) ≤ 6.4% (both criteria have to be met)

Fasting Serum amylase ≤ 2 × ULN

Fasting Serum lipase ≤ ULN
*For patients with FPG ≥ 100 mg/dL and/or HbA1c ≥5.7% (i.e. threshold for pre-diabetes) at 
screening, recommend lifestyle changes according to ADA guidelines, i.e. dietary advice (e.g. 
small frequent meals, low carbohydrate content, high fiber, balancing carbohydrate intake over 
the course of the day, three small meals and 2 small snacks rather than one large meal) and
exercise. A consultation with a diabetologist is highly recommended.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patient with symptomatic visceral disease or any disease burden that makes the patient 
ineligible for endocrine therapy per the investigator’s best judgment.
2. Patient has received prior treatment with chemotherapy (except for neoadjuvant/ adjuvant 
chemotherapy), fulvestrant, any PI3K, mTOR or AKT inhibitor
3. Patient has a known hypersensitivity to alpelisib or fulvestrant, or to any of the excipients 
of alpelisib or fulvestrant.
4. Patient with inflammatory breast cancer at screening.
5. Patient is concurrently using other anti-cancer therapy.
6. Patient has had surgery within 14 days prior to starting study drug or has not recovered 
from major side effects.
7. Patient has not recovered from all toxicities related to prior anticancer therapies to NCI 
CTCAE version 4.03 Grade ≤1. Exception to this criterion: patients with any grade of 
alopecia are allowed to enter the study.
8. Patients with Child pugh score B or C.


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9. Patient 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) and/or from whom ≥ 25% of 
the bone marrow was irradiated.
10. Patient has a concurrent malignancy or malignancy within 3 years of randomization, with 
the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous 
skin cancer or curatively resected cervical cancer.
11. Patient has central nervous system (CNS) involvement
If patient is fulfilling the following 3 criteria she/he is eligible for the trial.

completed prior therapy (including radiation and/or surgery) for CNS metastases ≥ 28 
days prior to the start of study and

Central Nervous System (CNS) tumor is clinically stable at the time of screening and

patient is not receiving steroids and/or enzyme inducing anti-epileptic medications for 
brain metastases
12. Patients with an established diagnosis of diabetes mellitus type I or not controlled type II 
(based on FPG and HbA1c, see inclusion criterion 12)
13. Patient 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)
14. Patient has a known history of Human Immunodeficiency Virus (HIV) infection (testing 
not mandatory)
15. Patient 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, severe hepatic impairment, etc.)
16. Patient has currently documented pneumonitis (chest CT scan performed at baseline for 
the purpose of tumor assessment should be reviewed to confirm that there are no relevant 
pulmonary complications present).
17. Patient has clinically significant, uncontrolled heart disease and/or recent cardiac events 
including any of the following:

History of angina pectoris, coronary artery bypass graft (CABG), symptomatic 
pericarditis, or myocardial infarction within 12 months prior to the start of study 
treatment

History of documented congestive heart failure (New York Heart Association 
functional classification III-IV)

Documented cardiomyopathy

Patient has a Left Ventricular Ejection Fraction (LVEF) < 50% as determined by 
MUGA scan or ECHO

History of any cardiac arrhythmias, (e.g. ventricular tachycardia), complete left 
bundle branch block, high grade AV block (e.g. bifascicular block, Mobitz type II and 
third degree AV block), supraventricular, nodal arrhythmias, or conduction 
abnormality in the previous 12 months.


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
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.

Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome, or any of the following:

Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia

Concomitant medication(s) with a known risk to prolong the QT interval and/or 
known to cause TdP that cannot be discontinued or replaced by safe alternative 
medication

Bradycardia (heart rate < 50 at rest), by ECG or pulse.

On screening, inability to determine the QTcF interval on the ECG (i.e.: unreadable or 
not interpretable) or corrected QT (QTcF) >450 msec for males and >460 msec for 
females (using Fridericia’s correction). All as determined by screening ECG (mean of 
triplicate ECGs).
18. Patient is currently receiving any of the following medications and cannot be discontinued 
7 days prior to the start of the treatment:

That have a known risk to prolong the QT interval or induce TdP.

Herbal preparations/medications
19. Patient 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).
20. Sexually active males unless they are sterilized (at least 6 months prior to screening) or 
use a condom during intercourse while taking drug and for at least 8 months after stopping 
alpelisib and/or Fulvestrant medication and should not father a child in this period. A 
condom is required to be used also by vasectomized men in order to prevent delivery of 
the drug via seminal fluid.
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. Not able to understand and to comply with study instructions and requirements.
23. History of acute pancreatitis within1 year of screening or past medical history of chronic 
pancreatitis
24. Patient who relapsed with documented evidence of progression more than 12 months from 
completion of (neo)adjuvant endocrine therapy with no treatment for metastatic disease


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6
Treatment
6.1
Study treatment
For this study, the term “investigational drug” refers to Novartis study drug alpelisib. 
Fulvestrant is also being used in this study. Study treatment in this study refers to the 
combination of drugs in each of the study arms and includes alpelisib/placebo and fulvestrant. 
This is a double blind placebo controlled study, the investigator and patient will be blinded (i.e. 
will not know if the patient is receiving alpelisib or placebo). The storage conditions for the 
alpelisib/placebo will be described on the medication label.
Novartis Drug Supply Management or its designee will provide alpelisib and placebo as 50 mg 
and 200 mg tablets as individual patient supply, packaged in bottles. Alpelisib will be dosed on 
a flat scale of mg/day and not be adjusted to body weight or body surface area.
Fulvestrant will be procured locally according to local practice and regulation, or supplied by 
Novartis (or its designee). 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.
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record Case Report Form (CRF).
6.1.1
Dosing regimen
All eligible patients will be randomized to receive either:

Alpelisib 300 mg p.o. + fulvestrant 500 mg i.m. or

Alpelisib Placebo 300 mg p.o. + fulvestrant 500 mg i.m.
During randomized treatment phase, alpelisib 300 mg or alpelisib matching placebo will be 
administered orally once daily on a continuous dosing schedule starting on Cycle 1 Day 1 in 
combination with fulvestrant 500 mg starting on Cycle 1 Day 1 and 15 and Day 1 of every cycle 
thereafter (+/- 3 days) in a 28 days cycle. Treatment crossover from fulvestrant plus placebo to 
fulvestrant plus alpelisib will not be permitted in this study.
A complete cycle of treatment is defined as 28 days (± 3 days) of once daily continuous 
treatment of alpelisib or placebo in combination with fulvestrant.
The last day of a complete treatment cycle is Day 28. Day 1 of the next cycle starts on Day 29.
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record CRF.


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Table 6-1
Alpelisib/placebo and fulvestrant dose and treatment schedule
Study drugs
Pharmaceutical form and 
route of administration
Dose2
Frequency and/or Regimen
Alpelisib/plac
ebo
Film coated tablet for oral use
300 mg
(e.g. 2 x 50 mg 
tablets+1x200 mg tablet1)
Daily (continuous) starting 
C1D1
Fulvestrant
Injection for i.m. 
administration
500 mg
Days 1, 15 on Cycle 1 and Day 
1 at each cycle thereafter
1 In case of patient supply difficulties, any combination of alpelisib/placebo (according to patient assignment) 
may be taken to consume the total dose.
2 Dose reduction levels for alpelisib/placebo will be administered accordingly. For example, alpelisib/placebo 
250mg should preferentially be administered as 1 X 50 mg tablets + 1 x 200 mg tablet
6.1.1.1
Alpelisib/placebo dosing
Alpelisib at a dose of 300 mg or placebo will be administered orally once daily on a continuous 
dosing schedule starting on Cycle 1 day 1 in combination with fulvestrant 500 mg intra 
muscular at day of randomization.
Alpelisib/placebo is dosed on a flat scale of mg/day and not by weight or body surface area.
The maximum recommended daily dose of alpelisib/ placebo is 300 mg.
There will be no breaks between dosing cycles.
The investigator or responsible site personnel should instruct the patient to take the study drugs 
as per protocol (promote compliance). Drug accountability must be performed on a regular basis. 
Patients will be instructed to return unused study drugs to the site at the end of each cycle. The 
site personnel will ensure that the appropriate dose of each study drug is administered at each 
visit and will provide the patient with the correct amount of drugs for subsequent dosing.
The following general guidelines should be followed for alpelisib/placebo administration:

Patients should be instructed to take the dose of alpelisib/placebo once daily at 
approximately the same time each day immediately aftera meal (preferably in the morning 
after breakfast) except on the days blood collection is scheduled at the clinic, at which time 
the patients should take their doses at the clinic at any later point of time.

Alpelisib/placebo must be taken immediately after a meal or snack.  If, for any reason, a 
breakfast (or other meal) was not consumed, then the patient should take study treatment 
with a glass of water immediately after a snack. If this happens on days of PK sampling, it 
should be documented in the CRF.

If a dose of alpelisib/alpelisib matching-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 the usual time.

Alpelisib/placebo should be taken with a glass of water. Patients should swallow the tablet 
as a whole and not chew or crush them.

During treatment phase, the patient should record if the dose was taken or not in the 
alpelisib/placebo patient diary.


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
If the patient vomits after taking the alpelisib/alpelisib matching-placebo dose, the patient
should not take an additional dose on that day and should resume the usual dosing schedule 
the next day at the usual time.

The occurrence and frequency of any vomiting during a treatment cycle must be noted in 
the adverse events section of the CRF.
6.1.1.1.1 Additional dosing guidelines for pharmacokinetic sampling
On days with pharmacokinetic sampling

For sparse PK subset: Cycle 1 Days 8 and 15, Cycle 2, 4, 6, 8 Day1

For trough PK: Cycle 2, 4, 6, 8 Day 1
The following additional guidelines should be followed:
The pre-dose sample should be drawn before alpelisib/placebo dosing. On days and time points 
when PK, biochemistry, hematology or other blood samples are to be performed, the PK sample 
must be drawn first. The sampling time of the pre-dose PK sample and the dosing time of 
alpelisib/placebo must be precisely recorded in the CRF. Furthermore, the dosing time of 
alpelisib/placebo on the previous day must be precisely recorded in the CRF and in the 
alpelisib/placebo patient diary. If vomiting occurs, the exact time of the first vomiting episode 
within the first 4 hours post-dosing on that day must be noted. Time of administration of gastric 
protection agents on days of PK sampling should be precisely recorded in the CRF.
6.1.1.1.2 Additional dosing guidelines for fasting glucose and/or amylase/lipase 
and/or c-peptide and/or lipid profile sampling
On days with a pre-dose fasting (overnight) glucose and/or amylase/lipase and/or c-peptide 
and/or lipid profile samples as described in Table 7-1 and Section 7.2.2.5.3 the following 
additional guidelines should be followed:
The patient must be fasting overnight for 8-12 hours prior to the blood collection, but can freely 
drink water. After this blood sample, the patient should have a light breakfast. Alpelisib/placebo 
must be taken within 1 hour after the meal in the clinic. If a pharmacokinetic sample is also 
being drawn, then the sample should be taken before alpelisib/placebo dosing, as described in 
Section 7.2.3.
6.1.1.2
Fulvestrant dosing
Fulvestrant 500 mg will be given at Cycle 1 Day 1 and 15 after randomization and then at Day 
1 of each subsequent cycle during the randomized treatment phase (+/- 3 days). Fulvestrant is 
administered intramuscularly into the buttocks slowly as two 5mL injections, one in each 
buttock.
No dose modification is allowed for fulvestrant. Please refer to the local approved prescribing 
information. Any planned variance from these guidelines in the view of the patient safety must 
be previously discussed with the Sponsor unless there is an urgent need for action.


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6.1.1.2.1 Additional dosing guidelines for pharmacokinetic sampling
On days with fulvestrant pharmacokinetic sampling (Day 15 of Cycles 1, 2, 4, 6, and 8) the 
following additional guidelines should be followed: the pre-dose sample should be drawn just 
before fulvestrant dosing. The sampling time of the pre-dose PK sample and the dosing time of 
fulvestrant must be precisely recorded in the CRF. Furthermore, the dosing date and time of the 
previous dose of fulvestrant must be precisely recorded in the CRF.
6.1.2
Guidelines for continuation of treatment
For guidelines for continuation of treatment, refer to Section 6.3 Dosing modifications.
Patients who permanently discontinue one of the study drugs for any reason other than disease 
progression may continue the other study drug as part of the trial therapy at the investigators 
discretion until disease progression, unacceptable toxicity, death or discontinuation from study 
treatment due to any other reason and should follow the protocol safety and efficacy 
assessments as scheduled. After discontinuing all study treatment, further treatment is left to 
the physician’s discretion.
6.1.3
Ancillary treatments
Not applicable
6.1.4
Rescue medication
Not applicable
6.1.5
Treatment duration
Patients will be treated until disease progression (radiologically documented according to 
RECIST 1.1) or until discontinuation of study treatment due to any other reason.
6.2
Dose escalation guidelines
Not applicable.
6.3
Dose modifications
6.3.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. These changes must be 
recorded on the Dosage Administration Record CRF.
6.3.1.1
Fulvestrant
The established clinical dose of fulvestrant (500 mg) will be used in each arm and no dose 
modification of fulvestrant is planned in this study. For information on fulvestrant and 
management of related AEs refer to the Faslodex® SmPC or local Prescribing Information.


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6.3.1.2
Alpelisib/placebo
Management of severe or intolerable adverse reactions requires dose reduction, temporary 
interruption, and/or discontinuation of alpelisib therapy. A maximum of 2 dose reductions will 
be allowed, after which the patient will be discontinued from treatment with alpelisib/placebo. 
Dose reduction should be based on the worst preceding toxicity.
Please refer to Table 6-2 and Table 6-3 for guidance.
Table 6-2
Dose reduction sequential steps 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
Recommendations for dose reduction or dose interruption of alpelisib/placebo in the 
management of adverse reactions are summarized in Table 6-3. No dose modification for 
fulvestrant is permitted. Clinical judgment of the treating physician, including confirmation of 
lab values if deemed necessary, should guide the management plan of each patient based on 
individual benefit/risk assessment.
However, treatment must be discontinued as indicated in Table 6-3.
After treatment is resumed at a lower dose:

If the same toxicity recurs with the same severity, then the next treatment re-initiation 
must resume at a lower dose irrespective of duration.

Once the alpelisib/placebo dose has been reduced, no re-escalation will occur, even upon 
resolution of AE.
If a patient requires a dose delay of alpelisib/placebo for > 28 days from the intended day then 
the patient must be discontinued from alpelisib/placebo, but may continue on fulvestrant. All 
scheduled assessments will continue to be performed. If fulvestrant is held for more than 35 
days since a planned injection, then fulvestrant should be permanently discontinued. The patient 
may continue on alpelisib/placebo at the discretion of the investigator until study completion, 
in which case all scheduled assessments will continue to be performed.


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Table 6-3
Criteria for interruption and re-initiation of alpelisib/placebo treatment
Dose Modifications for alpelisib/placebo as specified below. Fulvestrant may be continued while 
alpelisib/placebo dose is being held, at the investigators discretion, and as specified in Section 6.3.1
Worst toxicity -CTCAE Grade (value)
Dose Modifications for alpelisib/placebo
Investigations (Fasting Plasma Glucose)
Hyperglycemia (see also Section 6.3.2.1.3)
Always consider consultation with a diabetologist and recommend/reinforce on lifestyle changes as per ADA, 
i.e. exercise and dietary advice (e.g. small frequent meals, low carb, high fiber, low process food intake, three 
macronutrient balanced meals and 2 optional small snacks rather than one large meal).
Note: this table provides dose management recommendations. The preferred option for treating alpelisib-induced 
hyperglycemia is metformin, given its wide availability and well characterized safety profile. However, in case of 
intolerance to or unavailability of metformin, investigator’s judgment should be exercised and other insulin 
sensitizers such as SGLT2 inhibitors, thiazolidinediones or dipeptidyl peptidase-4 Inhibitors can be used.
Grade 1 (> ULN - 160 mg/dL) [> ULN - 8.9 
mmol/L]
For patients with baseline values 
between >ULN – 140 mg/dL (ULN – 7.7 
mmol/L) this apply only for values > 140 
mg/dL (7.7 mmol/L)
Maintain dose level, and remind patient on lifestyle changes*. 
●If FPG < 140 mg/dl, consider adding metformin as per 
guidance below or in cooperation with diabetologist
●If FPG 140-160 mg/dl, start/intensify metformin as per 
guidance below or in cooperation with diabetologist
Metformin 500 mg once daily with dinner. If no gastrointestinal 
(GI) intolerance after several days, increase to 500 mg bid, with 
breakfast and dinner. If tolerated, increase to 500 mg with 
breakfast, and 1000 mg with dinner. If tolerated, 1000 mg bid with 
breakfast and dinner. If not tolerated, reduce to prior tolerated 
dose.
Monitor FPG as clinically indicated and at least weekly for 8 
weeks, then continue checking at least every two weeks until 
FPG is within baseline values.
Grade 2 (>160 - 250 mg/dL) [> 8.9 - 13.9 
mmol/L]
Maintain dose level and remind patient on lifestyle changes*, 
exclude confounding factors like e.g. urinary tract infection, 
consider consultation with a diabetologist and start oral-
antidiabetic treatment, e.g. metformin 500 mg bid with breakfast 
and dinner. If no GI intolerance, increase to 500 mg with 
breakfast, 1000 mg with dinner. If tolerated, 1000 mg bid with 
breakfast and dinner. If not tolerated, reduce to prior tolerated 
dose. Titrate to the maximum tolerated dose over a period of 3 
weeks. A second oral hypoglycemic agent may be initiated if 
needed.
If FPG is still rising on maximum tolerated dose of metformin or 
persistently >160mg/dl (>8.9 mmol/L, add an SGLT2 inhibitor if 
available, e.g. empagliflozin up to 25 mg (max. dose). 
Alternatively, an insulin-sensitizer, e.g. pioglitazone 30 mg (max. 
dose) can be added.
Monitor FPG as clinically indicated and at least weekly until FPG 
resolves to ≤ Grade 1
●If FPG does not resolve to ≤ Grade 1 within 21 days after 
institution of appropriate anti-diabetic treatment, reduce 
alpelisib/placebo by 1 dose level
●Continue with anti-diabetic treatment and check FPG at least 
weekly for 8 weeks, then continue checking at least every 2 
weeks, alert treating physician if FPG>250mg/dl


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Dose Modifications for alpelisib/placebo as specified below. Fulvestrant may be continued while 
alpelisib/placebo dose is being held, at the investigators discretion, and as specified in Section 6.3.1
Worst toxicity -CTCAE Grade (value)
Dose Modifications for alpelisib/placebo
Grade 3 (FPG > 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. Start metformin and titrate as outlined for Grade 2, add 
insulin sensitizers (i.e. pioglitazone) or a SGLT2 inhibitor, if 
available, as outlined for Grade 2. Insulin may be used for 1-2 days 
until hyperglycemia resolves, however this may not be necessary 
in the majority of alpelisib-induced hyperglycemia given the short 
half-life of alpelisib.
Monitor FPG as clinically indicated and at least twice weekly until 
FPG resolves to ≤ Grade 1.

If FPG resolves to ≤ 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 FPG at least weekly for 8 weeks, then 
continue checking at least every 2 weeks, alert treating 
physician if FPG>250mg/dl

If FPG does not resolve to ≤ 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  FPG 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 
patient from alpelisib/placebo treatment.
Grade 4 (FPG > 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.

Should consult with diabetologist, initiate or intensify 
medication with appropriate anti-diabetic treatment (see 
Grade 3), re-check within 24 hours.

If grade improves then follow specific grade recommendations

If FPG is confirmed at Grade 4 and confounding factors could 
be excluded, permanently discontinue patient from 
alpelisib/placebo.


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Dose Modifications for alpelisib/placebo as specified below. Fulvestrant may be continued while 
alpelisib/placebo dose is being held, at the investigators discretion, and as specified in Section 6.3.1
Worst toxicity -CTCAE Grade (value)
Dose Modifications for alpelisib/placebo
A diabetologist consultation should always be considered.
For all grades : instruct patient to follow dietary guidelines according to local and/or institutional standards for 
management of diabetes mellitus (such as those provided by the American Diabetes Association) during the 
study, e.g. controlled carbohydrate intake, high fiber, low processed food intake; three macronutrient balanced 
meals and 2 small snacks rather than one large meal.
* specific recommendations please see Section 6.3.2.1.3.
Thrombocytopenia
Grade 1 (PLT < LLN - 75 x 109/L)
Grade 2 (PLT < 75 - 50 x 109/L)
Maintain dose level
Grade 3 (PLT < 50-25 x 109/L)
Omit dose until resolved to ≤ Grade 1, then:

If resolved in ≤ 7 days, then maintain dose level

If resolved in > 7 days, then 1 dose level
Grade 4 (PLT < 25 x 109/L)
Omit dose until resolved to ≤ Grade 1, then 1 dose level
Investigations (Renal)
Serum creatinine
< 2 x ULN
Maintain dose level
2 – 3 x ULN
Omit dose until resolved to ≤ grade 1, then:

If resolved in ≤ 7 days, then maintain dose level

If resolved in > 7 days, then 1 dose level
Grade 3 (> 3.0 – 6.0 x ULN)
Permanently discontinue patient from alpelisib/placebo
Grade 4 ( > 6.0 x ULN)
Permanently discontinue patient from alpelisib/placebo
Investigations (Hepatic)
Isolated total Bilirubin elevation
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)
Omit dose until resolved to ≤ Grade 1, then:

If resolved in ≤ 14 days, then maintain dose level

If resolved in > 14 days, then 1 dose level
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 patient from alpelisib/placebo
Isolated AST or ALT Elevation
Grade 1 (> ULN – 3.0 x ULN)
Maintain dose level. Initiate appropriate medical therapy and 
monitor as clinically indicated.
Grade 2 (> 3.0 - 5.0 x ULN)

No dose adjustment is required. Initiate appropriate medical 
therapy and monitor as clinically indicated.


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Dose Modifications for alpelisib/placebo as specified below. Fulvestrant may be continued while 
alpelisib/placebo dose is being held, at the investigators discretion, and as specified in Section 6.3.1
Worst toxicity -CTCAE Grade (value)
Dose Modifications for alpelisib/placebo
Grade 3 (> 5.0 - 20.0 x ULN)

Interrupt dose until recovery to Grade ≤ 1, then resume at the 
next lower dose level.

Grade 4 (> 20.0 x ULN)

Permanently discontinue.
Combineda elevations of AST or ALT and 
total Bilirubin
Please see specific instructions in Section 6.3.2.1.5

All dose modifications should be based on the worst preceding toxicity.
a “Combined” defined as total bilirubin increase to the defined threshold concurrently with ALT/AST increase to 
the defined threshold
If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the 
instructions for isolated elevation of total bilirubin and isolated elevation of AST/ALT, and take a conservative 
action based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is 
needed for one parameter and discontinue treatment is required for another parameter). After all elevations 
resolve to the defined thresholds that allow treatment re-initiation, re-start the treatment either at the same 
dose or at one dose lower if meeting a criterion for dose reduction
* Note: If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as 
the etiology has been ruled out as per institutional guidelines (e.g. review of peripheral blood smear and 
haptoglobin determination), then 1 dose level and continue treatment at the discretion of the investigator.


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Dose Modifications for alpelisib/placebo as specified below. Fulvestrant may be continued while 
alpelisib/placebo dose is being held, at the investigators discretion, and as specified in Section 6.3.1
Worst toxicity -CTCAE Grade (value)
Dose Modifications for alpelisib/placebo
Investigations (Cardiac)
Cardiac – QTc prolongation
QTcF > 500 ms (≥ Grade 3)
or > 60 ms change from baseline
on at least two separate ECGs
First Occurrence:
1.
Assess the quality of the ECG recording and the QT value 
and repeat if needed
2.
Interrupt study treatment
3.
Determine the serum electrolyte levels (in particular 
hypokalemia, hypomagnesemia). If abnormal, correct 
abnormalities before resuming study drug treatment.
4.
Review concomitant medication use for other causes for QT 
prolongation (refer to crediblemeds.org for known QT 
prolonging drugs), and for drugs with the potential to 
increase the risk of drug exposure related QT prolongation
5.
Check study drug dosing schedule and treatment compliance
6.
Consider collecting a time-matched PK sample and record 
time and date of last study drug intake.
After confirming ECG reading at site, if QTcF > 500 ms or > 60 
ms change from baseline

Interrupt study treatment

Repeat ECG and confirm ECG diagnosis by a cardiologist
If QTcF confirmed > 500 ms or > 60 ms change from baseline

Correct electrolytes, eliminate culprit concomitant treatments, 
and identify clinical conditions that could potentially prolong 
the QT

Consult with a cardiologist (or qualified specialist)

Increase cardiac monitoring as indicated, until the QTcF 
returns to ≤ 480 ms or < 60ms change from baseline. 

After resolution to ≤ 480 ms /60 ms change from baseline, 
consider re-introducing treatment at reduced dose, and 
increase ECG monitoring

If QTcF remains ≤ 500 ms/60 ms change from baseline after 
dose reduction, continue planned ECG monitoring during 
subsequent treatment

If QTcF recurs > 500 ms/60 ms change from baseline after 
dose reduction, discontinue patientfrom alpelisib/placebo.
Cardiac - Left Ventricular Systolic Dysfunction
Asymptomatic,
resting ejection fraction 40-50%;
or 10-20% drop from baseline
-Maintain dose level, and continue alpelisib with caution
-Repeat LVEF within 4 weeks or as clinically appropriate
Symptomatic,
responsive to intervention,
ejection fraction 20-39%
or > 20% drop from baseline
-Omit alpelisib/placebo until resolved* (as defined below), then 
1 dose level
-LVEF measurement to be repeated, if not resolved* within 28 
days permanently discontinue patientfrom alpelisib/placebo 
treatment
Refractory or poorly controlled,
ejection fraction < 20%
Permanently discontinue patientfrom alpelisib/placebo
*the event is considered resolved when the patientis asymptomatic, has a resting ejection fraction ≥ 40% and 
≤20% decrease from baseline.


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Dose Modifications for alpelisib/placebo as specified below. Fulvestrant may be continued while 
alpelisib/placebo dose is being held, at the investigators discretion, and as specified in Section 6.3.1
Worst toxicity -CTCAE Grade (value)
Dose Modifications for alpelisib/placebo
Other Cardiac Events
Grade 1 or 2
Maintain dose level
Grade 3
Omit dose until resolved to ≤ Grade 1, then 1 dose level
Grade 4
Permanently discontinue patient from alpelisib/placebo
Investigations (Gastrointestinal)
Diarrhea (see also Appendix 4)
Grade 1
Maintain dose level but initiate appropriate medical therapy and 
monitor as clinically indicated
Grade 2
Omit dose until resolved to ≤ Grade 1, then restart at same dose
If diarrhea returns as ≥Grade 2, then omit dose until resolved to 
≤ Grade 1, then decrease 1 dose level
Grade 3
Omit dose until resolved to ≤ Grade 1, then 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
Grade 4
Discontinue patient 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.
Investigations (Pancreatic)
Pancreatitis
Grade 2 (enzymatic elevation or radiologic 
findings only)
Omit dose until resolved to Grade ≤ 1, then resume treatment at 
↓1 dose level. If toxicity recurs, permanently discontinue patient 
from alpelisib/placebo
Grade 3

For patients deriving clinical benefit 
upon investigator’s judgement:

For other patients:

Omit dose until complete resolution of symptoms and lipase 
resolved to Grade ≤ 1, then resume treatment at ↓1 dose 
level. Only 1 dose reduction is allowed.

If recovery to ≤ Grade 1 is greater than 28
days, the patient must be discontinued 
from the study.

If toxicity reoccurs, permanently 
discontinue patient from alpelisib/placebo

Permanently discontinue patient from alpelisib/placebo
Grade 4
Permanently discontinue patient from alpelisib/placebo
Stomatitis/Oral mucositis (see also Appendix 5)
Grade 1/Tolerable Grade 2
Maintain dose level.
Non-alcoholic or salt water mouth wash.
Intolerable Grade 2 or Grade 3
First occurrence: hold until ≤ Grade 1 and 1 dose level (if 
stomatitis is readily manageable with optimal management, re-
introduction at the same level might be considered at the 
discretion of the investigator).
Second occurrence: hold until ≤ Grade 1 and 1 dose level.
Grade 4
Permanently discontinue patient from alpelisib/placebo.


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Dose Modifications for alpelisib/placebo as specified below. Fulvestrant may be continued while 
alpelisib/placebo dose is being held, at the investigators discretion, and as specified in Section 6.3.1
Worst toxicity -CTCAE Grade (value)
Dose Modifications for alpelisib/placebo
Skin and subcutaneous tissue disorders
Consultation with a dermatologist is highly recommended for better assessment and management of alpelisib-
induced skin toxicity. (see also Section 6.3.2.1.2). 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 (DRESS)
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 as 
long as skin toxicity is active, during maximum 28 days
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/day.
For patients with symptoms like burning and/or pruritus add 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 as 
long as skin toxicity is active, up to max. 28 days

Add systemic corticosteroids 20-40mg/d  
If rash resolves to ≤ G1 within 10 days systemic corticosteroid 
may be discontinued. For patients with symptoms like burning, 
stinging and/or pruritus add non-sedating anti-histamine, 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, 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 resolves to ≤ G1 within 10 days systemic corticosteroid 
may be discontinued
Re-start alpelisib/placebo dose once rash /skin toxicity is no 
longer active but  fading (G1):
- at a reduced dose in case of first occurrence,
- If rash/skin toxicity still active in up to 10% BSA after more than 
14 days, continue oral corticosteroid for at least 48 hours upon re-
challenge with alpelisib/placebo; if rash and/or pruritus do not 
reoccur within 48 hours after re-challenge with alpelisib, systemic 
corticosteroid may be discontinued
For patients 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.


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Dose Modifications for alpelisib/placebo as specified below. Fulvestrant may be continued while 
alpelisib/placebo dose is being held, at the investigators discretion, and as specified in Section 6.3.1
Worst toxicity -CTCAE Grade (value)
Dose Modifications for alpelisib/placebo
Grade 4
(any % BSA associated with extensive 
superinfection, with IV antibiotics 
indicated; life-threatening consequences)
Permanently discontinue patient from alpelisib/placebo
Consult a dermatologist, ensure documentation by imaging like 
photographs, and obtain a skin biopsy 
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 (DRESS) or other 
SJS/TEN/DRESS like severe skin 
reactions  
Permanently discontinue patient from alpelisib/placebo 
Consult a dermatologist, ensure documentation by imaging like 
photographs, and obtain a skin biopsy 
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 6.3.2.1.6
Investigations (Pulmonary disorders)
Pneumonitis
Please see specific instructions in Section 6.3.2.1.1.
Investigations (Metabolic)
Asymptomatic amylase and/or lipase elevation (see also Section 6.3.2.1.4)
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 ↓1 dose level.
Note:

In cases of isolated amylase elevations only, dosing may be 
maintained provided amylase fractionation demonstrates that 
pancreatic amylase is ≤ Grade 1. Monitor total amylase (and 
continue to assess fractionated amylase) as specified in 
Section 6.3.2.1.4.
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 ↓1 dose level
Grade 4
Permanently discontinue 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)


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Dose Modifications for alpelisib/placebo as specified below. Fulvestrant may be continued while 
alpelisib/placebo dose is being held, at the investigators discretion, and as specified in Section 6.3.1
Worst toxicity -CTCAE Grade (value)
Dose Modifications for alpelisib/placebo
For additional details on the safety profile of alpelisib, please refer to the alpelisib Investigator Brochure.
6.3.2
Follow-up for toxicities
All patients 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 fulvestrant). Patients 
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 which includes all study assessments appropriate to monitor the event.
Further guidelines and recommendations for the management of specific study treatment 
combination-induced toxicities are provided below.
6.3.2.1
Additional follow-up for selected toxicities
6.3.2.1.1 Management of pneumonitis /Interstitial lung disease
Alpelisib is associated with pneumonitis/interstitial lung disease. Closely monitor all patients 
for signs and symptoms of pneumonitis.
All patients will be routinely asked about and observed for the occurrence of adverse events 
including new or changed pulmonary symptoms (consistent with lung abnormalities). Patients 
who are suspected to have developed pneumonitis should suspend (alpelisib/placebo) 
immediately (but may continue fulvestrant if clinically indicated) and undergo appropriate 
imaging (high resolution CT scan) and broncho-alveolar lavage (BAL) and biopsy should be 
considered if clinically appropriate. Infectious causes of interstitial lung disease should be ruled 
out. Infectious causes of interstitial lung disease should be ruled out. Investigators should follow 
institutional practice for management of pneumonitis which generally includes treatment with 
high dose corticosteroids; antibiotic therapy should be administered concurrently if infectious 
causes are suspected. Consultation with a pulmonologist is highly recommended for any 
pneumonitis case during the study treatment. After ruling out infectious etiology and upon 
making a diagnosis of pneumonitis, permanently discontinue treatment with alpelisib/placebo 
and promptly initiate appropriate treatment and supportive measures.
Alpelisib/placebo should be permanently discontinued in all subjects with confirmed 
pneumonitis.
6.3.2.1.2 Guidelines for the treatment of study drug induced skin toxicity
Skin toxicity is a class-effect adverse event observed with PI3Ki/mTORi agents.
Close monitoring of potential skin reactions will be performed at each planned visit and will be 
reported as adverse event. The most frequent skin adverse events reported are: maculopapular 
rash (only a minority present acneiform rash); pruritus and dry skin. The onset is typically 
within the first 2 months of treatment start and is reversible with adequate comedication and 
treatment interruption 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 severe cutaneous reaction like 


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Stevens-Johnson-Syndrome, Toxic Epidermal Necrolysis or Erythema multiforme or Drug 
Reaction with Eosinophilia and Systemic Symptoms (DRESS)is suspected. Workup for skin 
toxicity events 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.
Skin photographs must be taken and skin biopsy must be performed in case of Grade 4 skin 
toxicity and any grade of suspected severe cutaneous reactions. In case of Grade 3 skin toxicity, 
Novartis recommends that photographs are taken and a skin biopsy is performed. 
Skin biopsy will be sent to a Novartis designated laboratory, together with dermatologist and 
pathologist reports, if available, for further research purpose on the pathology and mechanism 
of PI3K inhibitor treatment induced skin toxicity
Antihistamines administered prior to rash onset may decrease incidence and severity of rash 
based on Study CBYL719C2301; therefore, at the Investigator’s discretion, non-sedating 
antihistamines (e.g. cetirizine (Zyrtec©), fexofenadine (Allegra), loratadine (Claritin)) may be 
used as prophylactic treatment to reduce severity of rash in all patients and especially for 
patients with a history of atopy such as allergic rhinitis, asthma, atopic dermatitis, or drug 
allergies.
For any grade of severe cutaneous reactions, alpelisib treatment must be permanently 
discontinued without any re-challenge.
Recommended therapies for skin toxicity events of all grades and as clinically indicated include:

Mid to high potency topical steroids: triamcinolone 0.01% 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 or solution preparation.

Gamma-aminobutyric acid (GABA) Agonists: Gabapentin 300mg every 8 hours,
Pregabalin 50-75 mg every 8 hours (to adjust of renal impairment). Depending on patient’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, EM, DRESS), alpelisib treatment must be permanently 
discontinued without any re-challenge.
Dry skin has been reported. It is recommended that patients with dry skin use mild and fragrance 
free soaps and detergents. 
Although preclinical experiments demonstrated that patients should avoid sun exposure during 
treatment with buparlisib or alpelisib, especially when they already have experienced rash or 
other skin toxicities as the increased blood flow of the skin may worsen skin symptoms. Patients 
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.


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6.3.2.1.3 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 2012). Alpelisib induced 
hyperglycemia is generally manageable with adequate antidiabetic treatment. Alpelisib induced 
hyperglycemia typically occurs within the first month of treatment. Patients with pre-diabetes 
( i.e. FPG 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 FPG while on alpelisib/placebo treatment. However all patients, 
even those with FPG within normal limits at screening, may develop alpelisib induced 
hyperglycemia. Patients should always be instructed to follow dietary guidelines provided by 
the American Diabetes Association, e.g. small frequent meals, low carbohydrate content, high 
fiber, balancing carbohydrates over the course of the day; three small meals and 2 small snacks 
rather than one large meal and exercise, as appropriate.
Detailed guidelines for management of alpelisib induced hyperglycemia is provided in Table 6-
3 following discussion with an advisory board. This includes early administration of metformin. 
Metformin may be titrated to a daily dose of 1000 mg BID. Local protocols per standard clinical 
practice may be followed for monitoring and managing hyperglycemia. Fasting plasma glucose 
may be performed both locally and/or centrally for rapid availability for safety evaluation and 
management guidance. Special attention should be paid to the risk of hypoglycemia in patients 
interrupting alpelisib treatment and concomitantly receiving insulin and/or sulfonylureas. Due 
to the short half-life of alpelisib, all glucose lowering medications should be discontinued when 
alpelisib is stopped.
Consultation with a diabetologist is highly recommended for better assessment and 
management of alpelisib-induced hyperglycemia.
6.3.2.1.4 .Follow-up on amylase or lipase elevation (≥ CTCAE Grade 3)
Patient with amylase or lipase elevation ≥ CTCAE Grade 3 must be tested weekly (or more 
frequently if clinically indicated) until ≤ Grade 1 (or baseline). 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).
Patients who discontinue study treatment due to pancreatic toxicity must be monitored weekly 
(or more frequently if clinically indicated) until the event resolves to ≤ grade 1 or stabilization 
occurs (no CTCAE grade change over 4 weeks).
If amylase and/or lipase elevations are accompanied by new or progressive unexplained 
abdominal symptoms such as severe pain or vomiting, withhold study treatment, then perform 
diagnostic procedures (e.g. abdominal CT scan or ultrasound) to exclude pancreatic pathology.
See also dose modification guidelines described in Table 6-3.


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6.3.2.1.5 Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potential DILI, and should be considered as clinically important events.
In general, any increase of serum aminotransferases to > 3 x ULN should be followed by repeat 
testing within 48 to 72 hours.
If total bilirubin is elevated > 2 x ULN, fractionation into direct and indirect bilirubin is 
required. The threshold for potential DILI may depend on the patient’s baseline AST/ALT and 
TBIL value; patients meeting any of the following criteria will require further follow-up as 
outlined below:

For patients 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 patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or elevation 
of ALP liver fraction in patients 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 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 the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.
Upon presentation:
1. Obtain PK sample,as close as possible to last dose of study drug, to determine exposure to 
study drug and metabolites
2. Perform comprehensive medical history including cardiac disease, blood transfusions, i.v. 
drug abuse, travel, work, alcohol intake, and full clinical examination for evidence of acute or 
chronic liver disease, cardiac disease and infection etc
3. History of concomitant drug use (including nonprescription medications and herbal and 
dietary supplement preparations), alcohol use, recreational drug use, special diets, and 
chemicals exposed to within one month of the onset of the liver injury 4. Exclude other 
causes of liver disease. Further testing for acute hepatitis A, B, C or E infection and liver 
imaging (e.g. biliary tract) may be warranted
Obtain PK sample,as close as possible to last dose of study drug, to determine exposure to 
study drug and metabolites
Patient monitoring:


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•Repeat liver chemistry tests within 48-72 hours
•Retest frequency can decrease to weekly or less if abnormalities stabilize, drug has been 
discontinued, and the patient is asymptomatic.
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before the diagnosis of DILI is confirmed (see Table 6-4). 
Liver biopsy has limited value in the diagnosis of DILI as histopathological findings in DILI 
can resemble many other liver conditions. However, biopsy can be useful to establish an 
alternative diagnosis especially if other tests are inconclusive.
If DILI confirmed: permanently discontinue.
If DILI 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 outweigh the risk. Any decision 
regarding re-administration of study drug/s and dose regimen should be discussed with the 
Novartis medical safety team.
Table 6-4
Alternative causes of liver disease
Disease
Assessment
Hepatitis A, B, C, E
IgM anti-HAV; HBsAg, IgM anti-HBc, HBV DNA; anti-
HCV, HCV RNA, IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV infection
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG 
anti-EBV
Autoimmune hepatitis
ANA & 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.
Biliary tract disease
Ultrasound or MRI, ERCP as appropriate.
Wilson disease
Caeruloplasmin
Hemochromatosis
Ferritin, transferrin
Alpha-1-antitrypsin deficiency
Alpha-1-antitrypsin
Following appropriate causality assessments, as outlined above, the causality of the drug is estimated as 
“probable” i.e. > 50% likely, if it appears greater than all other causes combined. 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 an 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”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented


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6.3.2.1.6 Guidelines for hypersensitivity
Alpelisib and combination drug are associated with hypersensitivity reactions, including 
anaphylaxis. These are manifested by symptoms including, but not limited to, dyspnea, flushing, 
rash, fever or tachycardia. Alpelisib and/or combination drug should be permanently 
discontinued and should not be re-introduced in patients with serious hypersensitivity reactions. 
Appropriate treatment should be promptly initiated.
6.3.3
Anticipated risks and safety concerns of the study drug
Appropriate eligibility criteria, as well as specific dose modification and stopping rules are 
included in this protocol (see Section 6.3 for details).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Medications to be used with caution during combined alpelisib/placebo and fulvestrant 
 
 
 
 
 
 
 
 
 


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6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential patient 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the patient is assigned to the next sequential Subject 
No. available to the investigator through the Oracle Clinical RDC interface.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Subject No. must 
not be reused for any other subject and the Subject No. for that individual must not be changed, 
even if the patient is re-screened. If the patient fails to be randomized or start treatment for any 
reason, the reason will be entered into the Screening Disposition page.
IRT must be notified within 2 days that the patient was not randomized.
6.5.2
Treatment assignment or randomization
Once eligibility criteria have been confirmed, patients will be classified into one of the two 
cohorts (i.e. PIK3CA mutant and PIK3CA non-mutant). The PIK3CA mutation status provided 
by the Novartis designated laboratory will not be communicated to the investigators nor the 
patients at time of the randomization in order to avoid any potential bias.
Patients in each cohort will be randomized to one of the 2 treatment arms (Section 4.1 and 
Section 6.1) in a ratio of 1:1.
Randomization will be stratified by presence of lung and/or liver metastasis and previous 
treatment with CDK4/6 inhibitor.
In addition the IRT will manage the limitation of the number of patients with prior CDK4/6 
inhibitors treatment up to 30% of the total number of the patients. If the study will continue in 
both cohorts to the final analyses, the maximum total number of CDK4/6 inhibitors pretreated 
patients will be 168.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of patient 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 
Drug Supply Management using a validated system that automates the random assignment of 
medication numbers to medication packs containing each of the study treatments.
Prior to dosing, all patients who fulfill all inclusion and none of exclusion criteria will be 
randomized via IRT to one of the treatment arms at Cycle 1 Day 1. The investigator or his/her 
delegate will call or log on to the IRT and confirm that the patient fulfills all the inclusion and 
none of exclusion criteria. The IRT will assign a randomization number to the patient, which 


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will be used to link the patient to a cohort and a treatment arm and will specify a unique 
medication number for the first package of alpelisib/placebo to be dispensed and administered 
to the patient in combination with fulvestrant at Cycle 1 Day 1. The randomization number will 
not be communicated to the caller.
6.5.3
Treatment blinding
This is a double blind placebo controlled study. In particular patients, investigators, Blinded 
Independent Review Committee (BIRC) and the local radiologists will remain blinded from 
randomization until the preparation of the study closure. Novartis study team will be blinded 
from the time of randomization until final PFS analysis in each cohort.
Randomization data are kept strictly confidential until the time of unblinding, and will not be 
accessible to anyone involved in the conduct of the study. The identity of the treatments will be 
concealed by the use of investigational drugs (alpelisib or placebo) that are identical in 
packaging, labeling, schedule of administration and in appearance. 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 patients.
Unblinding will only occur in the case of patient emergencies (Section 8.3), for regulatory 
reporting purposes and at the conclusion of the study.
In rare cases when unblinding occurs because of emergency patient management, the actual 
treatment arm will not be communicated to any of the Novartis employees involved in running 
the trial in order to remain blinded. The patient will be withdrawn from the study treatment.
An independent statistical group external to Novartis, not involved in the trial conduct, will 
prepare data reports for the DMC. Details will be presented in the DMC charter.
6.6
Study drug preparation and dispensation
Patients will be provided with an adequate supply of study drug for self-administration at home, 
including instructions for administration, until at least their next scheduled study visit. Patients 
will receive alpelisib/placebo on an outpatient basis.
Fulvestrant should be dispensed according to local prescribing information and practice.
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record CRF.
6.6.1
Study drug packaging and labeling
The study medication packaging has a 2-part label. A unique medication number is printed on 
each part of this label which corresponds to one of the treatment arms. Responsible site 
personnel will identify the study treatment package(s) to dispense to the patient by using the 
IRT and obtaining the medication number(s). Site personnel will add the patient number on the 
label. Immediately before dispensing the package to the patient, site personnel will detach the 
outer part of the label from the packaging and affix it to the source document (Drug Label Form) 
for that patient’s unique patient number.


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Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug and the medication number but no 
information about the patient.
Table 6-5
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
Alpelisib or placebo
Tablets in bottles
50 mg
200 mg
Labeled as BYL719 50mg/placebo and 
BYL719 200mg/placebo
Once daily dosing
Fulvestrant
Refer to local product information
Refer to local product information
Fulvestrant packaging and labeling will be according to locally available supplies of fulvestrant 
and according to local regulations.
6.6.2
Drug supply and storage
Study treatments must be received by designated personnel 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, the study treatment should be stored according to the 
instructions specified on the drug labels and in the [Alpelisib (BYL719) Investigators Brochure]. 
The receipt of alpelisib/placebo has to be acknowledged in the IRT system.
Study treatments will be procured locally according to local practice and regulation, or supplied 
by Novartis (or its designee).
Table 6-6
Supply and storage of study treatments
Study treatments
Supply
Storage
Alpelisib or placebo
Centrally supplied by Novartis
Refer to study drug label
Fulvestrant
Supplied by Novartis
Refer to local product information
Site staff will be responsible for managing adequate re-supplies for fulvestrant. Only 
alpelisib/placebo re-supplies are managed with the IRT system.
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit.
An alpelisib/placebo patient medication diary will be provided for each patient. Patients or 
caregivers are required to complete this diary during the entire study and not only when PK 
sampling occurs.
On PK sampling days, compliance will be assured by administrations of the study treatment 
under the supervision of investigator or his/her designee, and will be verified by determinations 
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6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study or at the time 
of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and 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.
6.6.3.3
Handling of other study treatment
Not applicable.
6.6.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. Study drug destruction at the investigational site will only be 
permitted if authorized by Novartis in a prior agreement and if permitted by local regulations.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. The table indicates which assessments produce data to be entered into the 
database (D) or remain in source documents only (S) (“Category” column).
No CRF will be used as a source document.
Allowed visit windows are specified as follows:

Screening assessments, apart from those listed below, must occur within 28 days of the 
randomization as per Table 7-1.

Tumor sample for molecular testing can be sent within 35 days of the randomization.

Vital signs, ECOG performance status, required labs, physical exam should be performed 
within 14 days of randomization.

Randomization and Cycle 1 Day 1 should occur on the same day.

For all other visits, a general ±3 days window is permitted on assessments to take into 
account scheduling over public holidays, if not explicitly specified otherwise.

No time window for sparse PK sampling is allowed (other than specified in Table 7-7), 
while, other PK samples may be obtained ± 1 day from the scheduled date.

Radiological and patient reported outcome assessments must be performed as outlined in 
Table 7-1. A visit window of ± 7 days is allowed (the whole body bone scan should be 
performed within 42 days or 6 weeks prior to randomization).


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Every effort should be made to follow the schedule outlined in Table 7-1.


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Table 7-1
Visit evaluation schedule
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Subsequent
cycles
End of study 
treatment 
(EoT)
Post treatment 
Follow-up phase
 
Survival 
follow-
up
Day of cycle
-35 
to -1
-28 
to -1
-14 
to -1
1
8
15
1
15
1
N/A
30 days 
after last 
dose for 
safety
Every 8 
weeks
for 
efficacy 
if appli 
cable
Every 12 
weeks
Obtain Informed Consent
D
11.3
x
 
IWRS/IRT Registration
S
x
Patient History
Demography
D
7.1.1.3
x
Inclusion/exclusion 
criteria
D
5.2/5.3
x
Eligibility checklist (within 
IRT)
S
7.1.1.1
x
Relevant medical 
history/current medical 
conditions
D
7.1.1.3
x
Diagnosis and extent of 
cancer
D
7.1.1.3
x
ER/PgR status
D
7.1.1.3
x
HER2 status
D
7.1.1.3
x
Prior antineoplastic 
therapy
D
7.1.1.3
x


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Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Subsequent
cycles
End of study 
treatment 
(EoT)
Post treatment 
Follow-up phase
 
Survival 
follow-
up
Day of cycle
-35 
to -1
-28 
to -1
-14 
to -1
1
8
15
1
15
1
N/A
30 days 
after last 
dose for 
safety
Every 8 
weeks
for 
efficacy 
if appli 
cable
Every 12 
weeks
Prior/concomitant 
medications
D
7.1.1.3
x
Continuous up to 30 days after last dose of study treatment
Procedures and 
Significant Non-Drug 
therapies
D
7.1.1.3
x
Continuous up to 30 days after last dose of study treatment
Antineoplastic therapies
since discontinuation of
study treatment
D
7.1.6
x
x
x
x
Randomization
IWRS/IRT Randomization
D
6.5.2
x
End of phase disposition
D
7.1.1.2
7.1.3
x
x
x
Physical Examination
Performance status 
(ECOG)
D
7.2.2.4
x
x
x
x
Height
D
7.2.2.3
x
Weight
D
7.2.2.3
x
x
C3D1 and then as 
clinically indicated
x
Vital signs
D
7.2.2.2
x
x
x
x
x
x
x
Physical examination
S
7.2.2.1
x
x
x
x
x
x
x
Laboratory Assessments
Hematology
D
7.2.2.5.1
x
x
x
x
x
x
Fasting Chemistry (Full)
D
7.2.2.5.2
x
x
x
x


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Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Subsequent
cycles
End of study 
treatment 
(EoT)
Post treatment 
Follow-up phase
 
Survival 
follow-
up
Day of cycle
-35 
to -1
-28 
to -1
-14 
to -1
1
8
15
1
15
1
N/A
30 days 
after last 
dose for 
safety
Every 8 
weeks
for 
efficacy 
if appli 
cable
Every 12 
weeks
Fasting Chemistry 
(Partial)
D
7.2.2.5.2
x
x
Fasting Plasma Glucose
D
7.2.2.5.3
x
x
x
x
x
x
x
HbA1c
D
7.2.2.5.3
x
C2D1 and then every 3 cycles
x
Fasting Lipid Panel
D
7.2.2.5.3
x
x
Cardiac Enzymes
D
7.2.2.7.3
x
As clinically indicated
x
Coagulation
D
7.2.2.5.4
x
C2D1 and then every 2 cycles
x
Fasting Lipase, Fasting 
Amylase
D
7.2.2.5.3
x
x
C2D1 and then every cycles
x
Urinalysis (macroscopic)
D
7.2.2.5.5
x
As clinically indicated
x
Imaging/Other Assessments
Tumor Assessment
D
7.2.1
x
Every 8 weeks during the first 18 months and every 12 weeks until 36 months, then 
change to as clinically indicated until disease progression, death, withdrawal of 
consent, loss to follow-up, subject/guardian decision, and at EOT (If PR/CR is 
reported, confirmation of response is required; confirmatory assessment should be 
performed ≥ 4 weeks after response is first documented).
Note: tumor assessments must be continued even after start of new antineoplastic 
therapy
Whole body bone scan
D
7.2.1.1
x (within 42 days 
prior to
randomization)
As clinically indicated


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Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Subsequent
cycles
End of study 
treatment 
(EoT)
Post treatment 
Follow-up phase
 
Survival 
follow-
up
Day of cycle
-35 
to -1
-28 
to -1
-14 
to -1
1
8
15
1
15
1
N/A
30 days 
after last 
dose for 
safety
Every 8 
weeks
for 
efficacy 
if appli 
cable
Every 12 
weeks
12-Lead ECG
D
7.2.2.7.1
x
X
x
C3D1 and then 
every 2 cycles until 
36 months, then 
change to as 
clinically indicated
x
Cardiac imaging (MUGA 
or ECHO)
D
7.2.2.7.2
x
C5D1 and then 
every 4 cycles until 
36 months, then 
change to as 
clinically indicated
x
Safety
Adverse events
D
8.1
x
Continuous, up to 30 days after the last dose of study treatment
 
 
 
 
 


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Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Subsequent
cycles
End of study 
treatment 
(EoT)
Post treatment 
Follow-up phase
 
Survival 
follow-
up
Day of cycle
-35 
to -1
-28 
to -1
-14 
to -1
1
8
15
1
15
1
N/A
30 days 
after last 
dose for 
safety
Every 8 
weeks
for 
efficacy 
if appli 
cable
Every 12 
weeks
 
 
 
 
 
 
 
 
Patient Reported Outcomes
EORTC QLQ-C30
D
7.2.6.1
x
Every 8 weeks during the first 18 months and every 12 weeks until 36 months, then 
align with the efficacy assessments until disease progression, death, withdrawal of 
consent, loss to follow-up, subject/guardian decision, and at EOT
 
 
 
 


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Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Subsequent
cycles
End of study 
treatment 
(EoT)
Post treatment 
Follow-up phase
 
Survival 
follow-
up
Day of cycle
-35 
to -1
-28 
to -1
-14 
to -1
1
8
15
1
15
1
N/A
30 days 
after last 
dose for 
safety
Every 8 
weeks
for 
efficacy 
if appli 
cable
Every 12 
weeks
Study Drug Administration
Patient Diary
S
6.1.1.1
6.6.3.1
Daily Continuous
Alpelisib/Placebo
D
6.6
Daily
Fulvestrant
D
6.6
x
x
x
x
Blood sample for 
Alpelisib/Placebo 
&Fulvestrant trough PK 
sampling
D
7.2.3
See Table 7-6 for time points of blood 
collection for Alpelisib/Placebo & Fulvestrant 
trough PK assessment
Blood sample for 
Alpelisib/Placebo &
Fulvestrant sparse PK 
sampling
D
7.2.3
See Table 7-7 for time points of blood 
collection for Alpelisib/Placebo & Fulvestrant 
sparse PK assessment
Survival Follow-up
D
7.1.7
x


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7.1.1
Screening
After signing the study ICF, the tumor sample for PIK3CA testing should be sent within days -
35 to -21 of the screening period. It is recommended to wait for the central PIK3CA testing 
results before conducting other screening assessments. All other screening assessments will be 
done within 1 to 28 days prior to randomization or within 1 to 14 days prior to randomization 
for selected assessments (see Table 7-1 for the list of assessments to be performed).  Note: Any 
screening assessment that is done outside the screening window (Day -28 to Day -1 or Day -14 
to Day -1 as applicable) must be repeated prior to randomization.
Re-screening of patients is only allowed once per patient if the patient was not registered as 
entering the treatment phase before (i.e. IRT randomization). In this case the Subject No. 
assigned to the patient initially will be used and the patient will be identified with this number 
throughout her entire participation to the study.
For laboratory evaluations used to determine eligibility, a repeated evaluation within the 
screening window is permitted for screening results out of the defined range. If the repeated 
laboratory result meets the criteria, that result may be used to determine eligibility. If the 
repeated laboratory result does not meet the criteria, the patient will be considered a screening 
failure. In case rescreening occurs, all evaluations re-assessed should meet the eligibility criteria.
Assessments of PROs should be collected prior to any clinical assessments, drug dosing or 
diagnostic testing.
Any imaging assessments already completed during the regular work-up of the patient within 
28 days prior to randomization (42 days prior to randomization for whole body scan), including 
before signing the main study ICF can be considered as the baseline images for this study.
An additional 
will be proposed to the patient for 
 
. For details, refer to Table 7-8 and Section 7.2.4.
7.1.1.1
Eligibility screening
In order to determine and confirm the eligibility of the patient, once all screening procedures 
are completed, an eligibility checklist must be completed via IRT by the investigator or designee 
prior randomization. Please refer and comply with detailed guidelines in the [IRT Manual].
7.1.1.2
Information to be collected on screening failures
Subjects who signed an Informed Consent Form but are found not eligible for any reason will 
be considered as screening failures, and data will be handled in the same manner.
The following CRFs must be completed for a screen failure patient:

Screening phase disposition page of CRF (including reason for not being started on 
treatment)

Informed Consent, 

Inclusion/Exclusion Criteria

Demography


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
Adverse events (only if the patient experienced a Serious Adverse Event during the 
screening period after signing the ICF (see Section 8 for Serious Adverse Event reporting 
details)

Withdrawal of informed consent, if applicable

Death, if applicable
If a screen failure patient experiences an adverse event which does not meet the Serious Adverse 
Event criteria, details about the adverse event will be recorded only in the investigator’s source 
documents. In case of an Serious Adverse Event, data must be recorded on both the adverse 
event page in CRF and Serious Adverse Event report must be submitted to Novartis within 24 
hours after becoming aware of it.
No other data will be entered into the clinical database for patients who are screen failures.
If the patient fails to in continue into the treatment phase, then IRT must be notified within 2 
days of the screen fail that the patient was not enrolled in the treatment phase (Section 6.5.1).
7.1.1.3
Patient demographics and other baseline characteristics
The data that will be collected on patient characteristics at screening includes:

Demography (Date of birth and initials (where permitted), sex, race, ethnicity, source of 
patient referral)

Diagnosis and extent of cancer (including staging at study entry and histology/cytology)

Medical history (e.g. important medical, surgical, and allergic conditions from the 
patient’s medical history which could have an impact on the patient’s evaluation) / current 
medical conditions (e.g. all relevant current medical conditions which are present at the 
time of signing informed consent). Ongoing medical conditions, symptoms and disease 
which are recorded on the Medical History CRF should include the toxicity grade.

ER, PgR and HER2 status

All prior antineoplastic therapies including surgical interventions and chemo-, biologic-, 
immunologic- and radiation-therapies provided as treatment for cancer prior to the 
administration of study drug.

All medications and significant non-drug therapies taken within 30 days before the first 
dose is administered. They must be recorded on the Prior and Concomitant medication or 
Surgical and medical procedures CRF page and updated on a continual basis if there are 
any new changes to the medications.

Patient-reported outcome questionnaires (EORTC QLQ-C30
) 
(see Section 7.2.6).
Furthermore the following assessments will be performed:

PIK3CA mutation status

Vital signs

Height, weight

Physical examination


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
Performance status (ECOG)

Laboratory evaluations (e.g. hematology, coagulation, biochemistry, fasting plasma 
glucose/c-peptide/serum lipid profile/HbA1c/lipase/amylase, urinalysis)

ECG

ECHO/MUGA

Radiological assessments (e.g. CT Scan)
7.1.2
Treatment period
Patients will be treated with fulvestrant + alpelisib or fulvestrant + placebo until disease 
progression, unacceptable toxicity, withdrawal of consent by the patient, patient is lost to 
follow-up, death, discontinuation from the study treatment due to any other reason or the 
sponsor terminates the study. For details of assessments, refer to Table 7-1.
7.1.3
Discontinuation of study treatment
Patients may voluntarily discontinue from alpelisib/placebo and/or fulvestrant for any reason at 
any time. If a patient decides to discontinue from the study treatment, the investigator must 
make every effort (e.g. telephone, e-mail, letter) to determine the primary reason for this 
decision and record this information in the patient’s chart and on the appropriate CRF pages. 
They may be considered withdrawn if they state an intention to withdraw, fail to return for visits, 
or become lost to follow-up for any other reason.
The investigator should discontinue alpelisib/placebo and/or fulvestrant for a given patient if, 
she/he believes that continuation would be detrimental to the patient’s well-being.
For patients who discontinue treatment for reasons other than documented disease progression, 
death, lost to follow-up, or withdrawal of consent, tumor assessments must continue to be 
performed every 8 weeks during the first 18 months, every 12 weeks until 36 months, then as 
clinically indicated until documented disease progression, death, lost to follow-up, or 
withdrawal of consent.
Study treatment must be discontinued under the following circumstances:

Adverse event or laboratory abnormalities as indicated in Section 6.3.

Pregnancy

Lost to follow-up

Physician decision

Subject/guardian decision

Death

Progressive Disease

Study terminated by sponsor

Technical problems

Use of prohibited treatment and medications refer to Section 6.4.3 and Section 14.2.

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The appropriate personnel from the site and Novartis will assess whether alpelisib/placebo plus 
fulvestrant treatment should be discontinued for any patient whose treatment code has been 
broken inadvertently for any reason.
Patients who discontinue only one of two medications (fulvestrant or alpelisib/placebo) should 
NOT be considered withdrawn from the study. They should continue taking fulvestrant only or 
alpelisib/placebo only (as applicable) as per investigators’ clinical judgment, and return for the 
assessments indicated in Table 7-1.
If they fail to return for these assessments for unknown reasons, every effort (e.g. telephone, 
email, letter) should be made to contact them as specified in Section 7.1.8.
In addition to the general withdrawal criteria, if alpelisib dosing is held for > 28 days from the 
intended day then alpelisib should be permanently discontinued. If fulvestrant is held for more 
than 35 days since a planned injection, then fulvestrant should be permanently discontinued.
Patients who completely discontinue study treatment (i.e. fulvestrant and alpelisib/placebo) 
should be scheduled for an End of Treatment (EOT) visit as soon as possible, and at least within 
14 days after the date study treatment is permanently discontinued, at which time all of the 
assessments listed in Table 7-1 for the EOT visit will be performed.
If the decision to withdraw the patient occurs at a regularly scheduled visit, that visit may 
become the EOT visit rather than having the patient return for an additional visit.
An end of phase disposition CRF page called “End of Treatment” disposition page should be 
completed, giving the date and primary reason for discontinuation.
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations during the 30 days following the 
last dose of study treatment.
The investigator must determine the primary reason for a patient’s premature withdrawal from 
the study and must contact IRT to register the patient’s treatment discontinuation within 2 days 
and record this information on the relevant end of phase disposition CRF page.
7.1.3.1
Replacement policy
Not applicable.
7.1.4
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient does not want to participate in the study any 
longer, and does not want any further visits or assessments, and does not want any further study 
related contact.
Novartis will continue to retain and use all research results that have already been collected for 
the study evaluation. All biological samples that have already been collected may be retained 
and analyzed at a later date (or as required by local regulations).
If a patient withdraws consent, the investigator must make every effort (e.g. telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information.


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Study treatment must be discontinued and no further assessments conducted.
Further attempts to contact the patient regarding the study related follow-up are not allowed 
unless safety findings require communication or follow-up.
7.1.5
Follow-up for safety evaluations
All patients 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) for 30 days after the last dose of study treatment. 
Patients 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 patients 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 patient 
should be documented in the source documents (e.g. dates of telephone calls, registered letters, 
etc.).
7.1.6
Efficacy follow-up
If a patient did not discontinue study treatment due to documented disease progression, death, 
lost to follow-up, or withdrawal of consent for efficacy follow-up, tumor and PRO assessments 
should continue to be performed every 8 weeks during the first 18 month and then every 12 
weeks until 36 months, then change to as clinically indicated until documented disease 
progression, death, lost to follow-up, or withdrawn consent to efficacy follow-up. At that time, 
the reason for study completion should be recorded on the Study Phase Completion Disposition 
CRF page. All tumor evaluation images collected during the efficacy follow-up phase will be 
sent to central vendor for independent review.
7.1.7
Survival follow-up
All patients will be followed for survival status every 3 months regardless of treatment 
discontinuation reason (except if consent is withdrawn or patient is lost to follow-up) until death, 
lost to follow-up, or withdrawal of consent for survival follow-up. Additional survival 
assessments may be performed outside the 3 months follow-up schedules if a survival update is 
required for an interim assessment to meet safety or regulatory needs.
Survival information can be obtained via phone, and information will be documented in the 
source documents and relevant CRFs.
the disease progression will be determined based on investigator assessment of 
progression 
For this purpose, 
since discontinuation of treatment eCRF.
7.1.8
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 


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in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow-up should be recorded as such on the appropriate 
Disposition CRF.
7.1.9
End of post-treatment follow-up
Prior to collecting survival follow-up information, the end of post treatment phase disposition 
CRF page will be completed once a patient has discontinued study treatment, completed safety 
follow-up, and can no longer perform efficacy assessment.
End of post-treatment follow-up may occur due to one of the following reasons:

Adverse event

Lost to follow-up

Physician decision

Pregnancy

Progressive disease

Protocol deviation

Study terminated by the sponsor

Technical problems

Subject/guardian decision

Death
7.2
Assessment types
7.2.1
Efficacy assessments
7.2.1.1
Imaging tumor assessments
Tumor response will be assessed locally and centrally according to the Novartis guideline 
version 3.1 (Appendix 3) based on RECIST 1.1 (Eisenhauer et al 2009). The imaging 
assessment collection plan is presented in Table 7-2. Further details regarding BIRC assessment 
will be provided in the BIRC charter. The central review of the scans will be carried out in a 
blinded fashion. The local investigator’s assessment will be used for treatment decision making.
Imaging data for all patients in each cohort will be centrally collected and checked for quality 
by an imaging CRO designated by Novartis. The results of the central evaluations in the 
PIK3CA mutant cohort will be used to support the primary objective.
Physical exam tumor assessments, photography, pathology/histology and cytology results, as 
well as, information regarding prior interventions, pre-existing radiographic findings that mimic 
metastatic disease at baseline/screening and on-study interventions should be captured in the 
appropriate CRFs and will be transmitted to the imaging CRO for review by a medical 
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Baseline imaging assessments
Imaging assessments will be performed at screening/baseline within 28 days prior to start of 
study treatment (Day -28 to Day -1 prior to Cycle 1 Day 1). The whole body scan can be 
performed within 42 days prior to start of study treatment. Any imaging assessments already 
completed during the regular work-up of the patient 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 as baseline images. The following assessments are required 
at screening/baseline:

Chest, abdomen and pelvis CT or Magnetic Resonance Imaging (MRI)

Brain CT or MRI, if clinically indicated

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

Color photography for any skin lesions present

CT or MRI of other metastatic sites (e.g. neck), if clinically indicated
If a patient is known to have a contraindication to CT i.v. 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.
If brain metastases are suspected at baseline, brain MRI or CT should be completed. Contrast 
enhanced brain MRI is preferred, however, if MRI contrast is contraindicated, then MRI without 
contrast or CT with/without contrast is acceptable.
At baseline all patients will undergo, a whole body bone scan 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], thereafter whole body scan should be 
performed as clinically indicated. 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.
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.
Each lesion that is measured at baseline must be measured by the same method (either same 
radiologic/nuclear method or by physical exam) throughout the study so that the comparison is 


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consistent. Criteria required for determining partial or complete response should be present for 
at least 4 weeks.
Chest x-rays and ultrasound should not be used to measure tumor lesions.
Post-baseline imaging assessments
Imaging assessments as described in Table 7-2 should be performed using the same imaging 
modality used at baseline, irrespective of study treatment interruption or actual dosing (see 
Table 7-1). 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) until 36 
months, then change to as clinically indicated. The 8-week (or 12 week) interval should be 
respected regardless of whether study treatment is temporarily withheld or unscheduled 
assessments are performed.
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a subject, 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 Positron Emission Tomography/Computed Tomography (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 (Appendix 3).
All study imaging (including any off-schedule imaging studies) should be submitted to the 
designated imaging CRO for quality control promptly after acquisition. If an off-schedule 
imaging assessment is performed to confirm response or if progression is suspected, subsequent 
imaging assessments should be performed in accordance with the original imaging schedule.


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Table 7-2
Imaging assessment collection plan
Procedure
Screening:***
Day-28 to Day -1
Treatment phase
End of 
treatment
Post-treatment follow-up 
phase: Efficacy
CT or MRI 
(Chest, 
Abdomen, 
Pelvis)
Mandated
Every 8 weeks after 
randomization date 
during the first 18 
months and every 12 
weeks until 36 months, 
then change to as 
clinically indicated
Mandated *
Every 8 weeks during the 
first 18 months and every 
12 weeks until 36 months, 
then change to as 
clinically indicated. if no 
documentation of 
progressive disease at 
end of treatment visit
CT or MRI for 
any site of 
disease
Mandated if 
suspected lesion at 
screening
If lesion at screening: 
every 8 weeks after 
randomization during 
the first 18 months and 
every 12 weeks until 36 
months, then change to 
as clinically indicated
Mandated if 
lesion at 
screening*
If lesion at screening:
Every 8 weeks during the 
first 18 months and every 
12 weeks until 36 months, 
then change to as 
clinically indicated if no 
documentation of 
progressive disease at 
end of treatment visit
Brain CT or MRI 
(only if existing 
or suspected 
brain metastasis)
Mandated at 
screening only if 
existing or 
suspected brain 
metastasis
If brain lesion at 
screening: every 8 
weeks after 
randomization during 
the first 18 months and 
every 12 weeks until 36 
months, then change to 
as clinically indicated r
Mandated 
only if brain 
lesion at 
screening *
If brain lesion at
screening:
Every 8 weeks during the 
first 18 months and every 
12 weeks until 36 months, 
then change to as 
clinically indicated if no 
documentation of 
progressive disease at 
end of treatment visit
Whole Body 
Bone scan**
Mandated, within 
42 days (6 weeks) 
prior to 
randomization.
As clinically indicated
As clinically 
indicated
As clinically indicated
Bone X-ray, CT 
or MRI
Mandated at 
screening only if 
skeletal 
abnormalities 
identified by bone 
scan at screening
If bone lesion at 
screening:
every 8 weeks after 
randomization during 
the first 18 months and 
every 12 weeks until 36 
months, then change to 
as clinically indicated
Mandated 
only if bone 
lesion at 
screening*
If bone lesion at 
screening:
Every 8 weeks during the 
first 18 months and every 
12 weeks until 36 months, 
then change to as 
clinically indicated if no 
documentation of 
progressive disease at 
end of treatment visit
Skin color 
photography
Mandated if skin 
lesions at 
screening
If skin lesions at 
screening
every 8 weeks after 
randomization during 
the first 18 months and 
every 12 weeks until 36 
months, then change to 
as clinically indicated r
Mandated if 
skin lesions 
at 
screening*
Mandated if skin lesions 
at screening
Every 8 weeks during the 
first 18 months and every 
12 weeks until 36 months, 
then change to as 
clinically indicated if no 
documentation of 
progressive disease at 
end of treatment visit


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Procedure
Screening:***
Day-28 to Day -1
Treatment phase
End of 
treatment
Post-treatment follow-up 
phase: Efficacy
* Mandated for patients who discontinue study treatment before the first scheduled post-screening tumor 
assessment and for patients whose previous tumor assessment did not demonstrate PD and was done more 
than 21 days prior to end of treatment visit. In addition, EOT tumor assessment should be done in patients who 
discontinue due to clinical progression (e.g. investigator decision) to confirm disease progression by RECIST.
** Type of whole body bone scan according to institutional guidelines
*** If CT or MRI scan available before signing of ICF but within 28 days of first dose, no need to repeat the 
procedures
Note: All scans will be acquired and analyzed for primary endpoint locally but should also be sent to the CRO 
designated by Novartis for central imaging interpretation.
 
 
 
7.2.1.3
Blinded independent review committee (BIRC) assessment
The primary end point of the study is the local investigator assessed PFS in the PIK3CA mutant 
cohort. The BIRC assessed PFS will serve as a supportive evidence of the primary end point, if 
the primary endpoint is statistically significant. The BIRC will perform an assessment of PFS 
data for a randomly selected subgroup of patients in the PIK3CA mutant cohort only. An 
independent random sampling process will select all scans (and relevant information) from 
approximately 50% of randomized patients, whose BIRC randomization identity will be 
unknown to the investigators. The central review of the scans will be carried out in a blinded 
fashion. The decision regarding patient management will remain with the investigators. If 
consistency of treatment effect is not established, the BIRC may perform an assessment of PFS 
data for all patients in the PIK3CA mutant cohort.  Further details regarding BIRC assessment 
will be provided in the BIRC charter. No BIRC assessment will be made in the PIK3CA non-
mutant cohort.
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing physical examination, vital signs, performance status 
evaluation, ECG, cardiac imaging, laboratory evaluations for hematology and biochemistry 
including glucose monitoring as well as collecting of the adverse events at every visit. For 
details on adverse event collection and reporting, refer to Section 8.1.
If one of study drugs is being held due to toxicity, scheduled visits and assessments should still 
be performed as described in Table 7-1.
7.2.2.1
Physical examination
A complete physical examination will be performed at screening (day-14 to day -1), at Day 8 
and Day 15 of Cycle 1, at Day 1 and Day 15 of Cycle 2, at Day 1 of each cycle at subsequent 
cycle, and at the EOT visit. The physical examination at screening can be done at Day 1 of 
Cycle 1 provided that it is done before the randomization of the patient. The physical 
examination comprises a total body examination that should include: general appearance, skin, 


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neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph-nodes, 
extremities, vascular and neurological review. If indicated, rectal, external genitalia, breast and 
pelvis exams will be performed. Information about the physical examination must be present in 
the source documentation at the study site.
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page on the patient’s CRF. Significant new findings that begin or worsen 
after informed consent must be recorded on the adverse event page of the patient’s CRF.
7.2.2.2
Vital signs
Vital signs (temperature, blood pressure (supine position preferred when ECG is collected) and 
pulse) will be monitored at screening (Day-14 to Day -1), Day 1 and Day 15 of Cycle 1 and 
Cycle 2 and then at Day 1 of each cycle and at the EOT visit. Blood pressure (systolic and 
diastolic) and pulse should be measured after the patient has been sitting for five minutes.
7.2.2.3
Height and weight
Height and body weight will be measured. Weight will be measured at the screening (Day-14 
to Day -1), at Day 1 of Cycle 2, at Day 1 Cycle 3, and at EOT. Height will be collected at 
screening only.
7.2.2.4
Performance status
The performance status will be assessed according to the ECOG performance status scale (Oken 
1982). ECOG performance status will be assessed at screening (Day-14 to Day -1), Day 1 of 
Cycle 2 and then at Day 1 of each cycle and at the EOT visit.
Table 7-3
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
7.2.2.5
Laboratory evaluations
Clinical laboratory analyses (hematology, fasting biochemistry (full or partial), coagulation, 
fasting lipase, fasting amylase, fasting lipid panel/glucose/c-peptide, HbA1C, cardiac enzymes 
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 7-1 and Table 7-4.


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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 this particular situation, 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.
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 is worse than the one reported by the 
central lab, or

There are no concomitant central results available
For assessment of patients’ eligibility to the study, only laboratory results from the central 
laboratory will be used.
At any time during the study, abnormal laboratory parameters which are clinically relevant and 
require an action to be taken with study treatment (e.g. require dose modification and/or 
interruption of study treatment, lead to clinical symptoms or signs, or require therapeutic 
intervention), whether specifically requested in the protocol or not, will be recorded on the AE 
eCRF page. Laboratory data will be summarized using the Common Terminology Criteria for 
Adverse events (CTCAE) version 4.0.3. 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 CRF. 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 patient has laboratory parameters obtained from a 
different laboratory, Novartis must be provided with a copy of the certification and a tabulation 
of the normal ranges and units for this laboratory as well. The investigator is responsible for 
reviewing all laboratory reports for patients in the study and evaluating any abnormalities for 
clinical significance.


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Table 7-4
Central clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelets, Red blood cells, White blood 
cells, RBC Morphology, - Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils)
Fasting Chemistry 
(full)
Calcium, Magnesium, Potassium, Sodium, 
 Alkaline phosphatase, ALT 
(SGPT), AST (SGOT), Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, GGT, Total 
Protein, Albumin, Creatinine, Creatine kinase (CK), Blood Urea Nitrogen (BUN) or Urea, 
Uric Acid, Lactate dehydrogenase (LDH)
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), and Activated partial thromboplastin time (aPTT) or 
Partial thromboplastin time (PTT)
Cardiac Enzymes
Troponine I or T
Additional tests
Amylase fasting, Lipase fasting, HbA1c, FPG
All laboratory analysis will be performed centrally; however for urgent safety management, laboratory 
assessments may be allowed to be done locally and entered on an unscheduled local CRF page (laboratory 
assessment performed locally should be sent to central laboratory as well for central analysis).
Note: 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.
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the [CBYL719C2301 Laboratory Manual].
7.2.2.5.1 Hematology
Hematology tests are to be performed by the central laboratory according to the schedule of 
assessments and collection plan outlined respectively in Table 7-1 and Table 7-4. The 
Hematology panel includes hematocrit, hemoglobin, MCH, MCHC, MCV, platelet count, total 
red blood cells (RBC), total white blood cells (WBC) count, and a WBC differential (absolute 
values) including neutrophils, lymphocytes, monocytes, eosinophils and basophils.
7.2.2.5.2 Fasting clinical chemistry
Biochemistry tests are to be performed by the central laboratory according to the schedule of 
assessments and collection plan outlined respectively in Table 7-1 and Table 7-4. The full 
biochemistry panel includes creatinine, creatine kinase, urea or BUN, uric acid, sodium, 
magnesium, potassium, calcium, direct, indirect and total bilirubin, c-peptide, alkaline 
phosphatase, Gamma-glutamyltranspeptidase (GGT), AST/SGOT, ALT/SGPT, total protein 
albumin, lactase dehydrogenase (LDH).
The partial biochemistry panel includes AST/SGOT, ALT/SGPT, total bilirubin, creatine kinase 
and creatinine.


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7.2.2.5.3 Monitoring fasting plasma glucose, 
fasting lipid panel, amylase, 
lipase and HbA1C
Fasting c-peptide and lipid panel will be assessed by the central laboratory according to the 
schedule of assessments and collection plan outlined respectively in Table 7-1 and Table 7-4. 
Patients must be fasting overnight for 8 to 12 hours prior to the blood draw. The study personnel 
will ask the patient whether she/he has been fasting, which will be captured in the CRF as well.
FPG will be taken at screening (Day -14 to Day-1), pre-dose on Day 8 and Day 15 of Cycle 1, 
Day 1 and 15 of Cycle 2, on Day 1 of each subsequent cycle and at the EOT visit.
 
Fasting lipid panel (total cholesterol, high density lipoprotein (HDL), low density lipoprotein 
(LDL), triglycerides) is to be performed at screening (Day -14 to Day-1), and at EOT.
Fasting amylase is to be performed at screening (Day -14 to Day-1), pre-dose on Day 8 of Cycle 
1, on Day 1 of each subsequent cycle thereafter, and at EOT.
Fasting lipase is to be performed at screening (Day -14 to Day-1), pre-dose on Day 8 of Cycle 
1, on Day 1 of each subsequent cycle thereafter, and at EOT.
Fasting HbA1c will be measured at screening (Day -14 to Day-1), Day 1 of Cycle 2, every 3 
cycles thereafter and at EOT.
7.2.2.5.4 Coagulation
International normalized ratio (INR) and partial thromboplastin time (PTT) or activated partial 
thromboplastin time (aPTT) will be assessed by the central laboratory according to the schedule 
of assessments and collection plan outlined respectively in Table 7-1 and Table 7-4 at screening 
(Day -14 to Day-1), Day 1 of Cycle 2, every 2 cycles and at EOT.
7.2.2.5.5 Urinalysis
Urinalysis dipstick analysis (WBC, blood, protein and glucose) will be performed by the central 
laboratory at screening, EOT and during the treatment phase if clinically indicated.
7.2.2.6
Radiological examinations
In case of pneumonitis, patients will be monitored carefully according to Section 6.3.2.1.1. If 
pneumonitis develops during treatment, additional chest CT scan or x-ray may be performed to 
follow-up on the event.
7.2.2.7
Cardiac assessments
7.2.2.7.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed after the patient has been resting for 5-10 min prior 
to each time point indicated in Table 7-5. At screening, triplicate ECGs should be taken 
approximately 2 minutes apart. The combined QTcF values will be averaged to provide a single 


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baseline value for each patient. This averaged value will be documented in the ECG section of 
the CRF.
The interpretation of the tracing must be made by a qualified physician and documented in the 
ECG section of the CRF. Each ECG tracing should be labeled with the study number, patient 
initials (if permitted by local regulations), Subject No, date, and kept in the source documents 
at the study site. Clinically significant abnormalities present when the patient signed informed 
consent should be reported on the Medical History CRF page. Clinically significant findings 
must be discussed with the Novartis Medical Monitor prior to enrolling the patient in the study. 
New or worsened clinically significant findings occurring after informed consent must be 
recorded on the adverse events CRF page.
Table 7-5
Local ECG collection plan
Cycle
Patients
Day
Time
ECG Type
Screening
All
Day -28 to -1
Anytime
Triplicate 12 Lead
Cycle 1
All
Day 1
Pre-dose1
12 Lead
Cycle 1
All1
Day 15
2h Post-dose ±
30 min1
12 Lead
Every 2 cycles
until 36 months, 
then change to as 
clinically indicated
All
Day 1
Pre-dose1
12 Lead
EOT
All
N/A
Anytime
12 Lead
Unscheduled sample2
Anytime
12 Lead
1 ECG assessments are to be done prior to PK sampling
2 If an unscheduled ECG is performed for safety reasons, it is recommended to collect a time-matched PK 
sample and record the time and date of the last study drug intake to determine the drug exposure
7.2.2.7.2 Cardiac imaging - MUGA scan or ECHO
The left ventricular heart function will be evaluated by ECHO or MUGA at Screening to 
confirm eligibility, at C5D1, every 4 cycles until 36 months, then change to as clinically 
indicated, 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.
7.2.2.7.3 Cardiac enzymes
Cardiac enzymes (Cardiac troponine I or T) will be assessed by the central laboratory according 
to the schedule of assessments and collection plan outlined respectively in Table 7-1 and Table 
7-4 at screening (Day -14 to Day-1), during the treatment phase if clinically indicated and at 
EOT.
7.2.3
Pharmacokinetics
Pharmacokinetic blood samples will be obtained from approximately 200 patients in the study 
for sparse PK for alpelisib. In all other patients, pre-dose samples will be taken for alpelisib and 
fulvestrant trough plasma concentrations.


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7.2.3.1
Alpelisib/placebo pharmacokinetic blood sampling schedules
Mandatory blood samples for sparse PK assessments of alpelisib will be collected in 
approximately 200 patients enrolled in the study. Measurement of alpelisib will be performed 
only in patients randomized to the alpelisib arms arm (i.e., 100 patients assuming a 1:1 ratio). 
PK will be assessed via a sparse strategy. Five samples will be collected at Cycle 1 Day 15 
(post-dose after alpelisib/placebo is started) during absorption, distribution and elimination 
phase of the PK (Table 7-7). Additionally trough levels will be collected on C1D8 and on 
separate days later in the trial to capture information on alpelisib clearance.
In all other patients only pre-dose levels will be collected on selected days (Table 7-6)
Population parameters will be determined and factors potentially influencing parameter 
variability will be investigated by through a prospectively defined covariate analysis. A detailed 
description of the planned analyses is given in Section 10.5.5.
7.2.3.2
Fulvestrant pharmacokinetic blood sampling schedules
The fulvestrant plasma concentration will be collected in order to assess the impact of alpelisib 
on fulvestrant exposure in approximately 200 patients (same population as for alpelisib sparse 
PK assessment). Fulvestrant is administered once monthly after the first cycle and steady state 
is fully reached after 6 administrations. Pre-dose plasma concentrations will be collected during 
this period and two cycles after (Table 7-6) in order to assess the time course to reach steady-
state.
In trough patients a single fulvestrant pre-dose sample will be taken at steady state at Cycle 6 
Day 1 (Table 7-6).
7.2.3.3
Pharmacokinetic blood sample collection and handling
Exact dates and clock times of drug administrations and actual blood draws will be collected 
on the appropriate Pharmacokinetic Blood Collection CRF pages. The time of the food intake 
prior to PK sampling, where post dose timepoints are collected, should be recorded in the 
appropriate alpelisib/placebo CRF page. On days of PK collection and on the day of previous 
administration the exact time of alpelisib/placebo or fulvestrant dosing, date sample taken and 
actual time of sampling must be entered on the CRF. Any sampling problem (e.g. study drug 
was administered before a presample dose) must be noted in the comments section of the CRF.
To ensure compliance with sampling procedures on the days of PK collection, patients will take 
their alpelisib/placebo doses at the clinic under the supervision of the investigator or his/her 
designee. Patients 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 patients 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 CRF and on appropriate source documentation.
If vomiting occurs within 4 hrs following study-drug administration of alpelisib/placebo on 
Cycle 1 Day 15, 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 CRF and on the transmittal forms, 


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which accompany the sample. No additional study medication should be taken in an effort to 
replace the material that has been vomited. If gastric protection agents were taken, this should 
be recorded in a separate section of the CRF and on the transmittal forms, which accompany 
the sample.
If the patient 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 and/or 
fulvestrant (preferably within 2 weeks after the last dose). Note: if only one drug is discontinued, 
only the sample for that drug has to be taken.
The date and time of the last dose is to be recorded in the CRF.
Whenever an ECG with a QTcF change from baseline > 60 msec or a new absolute QTcF ≥501 
msec result is obtained for patients treated with the drugs combination, a blood sample to assess 
concentrations of alpelisib and fulvestrant should be obtained and the time of sample collection 
noted.
7.2.3.3.1 General instructions for blood collection and processing
On days and time points when PK, biochemistry, hematology or other blood samples are to be 
performed, the PK sample must be drawn first. Complete instructions for sample processing, 
handling and shipment will be provided in the [CBYL719C2301 Laboratory Manual].
No time window for sparse PK sampling is allowed (other than specified in Table 7-7), while, 
other PK samples may be obtained ± 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, one or two 2 mL blood draws will be collected into tubes containing 
K3-EDTA (alpelisib) and Li-Heparin (fulvestrant) and gently inverted several times to 
thoroughly mix the anticoagulant. Tubes will be centrifuged to separate plasma and plasma will 
be immediately split and transferred into separate pre-labeled tubes for each analyte, i.e. 
alpelisib and fulvestrant as well as primary and backup samples. Plasma samples will be stored 
frozen in an upright position until shipment to the bioanalytical lab for analysis.
This 
could include 
In addition
Refer to the [BYL719C2301 Laboratory Manual] for detailed instructions for the collection, 
handling and shipment of PK samples.


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Table 7-6
Pharmacokinetic blood collection log for trough sampling
Cycle
Day
Scheduled
Time Point
Alpelisib/Placebo
Fulvestrant
Dose Ref.
ID§
PK 
Sample 
No
Blood 
Volume 
(mL)
Dose Ref.
ID§
PK 
Sample 
No
Blood 
Volume 
(mL)
2
1
Pre-dose*
101
1011
101
2
4
1
Pre-dose*
102
1021
102
2
6
1
Pre-dose*
103
1031
103
2
201
2011
201
2
8
1
Pre-dose*
104
1041
104
2
Anytime
Unscheduled
1001+
2
2001+
2
* Take sample immediately prior to study treatment dose; at days of PK evaluation oral treatment doses should 
be taken at the clinical site
+ Refer to Lab manual for naming conventions
§ Four digit dose reference ID for pre-dose and 24h post dose samples ending on 1 refers to the dose taken 
before the PK sample (last dose information)
Table 7-7
Pharmacokinetic blood collection log for sparse sampling
Cycle
Day
Scheduled
Time Point
Alpelisib/Placebo
Fulvestrant
Dose Ref.
ID§
PK 
Sample 
No
Blood 
Volume 
(mL)
Dose Ref.
ID§
PK 
Sample 
No
Blood 
Volume 
(mL)
1
8
Pre-dose*
301
3011
301
2
1
15
Pre-dose*
302
3021
302
2
401
4011
401
2
1
15
1 h post dose ± 
10 min
302
303
2
1
15
2 h post dose ± 
30 min
302
304
2
1
15
4 h post dose ± 
30 min
302
305
2
1
15
6 h post dose ± 
30 min
302
306
2
1
15
8 h post dose ± 
30 min
302
307
2
2
1
Pre-dose*
303
3031
308
2
402
4021
402
2
4
1
Pre-dose*
304
3041
309
2
403
4031
403
2
6
1
Pre-dose*
305
3051
310
2
404
4041
404
2
8
1
Pre-dose*
306
3061
311
2
405
4051
405
2
Anytime
Unscheduled
3001+
2
4001+
2
* Take sample immediately prior to study treatment dose; at days of PK evaluation oral treatment doses should 
be taken at the clinical site
+ Refer to Lab manual for naming conventions
§ Four digit dose reference ID for pre-dose and 24h post dose samples ending on 1 refers to the dose taken 
before the PK sample (last dose information)
7.2.3.4
Analytical method
Plasma concentrations of alpelisib and fulvestrant 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 alpelisib and 1.0 ng/mL for 


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fulvestrant. 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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7.2.6
Patient reported outcomes
The European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire (EORTC-QLQ-C30, version 3.0)
will be used to evaluate patient-reported outcome measures of health-related quality-of-life, 
functioning, disease symptoms, treatment-related side effects, global health status, and cancer-
related pain. The EORTC QLQ-C30
 recognized reliable and valid 
measures (Aaronson 1993, Rabin 2001, Cleeland 1994) frequently used in clinical trials of 
patients with advanced or metastatic breast cancer.
All patient reported outcome (PRO) measures (e.g. EORTC QLQ-C30
) will be administered before any study drug administrations at the visits indicated in Table 
7-1 and Table 7-10. Collection of PRO measures have a ± 7 day window unless otherwise 
indicated.
All PRO data will be collected using an electronic tablet device and should be provided in the 
patient’s local language at the beginning of the study visit prior to any interaction with the study 
investigator including any tests, treatments or receipt of results from any tests to avoid biasing 
the patient’s perspective. Patients should be given sufficient space and time to complete all 
study questionnaires and all administered questionnaires should be reviewed for completeness. 
If missing responses are noted, patients should be encouraged to complete any missing 
responses. Attempts should be made to collect responses to all questionnaires for all patients, 
including from those who discontinue prior to the study evaluation completion visit, however, 
if patients refuse to complete questionnaires, this should be documented in study source records. 
Patient’s refusal to complete study questionnaires are not protocol deviations.
Completed questionnaires, including both responses to the questions and any unsolicited 
comments written by the patient, must be reviewed and assessed by the investigator before the 
clinical examination for responses which may indicate potential adverse events or Serious 
Adverse Events. This review should be documented in study source records.
If an adverse event or Serious Adverse Event is confirmed then the physician should record the 
event as instructed in Section 8 of this protocol. Investigators should not encourage the patients 
to change responses reported in questionnaires.


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Table 7-10
Patient reported outcomes collection plan
Patient Questionnaires
Cycle
Day
Time
EORTC QLQ-C30
Screening
-28 to 1 day before randomization
Prior to any clinical 
assessments, drug 
dosing or diagnostic 
testing.
Subsequent 
cycles
Every 8 weeks after randomization 
during the first 18 months and every 
12 weeks until 36 months, then align 
with the efficacy assessments until 
progression
End of treatment
Day of end of treatment assessment
Efficacy follow-up
Continue collection every 8 weeks 
after randomization during the first 
18 months and every 12 weeks until 
36 months, then align with the 
efficacy assessments only in case 
end of treatment occurs for reasons 
other than death, lost to follow-up, 
withdrawal of consent, or disease 
progression
7.2.6.1
EORTC QLQ-C30
The EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and single-
item measures. These include five functional scales (physical, role, emotional, cognitive and 
social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items 
(dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global 
health status/QoL scale (Aaronson et al 1993).
All of the scales and single-item measures range in score from 0 to 100. A high scale score 
represents a higher response level. Thus a high score for a functional scale represents a 
high/healthy level of functioning; a high score for the global health status/QoL represents a high 
QoL, but a high score for a symptom scale/item represents a high level of 
symptomatology/problems. All scoring will follow the scoring procedures defined by the 
EORTC Scoring Manual (Fayers et al 2001).
 
 
 
 
 
 
 
 
 
 
 
 


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8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g. hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the adverse 
events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least 30 days following the last dose of study treatment. Adverse events 
(including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. When a clear 
diagnosis cannot be identified, each sign or symptom should be reported as a separate Adverse 
Event.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.


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If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected though a Death form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine:
1. The severity grade (CTCAE Grade 1-4)
2. Its duration (Start and end dates)
3. Its relationship to the study treatment (Reasonable possibility that adverse event is related: 
No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1
and which seriousness criteria have been met (include for NCDS trials)
7. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown)
If the event worsens the event should be reported a second time in the CRF 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 CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, 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 or as per Cheson's guidelines for 
hematological malignancies), should not be reported as a serious adverse event.
Adverse events separate from the progression of malignancy (example, 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.


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8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a Serious Adverse Event unless it meets the definition of serious as defined below 
and/or as per investigator’s discretion. A dose hold or medication for the lab abnormality may 
be required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.
8.1.3
Adverse events of special interest
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them.
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the Investigator Brochure.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
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
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 patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a Serious Adverse 
Event given above is not a serious adverse event
8.2.2
Reporting
To ensure patient safety, every Serious Adverse Event, regardless of suspected causality, 
occurring after the patient has provided main informed consent and until at least 30 days after 
the patient has stopped study treatment must be reported to Novartis within 24 hours of learning 
of its occurrence.
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event.
Any Serious Adverse Events experienced after this 30 days period should only be reported to 
Novartis if the investigator suspects a causal relationship to the study treatment.
Information about all Serious Adverse Events is collected and recorded on the Serious Adverse 
Event Report Form; all applicable sections of the form must be completed in order to provide a 
clinically thorough report. The investigator must assess and record the relationship of each 
Serious Adverse Event to each specific study treatment (if there is more than one study 
treatment), complete the Serious Adverse Event Report Form in English, and submit the 
completed form within 24 hours to Novartis. Detailed instructions regarding the SAE 
submission process and requirements for signatures are to be found in the investigator folder 
provided to each site. Detailed instructions regarding the SAE submission process and 
requirements for signatures are to be found in the investigator folder provided to each site
Follow-up information is submitted in the same way as the original SAE Report. Follow-up 
information is submitted in the same way as the original SAE Report. Each re-occurrence,
complication, or progression of the original event should be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the patient continued or withdrew from study participation.
If the Serious Adverse Event is not previously documented in the Investigator’s Brochure or 
Package Insert (new occurrence) and is thought to be related to the Novartis study treatment, 
an oncology Novartis DS&E department associate may urgently require further information 
from the investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN), to inform all investigators involved in any study with the same drug that this 
Serious Adverse Event has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 


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committees (ECs) in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
8.3
Emergency unblinding of treatment assignment
Emergency unblinding should only be undertaken when it is essential for effective treatment of 
the patient. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency code breaks are performed using the IRT. When the investigator contacts 
the IRT to unblind a patient, she/he must provide the requested patient identifying information 
and confirm the necessity to unblind the patient. The investigator will then receive details of 
the drug treatment for the specified patient and a fax confirming this information. The system 
will automatically inform the Novartis monitor for the site and the Study Lead that the code has 
been broken.
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The investigator will inform the patient how to contact his/her 
backup in cases of emergency when she/he is unavailable. The protocol number, study treatment 
name if available, patient number, and instructions for contacting the local Novartis CPO (or 
any entity to which it has delegated responsibility for emergency code breaks) will be provided 
to the patient in case emergency unblinding is required at a time when the investigator and 
backup are unavailable. However, if a mechanism is already in place to ensure that the 
investigator and/or back-up can always be reached in case of emergency then the procedure 
above is not required.
Study treatment must be discontinued once emergency unblinding has occurred.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis DS&E. Pregnancy follow-up should be recorded on the 
same form and should include an assessment of the possible relationship to the Novartis study 
treatment of any pregnancy outcome. Any Serious Adverse Event experienced during 
pregnancy must be reported on the Serious Adverse Event Report Form.
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 


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in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee
A DMC will be established to assess the safety and efficacy of alpelisib in an unblinded manner. 
The DMC will be responsible for reviewing the safety and efficacy results in each cohort from 
the futility interim, efficacy interim and final analyses for PFS, the interim analysis for OS as 
well as overseeing the safety data accruing in the trial at regular intervals of approximately 
every six months, provided that sufficient patients have been randomized. Also, if requested by 
the DMC Chair, additional safety reviews may be performed.
The DMC will consist of at least two oncologists and one biostatistician and will be formed 
prior to the randomization of the first patient. Detailed recruitment status and interim safety 
reports will be provided to the DMC on a regular basis. Recruitment will not be interrupted. 
Details will be provided in the DMC charter.
8.7
Steering Committee
The Steering Committee (SC) will be established comprising investigators participating in the 
trial, i.e., not being members of the DMC, and Novartis representatives from the Clinical Trial 
Team.
The SC will be an advisory board ensuring 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 SC will be defined in a SC charter. The SC will not have 
access to unblinded trial data.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened adverse events) at the end of their scheduled study period.


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The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or EC standards do not permit collection of these items, the 
system will not solicit Subject Initials. Year of birth will be solicited (in the place of exact date 
of birth) to establish that the subject satisfies protocol age requirements and to enable 
appropriate age-related normal ranges to be used in assessing laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol 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.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information recorded on CRFs must be traceable to source documents in the patient's file. The 
investigator must also keep the original signed informed consent form (a signed copy is given 
to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of Serious Adverse Events. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the 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 Code of 
Federal regulations (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 and, allow modification or verification of the entered data by the 
investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner.


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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.
Imaging data used for tumor assessments will be collected at the sites, transmitted to a 
designated CRO for centralized analysis, quality control, as well as further processing and data 
reconciliation. It will be prospectively reviewed by a BIRC.
PRO data must be recorded by patients onto the electronic tablet device maintained at the study 
site. The device will be programmed to ensure that all relevant observations are recorded.
9.4
Database management and quality control
For studies using eCRFs, 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.
Samples and/or data (e.g. blood, PK 
 samples; imaging and IRT data) will be 
processed centrally and the 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. The PRO database will be 
accessible to study sites and Novartis personnel (or a designated CRO) for data management. 
All PRO data will be sent electronically to Novartis personnel (or a designated CRO).
Randomization codes and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using an IRT. The system will be supplied by a 
vendor(s), who will also manage the database. The data will be sent electronically to Novartis 
personnel (or designated CRO).
At the conclusion of the study, the occurrence of any emergency code breaks will be determined 
after return of all code break reports and unused drug supplies to Novartis personnel (or 
designated CRO). The occurrence of any protocol violations will be determined. After these 
actions have been completed and the data has been verified to be complete and accurate, the 
database will be declared locked and the treatment codes will be unblinded and made available 
for data analysis. Authorization is required prior to making any database changes to locked data, 
by joint written agreement between the Global Head of Biostatistics and Data Management and 
the Global Head of Clinical Development.
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site.


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10
Statistical methods and data analysis
The data will be analyzed by Novartis and/or a designated CRO. Any data analysis carried out 
independently by an investigator should be submitted to Novartis before publication or 
presentation. The data from all centers that participate in this study will be combined in the final 
safety and efficacy analysis.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, patients will be analyzed according 
to the treatment and strata, they have been assigned to during the randomization procedure. FAS 
will be the primary population for the analysis of efficacy endpoints.
10.1.2
Safety Set
The Safety Set includes all patients who received at least one dose of study treatment. Patients 
will be analyzed according to the study treatment received, where treatment received is defined 
as the randomized treatment if the patient took at least one dose of that treatment or the first 
treatment received if the randomized treatment was never received.
10.1.3
Per-Protocol Set
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the clinical study protocol. All protocol deviations or conditions leading 
to exclusion from the PPS will be detailed in the data handling plan and statistical analysis plan. 
Sensitivity analyses of the primary endpoint of PFS for the PIK3CA mutant cohort may be 
performed using PPS of that cohort when the primary endpoint is statistically significant.
10.1.4
Dose-determining analysis set
Not applicable.
10.1.5
Pharmacokinetic analysis set
The PK Analysis Set (PAS) will consist of all patients who receive at least one dose of study 
treatment (alpelisib/placebo or fulvestrant) and have at least one evaluable concentration 
measurement.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data (including disease characteristics) will be listed and 
summarized in each of the PIK3CA mutant and non-mutant cohorts by treatment arm using the 
FAS. Categorical data, such as gender, race will be presented by contingency type tables. 
Descriptive summary statistics (e.g. frequency, mean, median, range and standard deviation) 
will be used to present numeric data.


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10.3
Treatments (study treatment, concomitant therapies, 
compliance)
Duration of study treatment exposure, cumulative dose and dose intensity, the number of 
patients with dose changes/interruptions along with reasons for the dose change/interruption 
will be presented in each of the PIK3CA mutant and non-mutant cohorts by treatment arm. The 
safety set will be used for the tables and listings.
Concomitant medications taken concurrently with the study drugs will be listed and 
summarized by Anatomical Therapeutic Chemical Classification System (ATC) term, preferred 
term by means of frequency counts and percentages, in each of the PIK3CA mutant and non-
mutant cohorts by treatment arm. Surgical and medical procedures will be coded using 
MedDRA and summarized by SOC and preferred term in each cohort by treatment arm. These 
summaries will include therapy starting on or after the start of study treatment (defined as Cycle 
1 Day 1) or therapy starting prior to the start of study treatment and continuing after the start of 
study treatment.
Any prior concomitant medications or significant non-drug therapies starting and ending prior 
to the start of study treatment will be listed. The safety set will be used for the tables and listings.
10.4
Primary objective
The primary objective of the study is to determine whether treatment with alpelisib in 
combination with fulvestrant prolongs PFS compared to treatment with placebo in men and 
postmenopausal women with HR+, HER2-negative advanced breast cancer which progressed 
on or after AI treatment for patients with PIK3CA mutant status.
10.4.1
Variable
The primary efficacy endpoint of the study 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 
patient has not had an event, PFS will be censored at the date of the last adequate tumor 
evaluation (see RECIST 1.1 in Appendix 3 for further details). Clinical deterioration without 
objective radiological evidence will not be considered as documented disease progression. The 
primary analysis for PFS will be performed based on local radiology assessment according to 
RECIST 1.1.
10.4.2
Statistical hypothesis, model, and method of analysis
The overall Type I error for the trial is one-sided 2.5%. The primary efficacy analysis of PFS 
based on the population of patients with PIK3CA mutant status will be performed at a one-sided 
2.0% level of significance. A secondary efficacy analysis of PFS based on the population of 
patients with PIK3CA non-mutant status will be performed at a one-sided 0.5% level of 
significance (see Section 10.5.2.1). This approach guarantees the protection of the overall type 
I error at 2.5% (based on a Bonferroni adjustment).
The primary efficacy analysis will be the comparison of PFS between the two treatment arms 
using a stratified log-rank test at one-sided 2.0% level of significance for the PIK3CA mutant 
cohort.


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Assuming proportional hazards model for PFS, the following statistical hypotheses will be 
tested at the one-sided 2.0% level of significance:
H01: θ1 ≥ 0 vs. Ha1: θ1 < 0
where θ1 is the log-hazard ratio (alpelisib + fulvestrant treatment arm vs. placebo+fulvestrant 
treatment arm) of PFS.
The primary efficacy endpoint PFS will be analyzed at the interim looks and final look of a 
group sequential design based on the FAS population according to the treatment arm patients 
were randomized to and the strata they were assigned to at randomization. PFS will be estimated 
using the Kaplan-Meier method. The median PFS along with 95% confidence intervals will be 
presented by treatment arm.
Under the proportional hazards assumption, a test based on the stratified log-rank test provides 
an asymptotically equivalent result as that of the stratified Cox regression model. In addition, 
the log-rank test is more powerful for detecting differences that exhibit proportional hazard 
form. A stratified Cox regression model will be used to estimate the hazard ratio of PFS, along 
with 95% confidence interval (using the same strata information as above).
10.4.3
Handling of missing values/censoring/discontinuations
PFS times will be censored if no PFS event is observed before the cut-off date. The censoring 
date will be the date of last adequate tumor assessment before the cut-off date. If a PFS event 
is observed after two or more missing or non-adequate tumor assessments, then PFS will be 
censored at the last adequate tumor assessment. If a PFS event is observed after a single missing 
or non-adequate tumor assessment, the actual date of event will be used (see RECIST 1.1. 
Appendix 3). It is not intended to censor patients for new anticancer therapy prior to 
documented disease progression in the primary analysis.
10.4.4
Supportive and sensitivity analyses
The following analyses of PFS will be performed in the PIK3CA mutant cohort to support the 
primary PFS analysis, where the primary endpoint is statistically significant.
A sensitivity analysis to support the primary PFS analysis will be conducted where patient’s 
PFS times are censored at the onset of new anticancer therapy.
Subgroup analyses of PFS may be performed in the PIK3CA mutant cohort (if the primary 
endpoint is statistically significant) based on each level of the stratification factors and other 
prognostic baseline demographic or disease characteristic factors listed below:

Age

Race

ECOG performance status at baseline

Measurable vs. non-measurable lesions at baseline

Previous treatment with endocrine therapy for metastatic disease
Additional baseline disease characteristic factors that are deemed relevant may be specified in 
the SAP. The analyses for the subgroups will include hazard ratios (together with associated 
two-sided 95% confidence intervals) from un-stratified Cox proportional hazards models.


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In addition, the analysis of PFS using stratified Cox proportional hazards model may be 
repeated using the PPS in the cohort where the primary endpoint is statistically significant.
PFS events will be described according to the type of events (death, documented progression) 
by treatment arm in the FAS. Censoring reasons will be described by treatment arm. A 
sensitivity analysis to support the primary PFS analysis will be conducted where patient’s PFS 
times are censored at the onset of new anticancer therapy.
PFS assessed by BIRC will serve as supportive evidence of the primary endpoint. A sample
based BIRC audit strategy will be used to assess PFS by BIRC. Two methods will be used to 
summarize the data from the sample-based BIRC assessment in the PIK3CA mutant cohort. 
The NCI (National Cancer Institute) method (Dodd et al 2011), uses an auxiliary variable 
estimator of the log-hazard ratio that combines information from patient-level investigator 
assessment from all patients in the PIK3CA mutant cohort and the BIRC assessment of these 
patients randomly selected for central review. This estimate and its one-sided 95% CI will be 
provided.  Details of the audit sample size calculation for the BIRC assessment are provided in 
Section 10.8. The NCI method will be used for audit sample size determination and summary 
of treatment effect (HR, 95% confidence intervals) based on the supportive BIRC assessment.
The data from the BIRC assessment generated following the sampling scheme as above will 
also be summarized using the method proposed by Amit et al 2011, referred to as the PhRMA 
(Pharmaceutical Research and Manufacturers in America) method. With this approach, the 
differential discordance (DD) of the early discrepancy rate (EDR) and late discrepancy rate 
(LDR) between the two arms will be estimated as the rate on the alpelisib+fulvestrant arm minus 
the rate on the placebo+fulvestrant arm. The EDR and LDR results will also be summarized by 
treatment arm. Further definitions and details will be provided in the statistical analysis plan.
10.5
Secondary objectives
All secondary efficacy analyses will be reported for each cohort by treatment arm where 
appropriate. Analyses will be based on the FAS unless otherwise specified.
10.5.1
Key secondary objective(s)
The key secondary objective of the study is to determine whether treatment with alpelisib in 
combination with fulvestrant prolongs OS compared to treatment with placebo for the cohort 
of patients with PIK3CA mutant status.
OS is defined as the time from date of randomization to date of death due to any cause. If a 
patient is not known to have died, then OS will be censored at the date of last known date patient 
alive.
In the PIK3CA mutant cohort, a hierarchical testing procedure will be adopted and the OS 
analyses will be performed only if the primary efficacy endpoint PFS is statistically significant.
Assuming proportional hazards model for OS, the following statistical hypothesis for OS will 
be tested using a stratified log-rank test (according to randomization stratification factors) at the 
one-sided 2.0% level of significance :
H02: θ2 ≥ 0 vs. Ha2: θ2 < 0


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where θ2 is the log-hazard ratio (alpelisib-fulvestrant treatment arm vs. placebo-fulvestrant 
treatment arm) of OS.
The analysis for OS will be based on the FAS population according to the treatment arm patients 
were randomized to and the strata they were assigned to at randomization.
The final OS analysis will not be performed at the time point of the final PFS analysis in the 
PIK3CA mutant cohort, but after additional follow-up. Therefore, a three-look group sequential 
design is considered for OS.
OS will be hierarchically tested for the PIK3CA mutant cohort in the following way:

The first potential timepoint for OS analysis will be at the time of the PFS efficacy interim 
analysis after approximately 37% of the expected deaths are observed, at which point 
approximately 66 deaths are expected. If PFS is not statistically significant at this stage, 
then OS will not be tested, in which case the next potential timepoint for OS analysis will 
be at the time of the final PFS analysis after approximately 57% of the expected deaths are 
observed, at which point approximately 101 deaths are expected to have been recorded in 
the clinical database.

If OS is not statistically significant at the first interim analysis, the 2nd OS analysis will be 
planned after approximately 85% of the expected deaths are observed, at which point 
approximately 151 deaths have been recorded in the clinical database.

If OS is not statistically significant at this stage, a final analysis is planned at the time 
approximately 178 deaths have been recorded.

If PFS is not statistically significant at the final analysis for PFS, then OS will not be 
tested.
The type I error probability will be controlled by using a separate Lan-DeMets (O’Brien-
Fleming) alpha spending function independent of the Haybittle-Peto boundary used for the 
primary efficacy analysis of PFS at a 2.0% level of significance for the PIK3CA mutant cohort. 
This guarantees the protection of the overall type I error (α = 2.5%) across all hypotheses and 
the repeated testing of the OS hypotheses at the interim and the final analyses (Glimm 2010). 
This includes hypotheses associated with the secondary endpoints PFS and OS in the PIK3CA
non-mutant cohort (PFS in the non-mutant cohort will be tested at a 0.5% level of significance 
if PoC is established).
OS will be estimated using the Kaplan-Meier method. The median OS along with 95% 
confidence intervals will be presented by treatment arm. Stratified Cox regression will be used 
to estimate the HR of OS, along with 95% confidence interval.
10.5.2
Other secondary efficacy objectives
Analyses will be based on the FAS.
10.5.2.1 PFS in patients with PIK3CA non-mutant status measured in tissue
PFS in the PIK3CA non-mutant cohort will be analyzed at a single look based on the FAS 
population according to the treatment arm patients were randomized to and the strata they were 
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PFS treatment effect in this cohort will be considered to be clinically relevant via a Bayesian 
decision rule if:

The estimated HR (stratified according to presence of lung and/or liver metastasis and 
previous treatment with CDK4/6 inhibitor) ≤ 0.60
and

The posterior probability (HR < 1) ≥ 90%
The posterior probability in the second criterion will be derived from the Bayesian posterior 
distribution of the HR. Assuming a non-informative prior distribution, the distribution of the 
HR will be updated with all available data from the patients included in the FAS in this cohort. 
The cumulative posterior distribution will be used to derive the probability that the true HR is 
less than 1.
If both these criteria are met then the comparison of PFS between the two treatment arms in this 
cohort using a stratified log-rank test at a one-sided 0.5% level of significance, will be made. 
Assuming proportional hazards model for PFS, the following statistical hypotheses will be 
tested at the one-sided 0.5% level of significance:
H01: θ1 ≥ 0 vs. Ha1: θ1 < 0
where θ1 is the log-hazard ratio (alpelisib + fulvestrant treatment arm vs. placebo+fulvestrant 
treatment arm) of PFS.
The median PFS along with 95% confidence intervals will be presented by treatment arm.
10.5.2.2 OS in patients with PIK3CA non-mutant status measured in tissue
OS analyses will be performed only if the secondary efficacy endpoint, PFS, in this cohort meets 
the PoC criteria given in Section 10.5.2.1 and is statistically significant. A hierarchical testing 
procedure will be adopted. Assuming proportional hazards model for OS, the following 
statistical hypotheses will be tested at the one-sided 0.5% level of significance:
H01: θ1 ≥ 0 vs. Ha1: θ1 < 0
where θ1 is the log-hazard ratio (alpelisib + fulvestrant treatment arm vs. placebo+fulvestrant 
treatment arm) of OS.
The analysis for OS will be based on the FAS population according to the treatment arm patients 
were randomized to and the strata they were assigned to at randomization.
The final OS analysis will not be performed at the time point of the final PFS analysis in the 
PIK3CA non-mutant cohort, but after additional follow-up. Therefore, a three-look group 
sequential design is considered for OS.
If PFS in the non-mutant cohort meets the PoC criteria and is statistically significant at a one-
sided 0.5% level of significance, OS will be hierarchically tested in the following way:

The first timepoint for OS analysis will be at the time of the final analysis for PFS 
(provided PFS is statistically significant) when approximately 29% of the expected deaths 
are observed, at which point approximately 36 deaths in the PIK3CA non-mutant cohort 
have been recorded (after approximately 18 months from the first patient to be randomized
in this cohort).


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
If OS is not statistically significant at the first interim analysis, the 2nd OS analysis will be 
planned after approximately 87% of the expected deaths are observed, at which point 
approximately 109 deaths are expected to have been recorded in the clinical database.

If OS is not statistically significant at the second interim analysis, a final analysis is 
planned after approximately 125 deaths are expected to have been recorded in the clinical 
database.

If PFS is not statistically significant, then OS will not be tested.
OS will be estimated using the Kaplan-Meier method. The median OS along with 95% 
confidence intervals will be presented by treatment arm. Stratified Cox regression will be used 
to estimate the HR of OS, along with 95% confidence interval.
10.5.2.3 Overall Response Rate (ORR)
ORR is defined as the proportion of patients with best overall response of complete response 
(CR) or partial response (PR) based on local investigator’s assessment according to RECIST 
1.1. It will be calculated along with the exact binomial two-sided 95% confidence interval 
(Clopper 1934) by treatment arm for the PIK3CA mutant and non-mutant cohorts. In addition, 
ORR analyses based on blinded independent central review will be performed, if relevant.
10.5.2.4 Clinical benefit rate
Clinical benefit rate is defined as the proportion of patients with a best overall response of CR 
or PR or SD or Non-CR/Non-PD lasting more than 24 weeks based on local investigator 
assessment. It will be calculated along with the exact binomial two-sided 95% confidence 
interval (Clopper 1934) by treatment arm for the PIK3CA mutant and non-mutant cohorts. In 
addition, clinical benefit rate analyses based on blinded independent central review will be 
performed, if relevant.
10.5.2.5 PFS in patients with PIK3CA mutant status measured in ctDNA
An analysis of PFS based on local radiology assessments and using RECIST 1.1 criteria for 
each of (i) patients with PIK3CA mutant status and (ii) patients with PIK3CA non-mutant status 
as measured in ctDNA at baseline will be conducted using the same analytical conventions as 
the primary analysis.
10.5.2.6 ECOG Performance Status
ECOG performance status will be used to assess physical health of patients. An analysis of the 
time to definitive deterioration of the ECOG performance status by one category of the score 
from baseline will be performed using Kaplan-Meier method. A deterioration is considered 
definitive if no improvements in the ECOG performance status is observed at a subsequent time 
of measurement during the treatment period following the time point where the deterioration is 
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10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
For primary safety analyses, the safety set will be used. All listings and tables will be presented 
by treatment arm for the PIK3CA mutant and non-mutant cohorts individually as well as
combined.
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g. 
ECG, vital signs) will be considered as appropriate. All safety data will be listed.
The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
3. post-treatment period: starting at day 31 after last dose of study medication
10.5.3.2 Adverse events (AEs)
Summary tables for adverse events will include only adverse events that started or worsened 
during the on-treatment period, the treatment-emergent adverse events.
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 v4.03 
grades), type of adverse event, relation to study treatment by treatment arm. Deaths reportable 
as Serious Adverse Events and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event and treatment arm.
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.
10.5.3.3 Laboratory abnormalities
For laboratory tests covered by the CTCAE version 4.03, the study’s biostatistical and reporting 
team will grade laboratory data accordingly. For laboratory tests covered by CTCAE, a 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, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests:


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
Number and percentage of patients with worst post-baseline CTC grade (regardless of the 
baseline status)

shift tables using CTCAE grades to compare baseline to the worst on-treatment value

for laboratory tests where CTCAE grades are not defined, shift tables using the
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value.

listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges.

listing of all notable laboratory abnormalities (i.e., newly occurring CTCAE grade 3 or 4 
laboratory toxicities)
In addition to the above mentioned tables and listings, 
, for example 
be specified in the statistical analysis plan.
Laboratory values collected later than 30 days after study treatment discontinuation will be 
flagged in the listings.
10.5.3.4 Other safety data
Summary statistics for data from other tests will be provided, notable values will be flagged, 
and any other information collected will be listed as appropriate.
Descriptive summary statistics will be provided for:

ECGs: changes from baseline results

Cardiac imaging: change from baseline to worst post-baseline in LVEF values

Vital signs: number and percentage of patients with at least one post-baseline vital sign 
abnormality
Listings with flagged notable values and any other information collected will be provided as 
appropriate.
10.5.3.5 Supportive analyses for secondary objectives
Not applicable.
10.5.3.6 Tolerability
Tolerability will be studied in terms of dose reductions and drug interruptions due to AE. 
Reasons for dose reductions and interruptions will be listed and summarized by treatment.
10.5.4
Patient-reported outcomes
The EORTC QLQ-C30 questionnaire
will be used to collect 
patient’s QoL data.
The global health status/QoL scale score of the QLQ-C30 is identified as the 
primary patient-reported outcome variable of interest. Physical functioning, emotional 
functioning and social functioning scale scores of the QLQ-C30, 
 


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Scoring of PRO data and methods for handling of missing items or missing assessments will be 
performed according to the scoring manual and user guide for each respective patient 
questionnaire (Fayers et al 2001; Oemar and Janssen 2013; Cleeland et al2009). No imputation 
procedures will be applied for missing items or missing assessments. 
 
 
 
The number of patients completing each questionnaire and the number of missing or incomplete 
assessments will be summarized by treatment group for each scheduled assessment time points 
for each cohort. No formal statistical tests will be performed and hence no multiplicity 
adjustment will be applied. The FAS will be used for analyzing PRO data.
Descriptive statistics will be used to summarize 
 QLQ-C30, 
, 
 
at each scheduled assessment 
time point for each cohort. Additionally, change from baseline 
 
will be summarized. 
 Patients with an evaluable baseline score and at least one evaluable 
post baseline score during the treatment period will be included in the change from baseline 
analyses.
In addition, a repeated measurement analysis model may be used to compare the two treatment 
groups with respect to changes in the domain scores (global health status/QoL scale score, 
physical functioning, emotional functioning and social functioning scale scores of the QLQ-
C30)
 longitudinally over time. 
 
Time to definitive 10% deterioration in the global health status/QoL, physical functioning, 
emotional functioning, and social functioning scales will be assessed in each cohort. The time 
to definitive 10% deterioration is defined as the time from the date of randomization to the date 
of event, which is defined as at least 10% relative to baseline worsening of the corresponding 
scale score or death due to any cause. If a patient has not had an event, time to deterioration will 
be censored at the date of the last adequate PRO evaluation. The distribution will be presented 
descriptively using Kaplan-Meier curves. Summary statistics from Kaplan-Meier distributions 
will be determined, including the median time to definitive 10% deterioration along with two-
sided 95% confidence interval. Additionally, time to definitive deterioration with different 
cutoff definitions (e.g. 5%, 15%) may be specified in the statistical analysis plan as deemed 
appropriate. A stratified Cox regression will be used to estimate the hazard ratio, along with 
two-sided 95% confidence interval.


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10.5.5
Pharmacokinetics
10.5.5.1 Trough concentrations
Pre-dose (Cmin) plasma concentrations of alpelisib and fulvestrant will be reported in summary 
statistics presenting n (number of values to be reported), arithmetic mean, geometric mean, 
median, standard deviation, coefficient of variation CV (%), Geometric mean CV (%), 
minimum and maximum using the PAS. Figures of geometric mean and arithmetic mean (+/-
standard deviation) of alpelisib and fulvestrant trough concentrations over time will also be 
presented for the PAS.
The fulvestrant pre-dose plasma concentration will be compared between both arms with or 
without concomitant alpelisib administration. The time-course of pre-dose plasma 
concentrations to reach steady state will be assessed using a descriptive approach.
A 
will be used to
A 
will be used to 
(such as selected 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.5.5.2.1
Individual Bayesian estimates
The listing of empirical Bayes estimates of the individual PK parameters will be provided for 
the patients treated with alpelisib and included in the PAS of this study using a population PK 
model. The individual concentration vs. time profile at steady state will be simulated. For each 
of the concentration vs. time profile, the Cmax, AUCtau and t1/2,eff will be determined. 
Concentrations and appropriate individual PK parameters of alpelisib will be reported in 
summary statistics presenting n (number of values to be reported), m (number of non-zero 


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values to be reported) arithmetic mean, geometric mean, median, SD, coefficient of variation 
CV (%), Geometric mean CV (%), minimum and maximum.
Geometric mean and the geometric CV (%) will be derived from non-zero concentrations. 
Concentrations below the limit of quantitation will not be imputed and will be treated as zero 
in summary statistics.
Further 
 might be performed to investigate any 
 
10.5.5.3 Data handling principles
Detailed data handling methods will be addressed in the statistical analysis plan.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.7
Interim analysis
10.7.1
Primary endpoint: Progression-free survival in the PIK3CA mutant 
cohort
Two interim analyses are planned after approximately 97 and 185 of the 243 targeted PFS 
events (40% and 76% information fractions respectively) have been documented. These 
analyses are expected to take place around 19 and 25 months from the date of first patient 
randomized in the study. Approximately 243 patients are expected to be randomized when the 
97th PFS event occurs at the time of the first interim analysis if H0 is true (HR.=1). The primary 
intent of the first interim analysis is to allow the cohort to stop early for lack of efficacy (futility). 
There is no intent to carry out an analysis to declare superior efficacy at the time of the first 
interim analysis. The second interim analysis will allow the study to stop early for outstanding 
efficacy. The second interim analysis will only be carried out after all patients have been 
randomized in the PIK3CA mutant cohort and approximately 76% of the 243 targeted PFS 
events have been observed.
The assessment of futility will be guided based on two criteria,
A user-defined gamma spending function (γ=5) will be used as a beta-spending function to 
determine the non-binding futility boundary. One important feature of the design is that the 
efficacy stopping boundaries will not be affected by the presence of non-binding futility 
stopping boundaries.
Based on the choice of α-spending and β-spending function described above, the futility 
boundary in terms of p-value scale (or Z-statistic scale) at the interim is calculated as p =0.128
(or Z=1.134). The observed (i.e. nominal) p-value has to be greater than 0.128 to conclude 
futility according to this criterion at the time of the first interim analysis. 
In addition to the stopping boundary based on the β-spending function described above, DMC
will be instructed to include in their recommendation whether the conditional probability of 
observing a clinically relevant PFS treatment effect at the final PFS analysis is less than 0.20, 
i.e.:
Conditional probability (HRfinal ≤ 0.6¦ HRinterim) < 0.20
This criterion uses the observed interim data and an assumption regarding the distribution of 
future unobserved data at the final analysis, conditioned under the alternative hypothesis
(HR.=0.6). The futility boundary for this criterion in terms of p-value scale at the interim is 
calculated as p=0.068. Thus the observed (i.e. nominal) p-value has to be greater than the p-
value scale futility boundary = 0.068 to conclude futility according to this criterion.
Details of the methodology as well as the operating characteristics for the futility criterion based 
on conditional probability is described in Appendix 6.


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Therefore at the time of the futility analysis, the PIK3CA mutant cohort may be stopped for 
futility if one or both of the criteria are met.
In addition, the predictive probability of success based on the final planned number of PFS 
events will be calculated given the interim data, and provided to the DMC at the time of the 
futility interim analysis as supportive information.
A Haybittle-Peto stopping boundary (as implemented in East 6.3) will be used for interim and 
final PFS analyses. At the second interim analysis, the observed p-value has to be less than or 
equal to 0.0001 (or Z=3.719) in order to conclude superior efficacy. If the study continues to 
final analysis, the p-value that will be used to declare statistical significance at the final analysis 
will be 0.0199 (Z=2.054).
Since the observed number of events at the interim analyses may not be exactly equal to the 
planned number of events, the efficacy and futility boundaries will need to be re-calculated (or 
updated) based on the actual number of observed events using the pre-specified Haybittle-Peto 
boundary and β-spending function. Therefore, the observed p-values at the interim analyses will 
be compared with the updated boundaries.
If the study continues to final analysis, the p-value that will be used to declare statistical 
significance at the final analysis will be based on the actual number of PFS events documented 
at the cut-off date for the final analysis and the alpha already spent at the interim analysis. 
Therefore, if the interim analyses were carried out after exactly 40% and 76% of the planned 
number of events, and the cohort continued until the final analysis, the observed p-value will 
have to be less than 0.0199 to declare statistical significance. If the number of events in the final 
analysis deviates from the expected number, the final analysis criteria will be determined so 
that the significance level is maintained at 0.02 in this cohort.
Statistical properties of the group sequential design in this cohort are summarized in Table 10-
1 below.
Table 10-1
Simulated probabilities to stop for futility or efficacy at the interim or 
final analysis in the PIK3CA mutant cohort
Scenario
Look
# PFS 
events
Cumulative probabilities 
(%)
Incremental probabilities 
(%)
Stop for 
efficacy
Stop for 
futility
Stop for 
efficacy
Stop for 
futility
Under H0 (HR=1)
Interim 1
97
0
92.98
0
92.98
Interim 2
185
0.02
-
0.02
-
Final
243
0.98
-
0.96
-
Under Ha (HR=0.6)
Interim 1
97
0.34
15.31
0.34
15.31
Interim 2
185
38.50
-
38.50
-
Final
243
83.95
-
45.45
-
Note: The study will not stop for outstanding efficacy at the first (futility) interim analysis. Operating 
characteristics performed in SAS v9.4 with 10,000 simulations and random seed = 111064
Interim PFS analysis in the PIK3CA mutant cohort will be performed by an independent 
statistician (not involved with the conduct of the study). Further details will be described in the 
DMC Charter. The results of the interim analyses will be provided to the DMC by the 
independent statistician.


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10.7.2
Key secondary endpoint: Overall survival in the PIK3CA mutant cohort
OS will be compared between the two treatment groups, provided the primary endpoint PFS is 
statistically significant favouring alpelisib, in the PIK3CA mutant cohort. A hierarchical testing 
procedure will be adopted in this study and the OS analyses will be performed only if the 
primary efficacy endpoint PFS is statistically significant. A maximum of three analyses are 
planned for OS:

at the time of the interim efficacy or final analysis for PFS (provided PFS is statistically 
significant) when approximately 37% or 57% respectively of the expected deaths are 
observed, at which point 66 or 101 deaths respectively have been recorded (after 
approximately 25 or 32 months respectively from the first patient to be randomized in this 
cohort);

at the time when approximately 85% of the expected deaths in the PIK3CA mutant cohort 
are observed, at which point approximately 151 deaths in the PIK3CA mutant cohort have 
been recorded (after approximately 45 months from the first patient to be randomized);

a final analysis for OS when approximately 178 deaths in the PIK3CA mutant cohort have 
been recorded (approximately 54 months from date of first patient to be randomized).
In the PIK3CA mutant cohort, an α-spending function according to Lan-DeMets (O’Brien-
Fleming) independent of the Haybittle-Peto boundary used for the primary efficacy analysis, 
along with the testing strategy outlined below will be used to maintain the overall type I error 
probability (Lan and DeMets 1983). This guarantees the protection of the 2.5% overall level of 
significance across all hypotheses and the repeated testing of the OS hypotheses at interim and 
the final analysis (Glimm 2010). This includes hypotheses associated with the secondary 
endpoints PFS and OS in the PIK3CA non-mutant cohort (PFS in the non-mutant cohort will be 
tested at a 0.5% level of significance if PoC is established).
The trial allows for the stopping of the PIK3CA mutant cohort for a superior OS result, provided 
the primary endpoint PFS has already been shown to be statistically significant favouring the 
alpelisib arm in that cohort. Further, the exact nominal p-values that will need to be observed 
to declare statistical significance at the time of these analyses for OS will depend on the number 
of OS events that have been observed at the time of these analyses and the α for OS already 
spent at the time of earlier analyses.
Given the hierarchical testing strategy of PFS and OS, the design concerning OS analyses will 
have the following characteristics based on simulations in East 6.3. The probabilities shown in 
Table 10-2 are conditional probabilities (conditional on PFS being statistically significant) not 
marginal probabilities.
At the final PFS analysis in the PIK3CA mutant cohort:

The cumulative probability to show efficacy on OS (alternative hypothesis Ha is true) by 
the final analysis is 71.57%; while the cumulative type I error (rejecting the null 
hypothesis H0 if H0 is true) is 1.91%.

The cumulative probability to detect efficacy on OS if the alternative hypothesis Ha is true 
is 19.14% at the first interim analysis, 56.60% at the second interim analysis and 71.57% 
at the final PFS analysis.
Statistical properties the PIK3CA mutant cohort are summarized in Table 10-2 below.


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Table 10-2
Simulated probabilities to stop for efficacy at 1st interim, 2nd interim, 
or final OS analysis in the PIK3CA mutant cohort
Scenario
Look
# deaths
Simulated 
cumulative 
probabilities (%)*
Simulated 
incremental 
probabilities (%) *
Stop for efficacy
Stop for efficacy
Scenario 1: The first IA for OS is performed at the time of the PFS IA for efficacy
Under H0 (HR.=1)
1st Interim
66
0.01
0.01
2nd Interim
151
1.11
1.09
Final OS
178
1.89
0.79
Under Ha (HR.=0.67)
1st Interim
66
1.94
1.94
2nd Interim
151
57.01
55.07
Final OS
178
71.62
14.61
Scenario 2: The first IA for OS is performed at the time of the final PFS analysis
Under H0 (HR.=1)
1st Interim
101
0.17
0.17
2nd Interim
151
1.12
0.95
Final OS
178
1.91
0.79
Under Ha (HR.=0.67)
1st Interim
101
19.14
19.14
2nd Interim
151
56.60
37.46
Final OS
178
71.57
14.97
Note: Simulations are performed in East 6.3 with number of simulations = 10,000 and randomization seed 
=37059.
* Probabilities are reported as if OS was tested alone, regardless the testing strategy with PFS. The true 
probabilities should take into account the probability of PFS at each look. Simulated probabilities shown based 
on the alpha allocated for testing (p=0.02).
At the time of final PFS analysis in this cohort, both PFS and interim OS analysis will be 
performed by the Sponsor's clinical team. Investigators and patients will remain blinded to 
study treatment and all patients will continue to be followed for OS until the final OS analysis 
(or earlier if OS reaches statistical significance at any of the interim analyses).
10.7.3
Secondary endpoint: Overall survival in the PIK3CA non-mutant 
cohort:
OS will be compared between the two treatment groups, provided PFS is statistically significant 
favouring alpelisib, in the PIK3CA non-mutant cohort. A hierarchical testing procedure will be 
adopted in this study and the OS analyses will be performed only if PFS is statistically 
significant. A maximum of three analyses are planned for OS:

at the time of the final analysis for PFS (provided PFS is statistically significant) when 
approximately 29% of the expected deaths are observed, at which point approximately 36 
deaths in the PIK3CA non-mutant cohort have been recorded (after approximately 18 
months from the first patient to be randomized in this cohort);

at the time when approximately 87% of the expected deaths are observed, at which point 
approximately 109 deaths in the PIK3CA non-mutant cohort have been recorded (after 
approximately 45 months from the first patient to be randomized in this cohort);


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
a final analysis for OS when approximately 125 deaths in the PIK3CA non-mutant cohort 
have been recorded (approximately 54 months from date of first patient to be randomized 
in this cohort).
An α-spending function according to Lan-DeMets (O’Brien-Fleming will be used to maintain 
the overall type I error probability (Lan and DeMets 1983). The exact nominal p-values that 
will need to be observed to declare statistical significance at the time of these analyses for OS 
will depend on the number of OS events that have been observed at the time of these analyses 
and the α for OS already spent at the time of earlier analyses.
Given the hierarchical testing strategy of PFS and OS, the design concerning OS analyses will 
have the following characteristics based on simulations in East 6.3. The probabilities shown in 
Table 10-3 are conditional probabilities (conditional on PFS being statistically significant) not 
marginal probabilities.
Table 10-3
Simulated probabilities to stop for efficacy at 1st interim, 2nd interim, 
or final OS analysis in the PIK3CA non-mutant cohort
Scenario
Look
# 
deaths
Simulated cumulative 
probabilities (%)*
Simulated incremental 
probabilities (%)*
Stop for efficacy
Stop for efficacy
Under H0 (HR.=1)
1st Interim
36
<0.001
<0.001
2nd Interim
109
0.31
0.31
Final OS
125
0.59
0.28
Under Ha (HR.=0.67)
1st Interim
36
0.001
0.001
2nd Interim
109
24.59
24.58
Final OS
125
36.74
12.15
Note: Simulations are performed in East 6.3 with number of simulations = 10,000 and randomization seed 
=60030. 1st Interim analysis will be conducted at the time of final analysis for PFS
* Probabilities are reported as if OS was tested alone, regardless the testing strategy with PFS. The true 
probabilities should take into account the probability of PFS at each look. Simulated probabilities shown based 
on the alpha allocated for testing (p=0.005).
At the time of final PFS analysis in this cohort, both PFS and interim OS analysis will be 
performed by the independent statistical group for the DMC. The Novartis Clinical team will 
remain blinded to study treatment allocations up until such point the PIK3CA mutant cohort 
can be unblinded. Investigators and patients will remain blinded to study treatment and all 
patients will continue to be followed for OS until the final OS analysis (or earlier if OS reaches 
statistical significance at any of the interim analyses).
10.8
Sample size calculation
The median TTP for fulvestrant in first line post-menopausal advanced breast cancer patients 
with endocrine sensitive disease is estimated to be between 8 months (Howell et al 2004) and 
23 months in FIRST trial (Robertson et al 2014). For sample size calculation, it is assumed that 
approximately 8% patients in the PIK3CA mutant cohort and 15% of patients in the PIK3CA 
non-mutant cohort will comprise these patients with an expected median PFS for fulvestrant of 
18 months.
Two main studies have been reported assessing fulvestrant in relapsed advanced breast cancer: 
SoFEA trial with a median PFS of 4.8 months (Johnston et al 2013) and CONFIRM trial with 


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a median PFS of 6.5 months (Di Leo et al 2010). However, in the SoFEA study after a first 
induction with fulvestrant at 500 mg, the dose of fulvestrant continued at 250 mg; in CONFIRM 
fulvestrant was given at 500 mg throughout. Approximately 92% patients in the PIK3CA 
mutant cohort and 85% of patients in the PIK3CA non-mutant cohort enrolled in the current 
study will have similar clinical features to the population treated in CONFIRM trial, therefore 
for sample size calculation, the median PFS for fulvestrant in this group is assumed to be 6.5 
months.
For the overall population in the PIK3CA mutant cohort, the median PFS in the control arm 
(fulvestrant + placebo) is estimated via simulation to be around 7.0 months.
For the overall population in the PIK3CA non-mutant cohort, the median PFS in the control 
arm (fulvestrant + placebo) is estimated via simulation to be around 7.4 months.
It is expected that treatment with alpelisib + fulvestrant in both cohorts will result in a 40% 
reduction in the hazard rate (corresponding to an increase in median PFS from 7.0 months to 
11.67 months in the PIK3CA mutant cohort and from 7.4 months to 12.33 months in the 
PIK3CA non-mutant cohort, under the exponential model assumption).
Patients with PIK3CA mutant status:
If the true hazard ratio is 0.6 (under alternative hypothesis), a total of 243 PFS events are 
required to have 83.80% power at an one-sided overall 2.0% level of significance to reject the 
null hypothesis (HR.=1) using a log-rank test for a 3-look group sequential design using a 
Haybittle-Peto boundary to determine the efficacy boundary along with (i) a gamma spending 
function (γ = 5) and (ii) a conditional probability function to determine the non-binding futility 
boundaries. Assuming that 40% of the patients will have a PIK3CA mutant status, an enrollment 
rate of 12 patients during the first 6 months (5 with PIK3CA mutant status), 35 patients up to 
12 months (14 with PIK3CA mutant status) and 59 patients afterwards (24 with PIK3CA mutant 
status) and 10% patients will be lost to follow-up for PFS final analysis, a total of 340 patients 
will need to be randomized in this cohort to the two treatment arms in a 1:1 ratio. Given the 
above assumptions, it is estimated that the 243rd PFS event will be observed at approximately 
32 months from the date of first patient randomized in the cohort.
The estimated timelines for interim and final PFS analyses are provided in Table 10-4.
Table 10-4
Estimated timelines for interim and final PFS analyses in the PIK3CA
mutant cohort
Look
Months after randomization of 
the first patient
Number of PFS 
events
Number of patients expected 
to be randomized (HR.=1).
Interim 1 (futility)
19
97
271
Interim 2 (efficacy)
25
185
340
Final
32
243
340
Patients with PIK3CA non-mutant status:
The proof of concept criteria require:
(a) an estimate for PFS HR reaching a critical value i.e. HR ≤ 0.60


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(b) strong evidence that the treatment results in a HR that is better than the value of no interest. 
i.e. Posterior Probability (HR < 1) ≥ 90%
Based on the dual criteria a minimum of 102 PFS events are required (please refer to Section 
14.6). Assuming an enrollment rate of 12 patients during the first 6 months (7 with PIK3CA
non-mutant status), 35 patients up to 12 months (21 with PIK3CA non-mutant status) and 59
patients afterwards (35 with PIK3CA non-mutant status) and 10% patients will be lost to follow-
up, 220 patients will be randomized (110 per arm), in order to observe the required 102 PFS 
events in approximately 18 months (if the observed HR is 0.60 and the median PFS for the 
control arm is 7.4 months).
The primary analysis to estimate the HR will be performed after approximately 102 PFS events 
have been observed. If the true HR is 1, the probability (obtained by simulation) to obtain a 
positive conclusion is 0.005; if the true HR is 0.50, the probability to meet efficacy criteria is 
0.813. If the true HR is 0.60 (reflecting the minimum clinically relevant difference), the 
probability to meet efficacy criteria is 0.491. Simulation results are provided in Table 10-5.
Table 10-5
Operating characteristics for PoC criteria in PIK3CA non-mutant 
cohort
True HR
True Median PFS 
alpelisib (months)
Probability to PoC
Expected duration of 
cohort (months)
0.3
24.67
0.999
21.0
0.4
18.50
0.975
19.7
0.5
14.80
0.813
18.7
0.6
12.33
0.491
18.0
0.7
10.57
0.220
17.4
0.8
9.25
0.076
16.9
0.9
8.22
0.020
16.5
1.0
7.4
0.005
16.0
Assumes: (1) HR.=0.6, (2) true median PFS for fulvestrant = 7.4 months, (3) protocol planned accrual rates, (4) 
Analysis after 102 PFS events have been observed
Audit size for BIRC assessed PFS in the PIK3CA mutant cohort
The audit size of the sample-based BIRC assessment will be 50% of all randomized patients in 
the PIK3CA mutant cohort. Based on the audit size calculation approach proposed by Dodd, et 
al (2011), assuming investigator and BIRC assessments are similar and the estimated log of 
investigator-based HR is -0.51 (i.e. HR.=0.60), the audit size of 50% will ensure that the upper 
bound of a one-sided 95% CI for BIRC-based log-hazard ratio has 94% probability of being 
below 0 (i.e. HR. < 1) if the correlation between investigator assessment and BIRC assessment 
is 0.65 (the estimated correlation based on data from the Bolero-2 [CRAD001Y2301] study in 
metastatic breast cancer).
10.9
Power for analysis of key secondary variable
For first line patients no phase III data are available with single agent fulvestrant. Data from 
phase III studies have been reported with letrozole showing a median OS of 34 months 
(Mouridsen et al 2003) and with anastrozole showing a median OS of 38 months (Bergh et al


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2012). OS data with fulvestrant alone in first line setting have been recently presented within 
the phase II study FIRST. In that study the median OS for fulvestrant was 54 months (Robertson
et al 2014). Therefore, for sample size calculation, median OS for fulvestrant alone in the 
current study for patients with progression more than 12 months from completion of 
(neo)adjuvant endocrine therapy is assumed to exceed 50 months.
Median OS for fulvestrant in relapsed post-menopausal advanced breast cancer patients is 
estimated to be between 19 months (SoFEA trial, Johnston et al 2013) and 26 months 
(CONFIRM trial, Di Leo et al 2013). For sample size calculation, the median OS for fulvestrant 
in second line is thus assumed to be 26 months.
Based on the expected split of the patient population as mentioned in Section 10.8, the median 
OS of control arm is estimated via simulation to be approximately 30 months. It is hypothesized 
that adding alpelisib to fulvestrant will result in a 33% reduction in the hazard rate for OS 
(corresponding to an increase in median survival to 44.8 months).
Patients with PIK3CA mutant status:
OS will be compared between the two treatment groups, provided that the primary endpoint 
PFS is statistically significant in this cohort of patients. If the true hazard ratio is 0.67 (under 
alternative hypothesis), a total of 178 deaths are needed to be observed to have 72% power at 
an one-sided overall 2.0% level of significance to reject the null hypothesis (HR.=1) using a 
log-rank test and a 3-look group sequential design. Based on the same number of patients that 
are planned to be enrolled in this study to detect the primary endpoint and assuming 5% dropout 
rate by the time of the OS final analysis, it is estimated that these 178 deaths will be observed 
at approximately 54 months from the date of first patient to be randomized in this cohort.
The estimated timelines for interim and final OS analyses are provided in Table 10-6.
Table 10-6
Estimated timelines for interim and final OS analyses in the PIK3CA
mutant cohort
Look
Months after randomization of the first patient
Number of OS events
1st OS Interim at time of interim 
PFS analysis
25
66
1st OS Interim at time of final 
PFS analysis
32
101
2nd Interim
45
151
Final
54
178
10.9.1
Patients with PIK3CA non-mutant status (secondary endpoint):
OS will be compared between the two treatment groups, provided that the secondary endpoint 
PFS is statistically significant in this cohort of patients. The final analysis of OS for the PIK3CA
non-mutant cohort will be performed at approximately 54 months from the date of first patient 
to be randomized in the PIK3CA non-mutant cohort. Based on the same number of patients that 
are planned to be enrolled in the PIK3CA non-mutant cohort to detect the primary endpoint and
assuming 5% dropout rate by the time of the OS final analysis, it is estimated that approximately 
125 deaths will be observed. If the true hazard ratio is 0.67 (under alternative hypothesis), a 


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total of 125 deaths will allow 36.1% power at a one-sided overall 0.5% level of significance to 
reject the null hypothesis (HR.=1) using a log-rank test and a 3-look group sequential design.
The power calculations were conducted with software package East 6.3.
The estimated timelines for interim and final OS analyses are provided in Table 10-7.
Table 10-7
Estimated timelines for interim and final OS analyses in the PIK3CA
non-mutant cohort
Look
Months after randomization of the first patient
Number of OS events
1st Interim
18
36
2nd Interim
45
109
Final
54
125
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, she/he should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their eCRFs.


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Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication 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 requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
 
 
 
 
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted in a on the publicly accessible database, e.g. such as www.clinicaltrials.gov, 
before study start. In addition, results of interventional clinical trials in adult patients are posted 
on www.novartisclinicaltrials.com, a publicly accessible database of clinical study results 
within 1 year of upon study completion (i.e., LPLV), and finalization of the study report the 
results of this study will be either submitted for publication and/or posted in those for 
interventional clinical trials involving pediatric patients within 6 months of study completion. 
Novartis follows the ICMJE authorship guidelines (www.icmje.org) and other specific 
guidelines of the journal or congress to which the publication will be submitted.
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations. 
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable. 


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For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study CRF is the primary data collection instrument for the 
study. The investigator should ensure the accuracy, completeness, legibility, and timeliness of 
the data reported in the CRFs and all other required reports. Data reported on the CRF, that are 
derived from source documents, should be consistent with the source documents or the 
discrepancies should be explained. All data requested on the CRF must be recorded. Any 
missing data must be explained. Any change or correction to a paper CRF should be dated, 
initialed, and explained (if necessary) and should not obscure the original entry. For electronic 
CRFs an audit trail will be maintained by the system. The investigator should retain records of 
the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.


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11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
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/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
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/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
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 (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days.


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13
References (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. Mar 3;85(5):365-76.
Addo S, Yates RA, Laight A (2002) A phase I trial to assess the pharmacology of the new 
oestrogen receptor antagonist fulvestrant on the endometrium in healthy postmenopausal 
volunteers. Br J Cancer. 87(12):1354-9.
Agrawal A, Ayantunde A, Rampaul R. et al (2007) Male breast cancer: a review of clinical 
management Breast Cancer Res Treat 103:11–21.
Amit O, Mannino F, Stone AM, et al (2011) Blinded independent central review of 
progression in cancer clinical trials: results from a meta-analysis. European Journal of Cancer; 
47: 1772-1778.
Apone S, Lee MY, Eyre DR (1997) Osteoclasts generate cross-linked collagen N-telopeptides 
(NTx) but not free pyridinolines when cultured on human bone. Bone;21:129-136.
Bader AG, Kang S, Zhao L, et al (2005) Oncogenic PI3K deregulates transcription and 
translation. Nat Rev Cancer; 5(12)921-9.
Baselga J, Campone M, Piccart M, et al (2012) Everolimus in postmenopausal hormone-
receptor-positive advanced breast cancer. N Engl J Med;366(6):520-9.
Benson AB 3rd, Ajani JA, Catalano RB, et al (2004) Recommended guidelines for the 
treatment of cancer treatment-induced diarrhea. J Clin Oncol. Jul 15;22(14):2918-26.
Bergh J, Jönsson PE, Kerstin Lidbrink E,Trudeau, et al (2012) FACT: An Open-Label 
Randomized Phase III Study of Fulvestrant and Anastrozole in Combination Compared With 
Anastrozole Alone As First-Line Therapy for Patients With Receptor-Positive 
Postmenopausal Breast Cancer. J.Clin.Oncol.; 30 (16): 1919-25.
Beslija S, Bonneterre J, Burstein HJ, et al (2009) Third consensus on medical treatment of 
metastatic breast cancer. Ann Oncol; 20: 1771-85.
Bjornsti MA, Houghton PJ (2004) The TOR pathway: a target for cancer therapy. Nature 
Reviews Cancer; 4: 335-348.
Board RE, Wardley AM, Dixon JM (2010) Detection of PIK3CA mutations in circulating free
DNA in patients with breast cancer. Breast Cancer Res Treat.;120(2):461-7.
Borroni RG (2015) Role of dermatology in pharmacogenomics: drug-induced skin injury. 
Pharmacogenomics. 16(4):401-12.
Bosh A, Ellis H, Tao J, et al (2013) PI3K pathway inhibitors sensitize to anti-estrogen therapy 
as a result of increased estrogen receptor levels and signaling; Abstract ESMO 2013.
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. 2012 Sep 18;109(38):15259-64.
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.10;30(23):2919-
28.


Novartis
Confidential
Page 161
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Protocol No. CBYL719C2301
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;276:9817–9824.
Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast 
tumors. Nature; 490 (7418): 61–70.
Chia S, Gradishar W, Mauriac L, et al (2008) Double-blind, randomized placebo controlled 
trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor 
therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: 
results from EFECT. J.Clin.Oncol.; 26 (10):1664-1670.
Chow LM, Baker SJ (2006) PTEN function in normal and neoplastic growth. Cancer Lett. 
Sep 28;241(2):184-96.
Ciruelos E, Pascual T, Arroyo Vozmediano ML, et al (2014) The therapeutic role of 
fulvestrant in the management of patients with hormone receptor-positive breast cancer. 
Breast. (3):201-8.
Clark GM, Sledge GW, Osborne CK, et al (1987) Survival from first recurrence: relative 
importance of prognostic factors in 1,015 breast cancer patients. Journal of Clinical Oncology; 
5(1):55-61.
 
Clopper C J, Pearson ES (1934) "The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial," Biometrika 26, 404–413.
Crespo JL, Powers T, Fowler B, et al (2002) The TOR-controlled transcription activators 
GLN3, RTG1, and RTG3 are regulated in response to intracellular levels of glutamine; Proc 
Natl Acad Sci U S A;99(10):6784-9.
Crowder RJ, Phommaly C, Tao Y, et al (2009) PIK3CA and PIK3CB inhibition produce 
synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive 
breast cancer. Cancer Res.; 69 (9):3955-3962.
Cully M, You H, Levine AJ, et al (2006) Beyond PTEN mutations: the PI3K pathway as an 
integrator of multiple inputs during tumorigenesis. Nat Rev Cancer. Mar;6(3):184-92.
De Buck SS, Jakab A, Boehm M, et al (2014) Population pharmacokinetics and 
pharmacodynamics of BYL719, a phosphoinositide 3-kinase antagonist, in adult patients with 
advanced solid malignancies. Br J Clin Pharmacol; 78(3):543-555.
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.
Di Leo A, Jerusalem G, Petruzelka L, et al (2010) Results of the CONFIRM phase III trial 
comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with 
estrogen receptor-positive advanced breast cancer.J Clin Oncol. Oct 20;28(30):4594-600. 
Erratum in: J Clin Oncol.2011 Jun 1;29(16):2293.


Novartis
Confidential
Page 162
Amended Protocol Version 05 (Clean)
Protocol No. CBYL719C2301
Di Leo A, Jerusalem G, Petruzelka L, et al (2013) Final Overall Survival: Fulvestrant 500 mg 
vs 250 mg in the Randomized CONFIRM Trial. JNCI J Natl Cancer Inst 106(1).
Dickler M, Shah PD1, Moynahan ME, et al (2014) Phase I trial of PI3Kα inhibitor BYL719 
plus letrozole or exemestane for patients with hormone receptor-positive (HR+) metastatic 
breast cancer (MBC). Poster at San Antonio Breast Cancer Symposium.
Dodd E L, Korn L E, Freidlin B, Gray R, Bhattacharya S. An audit strategy for progression-
free survival. Biometrics, Vol 67, Issue 3; 1092-99, 2011.
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.
EuroQol Group (1990) EuroQol-a new facility for the measurement of health-related quality 
of life. Health Policy 1990;16:199-208.
Fahmi O, Maurer T, Kish M, et al (2008) A Combined Model for Predicting CYP3A4 Clinical 
Net Drug-Drug Interaction Based on CYP3A4 Inhibition, Inactivation, and Induction 
Determined in Vitro. DMD 36:1698–1708.
Fayers PM, Aaronson NK, Bjordal K, et al (2001) on behalf of the EORTC Quality of Life 
Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). Published by: European 
Organisation for Research and Treatment of Cancer,Brussels 2001.
FDA briefing Document Oncologic Drugs Advisory Committee Meeting, July 24, 2012, 
Evaluation of radiologic review of progression-free survival in Non-hematologic 
malignancies.
Fine KD, Schiller LR (1999) AGA technical review on the evaluation and management of 
chronic diarrhea. Gastroenterology. 116(6):1464-86.
Finn Rs, Crown JP, Lang I, et al (2015) The cyclin-dependent kinase 4/6 inhibitor palbociclib 
in combination with letrozole versus letrozole alone as first-line treatment of oestrogen 
receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a 
randomised phase 2 study. Lancet Oncology, Vol.16(1).
Foerster R, Schroeder L, Foerster F, et al (2014) Metastatic male breast cancer: a retrospective 
cohort analysis Breast Care.;9(4):267-71.
Fritsch C, Huang A, Chatenay-Rivauday C, et al (2014) Characterization of the novel and 
specific PI3Kalpha inhibitor NVP-BYL719 and development of the patient stratification 
strategy for clinical trials. Mol Cancer Ther; 13(5):1117-29.
Giordano S, Buzdar A, Hortobagyi G, et al (2002) Breast Cancer in Men. Ann Intern 
Med.;137:678-687.
Glimm E, Maurer W, Bretz F (2010) Hierarchical testing of multiple endpoints in group-
sequential trials. Statistics in Medicine 29, 219-228.
Gomez B Jr, Ardakani S, Ju J, et al (1995) Monoclonal antibody assay for measuring bone-
specific alkaline phosphatase activity in serum. Clin Chem 41:1560-1566.
Higgins MJ, Jelovac D, Barnathan E (2012) Detection of tumor PIK3CA status in metastatic 
breast cancer using peripheral blood. Clin Cancer Res.;18(12):3462-9.
Hirst JA, Stevens RJ, Farmer AJ (2014) Changes in HbA1c level over a 12-week follow-up in 
patients with type 2 diabetes following a medication change. Pols One; 9(3): e92458.


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Hon WC, Berndt A, Williams RL (2012) Regulation of lipid binding underlies the activation 
mechanism of class IA PI3-kinases. Oncogene.;31(32):3655-66.
Howell A, Robertson JF, Abram P, et al (2004) Comparison of fulvestrant versus tamoxifen 
for the treatment of advanced breast cancer in postmenopausal women previously untreated 
with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol.; 
22(9):1605- 1613.
Huang A, Sun D, Wu Z, et al (2004) Estrogen elicits cytochrome P450--mediated 
flowinduced dilation of arterioles in NO deficiency: role of PI3K-Akt phosphorylation in 
genomic regulation. Circ Res;94(2):245-52.
Janku F, Hong D, Fu S, et al (2014) Assessing PIK3CA and PTEN in Early-Phase Trials with 
PI3K/AKT/mTOR Inhibitors. Cell Reports 6, 377–387.
Jennison C, Turnbull B (2000) Group sequential methods with applications to clinical trials. 
Boca Raton, Chapman & Hall/CRC
Johnston SR, Kilburn LS, Ellis P, et al (2013) SoFEA investigators. Fulvestrant plus 
anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase 
inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or 
metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet 
Oncol.;14(10):989-998.
Juric D (2014) Phase I Study of the PI3Kα Inhibitor Alpelisib (BYL719), as a advanced Solid 
Tumors (aST), ESMO Poster.
Juric D, Castel P, Griffith M, et al (2015) Convergent loss of PTEN leads to clinical resistance 
to a PI(3)Kα inhibitor. Nature. 2015 Feb 12;518(7538):240-4.
Juric D, et al (2012) Phase I study of BYL719, an alpha-specific PI3K inhibitor, in patients 
with PIK3CA mutant advanced solid tumors: preliminary efficacy and safety in patients with 
PIK3CA mutant ER-positive (ER+) metastatic breast cancer (MBC). Cancer Res 72: (24), S3.
Karakas B, Bachman KE, Park BH (2006) Mutation of the PIK3CA oncogene in human 
cancers. Br J Cancer; 94(4):455-9.
Katso R, Okkenhaug K, Ahmadi K, et al (2001) Cellular function of phosphoinositide 3-
kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev 
Biol.;17:615-75.
Kornblau S, Bensen AB, Catalano R, et al (2000) Management of cancer treatment-related 
diarrhea: Issues and therapeutic strategies. Journal of Pain and Symptom Management; 
19:118-129.
Krop I, Johnston, Mayer IA, et al (2014) The FERGI phase II study of the PI3K inhibitor 
pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER+, 
aromatase inhibitor (AI)-resistant advanced or metastatic breast cancer – Part I results; 2014 
San Antonio Breast Cancer Symposium.
Lan KKG, Demets DL (1983) Discrete sequential boundaries for clinical trials. Biometrika 
70, 659-63.
Liu P, Cheng H, Roberts TM, et al (2009) Targeting the phosphoinositide 3-kinase pathway in 
cancer. Nat Rev Drug Discov. Aug;8(8):627-44.


Novartis
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Page 164
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Protocol No. CBYL719C2301
Mankoo PK, Sukumar S, Karchin R (2009) PIK3CA somatic mutations in breast cancer: 
Mechanistic insights from Langevin dynamics simulations. Proteins; 75:499–508.
Mayer IA, Abramson VG, Balko JM, et al (2014) A suc2C phase Ib study of the PI3Kα 
inhibitor BYL719 and letrozole in ER+/HER2- metastatic breast cancer; poster ASCO 2014.
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.
Miller TW, Balko JM, Arteaga CL (2011a) Phosphatidylinositol 3-kinase and antiestrogen 
resistance in breast cancer. J.Clin.Oncol. 29 (33):4452-4461.
Mita MM, Mita A, Rowinsky EK (2003) The molecular target of rapamycin (mTOR) as a 
therapeutic target against cancer. Cancer Biol. Ther. 2, S169–S177.
Mouridsen H, Gershanovich M, Sun Y, et al (2003) Phase III study of letrozole versus 
tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis 
of survival and update of efficacy from the International Letrozole Breast Cancer Group. J 
Clin Oncol; 21 (11): 2101-09.
Moynahan (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). abstract shared at ASCO 2014.
Munster (2014) Ph IB study of LEE011 and BYL719 in combination with letrozole in ER+, 
HER2- breast cancer, poster at ASCO.
National Cancer Center Network Treatment Guidelines for Breast Cancer, Version 2.2015. 
//nccn.org/professionals/physician_gls/pdf/breast.pdf.
Nicholson RI, Hutcheson IR, Hiscox SE, et al (2005) Growth factor signalling and resistance 
to selective oestrogen receptor modulators and pure anti-oestrogens: the use of anti-growth 
factor therapies to treat or delay endocrine resistance in breast cancer. Endocr Relat Cancer. 
Suppl 1:S29-36.
O’Brien NA, McDonald K, Tong L, et al (2014) Targeting PI3K:mTOR Overcomes 
Resistance to HER-Targeted Therapy Independent of Feedback Activation of AKT. 
Clin.Cancer Res. 20 (13): 3507-20.
Oken MM, Creech RH, Tormey DC, et al (1982) Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. Dec;5(6):649-55.
Osborne CK, Schiff R (2011) Mechanisms of endocrine resistance in breast cancer. Annu Rev 
Med. 2011;62:233-47.
Patten D, Sharifi L, Fazel M (2013) New Approaches in the Management of Male Breast 
Cancer Clin Breast Cancer, Vol. 13, No. 5, 309-14.
Perou CM, Sørlie T, Eisen MB, et al (2000) Molecular portraits of human breast 
tumours.Nature; 406(6797):747-52.


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Pirmohamed M, Ostrov DA, Park BK (2015) New genetic findings lead the way to a better 
understanding of fundamental mechanisms of drug hypersensitivity. J Allergy Clin 
Immunol.136(2):236-44.
 
Robertson J, Lindemann J, Sally Garnett S, et al (2014) A Good Drug Made Better: The 
Fulvestrant Dose-Response Story Clin Breast Cancer, Vol. 14, No. 6, 381-9.
Robertson JF, Harrison M (2004) Fulvestrant: pharmacokinetics and pharmacology. Br J 
Cancer. Mar;90 Suppl 1:S7-10.
Samuels Y, Wang Z, Bardelli A, et al (2004) High frequency of mutations of the PIK3CA 
gene in human cancers. Science; 304:554.
Schoenfeld D (1981) The asymptotic properties of nonparametric tests for comparing survival 
distributions. Biometrika 68, 316-19.
Shinohara M, Nakamura M, Masuda H (2012) Class IA phosphatidylinositol 3-kinase 
regulates osteoclastic bone resorption through protein kinase B-mediated vesicle transport. J 
Bone Miner Res. (12):2464-75.
Shoman N, Klassen S, McFadden A, et al (2005) Reduced PTEN expression predicts relapse 
in patients with breast carcinoma treated by tamoxifen. Mod.Pathol.; 18 (2):250-59.
Sotiriou C, Pusztai L (2009) Gene-expression signatures in breast cancer. N Engl 
JMed;360(8):790-800.
Tenner S, Baillie J, DeWitt J, et al (2013) Management of acute pancreatitis American 
College of Gastroenterology. Am J Gastroenterol.;108(9):1400-15.
Wadler S, Benson AB, Engelking C, et al (1998) Recommended guidelines for the treatment 
of chemotherapy-induced diarrhea. J Clin Oncol; 16:3169-3178.
Wakeling AE (2000) Similarities and distinctions in the mode of action of different classes of 
antioestrogens. Endocr Relat Cancer. Mar;7(1):17-28.
Wullschleger S, Loewith R, Hall MN (2006) TOR Signaling in Growth and Metabolism.Cell; 
124(3):471-84.
Yardley D, Noguchi S, Pritchard K, et al (2014) Everolimus Plus Exemestane in 
Postmenopausal Patients with HR+ Breast Cancer: BOLERO-2 Final Progression-Free 
Survival Analysis Adv Ther 30:870–84.
Zhang JJ, Chen H, He K, et al (2012) Evaluation of blinded independent central review of 
tumor progression in oncology clinical trials: a meta-analysis. Therapeutic innovation & 
regulatory science: 47(2): 167-74
Zhao L, Vogt PK (2008) Class I PI3K in oncogenic cellular transformation. Oncogene; 
27:5486-5496.


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Appendices
 
 
 
 
 
 
 
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Appendix 2 – Patient Patient reported outcomes
Figure 14-1
EORTC QLQ-C30


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14.3
Appendix 3 - 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: 11-Feb-2016
Version 3.1: 29-Nov-2011
Version 3:0: 19-Oct-2009
Version 2:0: 18-Jan-2007
Version 1:0: 13-Dec-2002
Release date:
11-Feb-2016
Authors (Version 3.2):
 
 
Authors (Version 3.1):
 
Authors (Version 3):
 
Authors (Version 2):
 
Authors (Version 1):


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Glossary
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
DFS
Disease-free survival
eCRF
Electronic Case Report Form
FPFV
First patient first visit
GBM
Glioblastoma multiforme
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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14.3.1
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 (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 14.3.2 and the definition of best response in 
Section 14.3.17 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.3.18 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 14.3.29 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the RAP (Reporting and Analysis Plan) to provide further details needed for programming.
14.3.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247.
14.3.3
Definitions
14.3.4
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 patients without measurable disease see Section 14.3.27.
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 5mm 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 
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
Cystic lesions:

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 patient, 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.
14.3.5
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient 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 patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in Section 
14.3.27.
14.3.6
Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v) 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 patients, 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 patient 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 of abdomen and pelvis.


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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 (US) 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. US 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 
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
Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers 
 
can be 
integrated as non-target disease. If markers are initially above the upper normal limit they 
must normalize for a patient 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.
14.3.7
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 CRF 
(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 14.3.4.

Nodal target: See Section 14.3.4.
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 


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a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.
14.3.8
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 14-5) and non-target lesions (Table 14-6) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 14-7) as well as the presence or absence of new lesions.
14.3.9
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.
14.3.10
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 subject 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.
14.3.11
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 


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for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval.
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.
14.3.12
Determination of target lesion response
Table 14-5
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 14.3.6.)
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 CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 14-5 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 patients who 


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have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section.

For those patients 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 case report form 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 case report form, 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 
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
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 
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.
14.3.13
Determination of non-target lesion response
Table 14-6
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 
baseline.
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 does 
prevail
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 


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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 
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 14.3.12 for assigning PD following a CR for the 
non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.
14.3.14
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 CRF 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 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 14.3.15).

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 14.3.6.
14.3.15
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 14-
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Table 14-7
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 14.3.8.
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).
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.
14.3.16
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.3.27 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
14.3.17
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 patient'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.


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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 patient 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 
prior to progression where confirmation not required

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 defaults based on a 6 
week tumor assessment frequency. 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 patient 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 patient 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 


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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 patient. 
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 patient 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 patient 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

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/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses.
Based on the patients’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of patients 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 patients with a best overall response of CR or
PR or SD. The objective of this endpoint is to summarize patients 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 patients 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 patients 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 and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be at 


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8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients 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, 
patients 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 ITT approach).
14.3.18
Time to event variables
The protocol should state which of the following variables is used in that study.
14.3.19
Progression-free survival
Usually in all Oncology studies, patients 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.
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 
patient 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. 
14.3.20
Overall survival
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient 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 patient is not known to have died, survival will be censored 
at the date of last known date patient alive.
14.3.21
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 patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment.


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14.3.22
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 
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.
Time to treatment failure (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’. The time to treatment 
failure for patients who did not experience treatment failure will be censored at last adequate 
tumor assessment.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.3.26
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 
, the randomization/ date of 
treatment start will be used as the start date.
For the calculation of 
 the following start date should be used:
 
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 back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.3.27).
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.


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
Date of last contact is defined as the last date the patient 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 patient 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.
14.3.27
Handling of patients with non-measurable disease only at baseline
It is possible that patients with only non-measurable disease present at baseline are entered into 
the study, either 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 patients 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 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with measurable 
disease is derived slightly differently according to Table 14-8.
Table 14-8
Overall lesion response at each assessment: patients 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 14.3.8.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients 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 patients 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 patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 


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exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease.
14.3.28
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 patient being lost to follow-up? It is important that the protocol and RAP 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 14.3.26, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 2005) 
as a reference, the following analyses can be considered:


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Table 14-9
Options for event dates used in PFS, TTP
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
 
)
1.=Definitions can be found in Section 14.3.26.
2.=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 
14.3.26.
3.=The rare exception to this is if the patient 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.
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.


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Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients 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/
 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/
 analysis.
It is strongly recommended that a tumor assessment is performed before the patient is switched 
to a new cancer therapy. 
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 14-9 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.


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14.3.29
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).
14.3.30
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).
14.3.31
End of treatment phase completion
Patients 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 patients 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 patient, 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.
Patients may discontinue study treatment for any of the following reasons:

Adverse event(s)

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

Progressive disease

Study terminated by the sponsor

Non-compliant with study treatment

No longer requires treatment
14.3.32
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.
Patients may provide study phase completion information for one of the following reasons:

Adverse event

Lost to follow-up


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
Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

Progressive disease

Study terminated by the sponsor
14.3.33
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.
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 patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
14.3.34
Programming rules
The following should be used for programming of efficacy results:
14.3.35
Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)


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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.
14.3.36
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 14.3.26). 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.
14.3.37
Incomplete dates for last known date patient 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.
14.3.38
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)’.
14.3.39
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
14.3.40
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 
 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 14-9)


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
Death due to reason other than underlying cancer (only used for TTP
)

Initiation of new anti-cancer therapy
*Adequate assessment is defined in Section 14.3.26. 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 patients 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, 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.


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14.3.41
References (available upon request)
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791.
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47.
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465.
EMA Guidance: 2012 Guideline on the evaluation of anticancer medicinal products in man
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005.
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 S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16.


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14.4
Appendix 4 - Guidelines for the treatment of study drug 
combination induced diarrhea
Mild to moderate diarrhea has been reported within the ongoing studies of single-agent BYL719. 
In order to effectively manage diarrhea and mitigate the escalation in severity or duration of 
diarrhea, patient education as well as proper management of diarrhea is mandatory. The 
following section outlines the recommended algorithm for management and treatment of 
BYL719 induced diarrhea (Benson et al 2004; Kornblau et al 2000; Wadler et al 1998).
The algorithm for treatment for diarrhea management is based on (Wadler et al 1998; Kornblau 
et al 2000).
Patient history of diarrhea
At screening, the patient’s history of diarrhea should be reviewed and the patient should be 
appropriately informed of potential study drug-induced diarrhea and its management:

Review previous medical history of diarrhea within the last 12 months; laxative use, colon 
surgery, abdominal and pelvic irradiation, nocturnal diarrhea, pain, ulcerative colitis and 
other diarrhea-inducing diseases/conditions;

Stop all diarrheogenic agents at screening if possible, otherwise exclude from trial;

Instruct patients regarding risk of developing diarrhea;

Perform baseline clinical/laboratory studies according to the trial protocol (e.g. one could 
rule out carrier state of Salmonella spp., Clostridium difficile, Campylobacter spp., 
Giardia, Entamoeba, Cryptosporidium which can lead to opportunistic infections in 
immunosuppressed patients);

Explain the frequency of diarrhea and its relationship to NCI CTCAE grading (Table 14-
10).
Table 14-10
NCI CTCAE version 4.03 grading of diarrhea for patients without 
colostomy
Toxicity
0
1
2
3
4
Diarrhea
None
Increase of < 4 
stools per day 
over baseline
Increase of 4-6 
stools per day 
over baseline
Increase of 7 stools per day 
over baseline; incontinence; 
hospitalization indicated; 
limiting self-care ADL
Life-threatening 
consequences; 
urgent intervention 
indicated
Diarrhea is defined as: A disorder characterized by frequent and watery bowel movements.
First report of diarrhea

Obtain history of onset and duration of diarrhea

Description of number of stools and stool composition (e.g. watery, blood, mucus in stool)

Assess patient for fever, abdominal pain, cramps, distension, bloating, nausea, vomiting, 
dizziness, weakness (i.e., rule out risk for sepsis, bowel obstruction, dehydration)

Obtain medication profile (i.e., to identify any diarrheogenic agents) and dietary profile 
(i.e., to identify diarrhea-enhancing foods)
Proactively look for occurrence of diarrhea. If no problems occur, instruct the patient to call 
when a problem does arise.


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Management of diarrhea
General recommendations:

Stop all lactose-containing products, alcohol

Stop laxatives, bulk fiber (e.g. Metamucil®) and stool softeners (e.g. docusate sodium, 
Colace®)

Stop high-osmolar food supplements such as Ensure Plus® and Jevity Plus® (with fiber)

Drink 8 to 10 large glasses of clear liquids per day (e.g. water, Pedialyte®, Gatorade®, 
broth)

Eat frequent small meals (e.g. bananas, rice, apple sauce, toast)
It is recommended that patients are provided with loperamide tablets at the start of each cycle. 
Patients should be instructed on the use of loperamide at Cycle 1 in order to manage signs or 
symptoms of diarrhea at home. Patients should be instructed to start oral loperamide (initial 
administration of 4 mg, then 2 mg every 4 hrs (maximum of 16 mg/day) at the first sign of loose 
stool or symptoms of abdominal pain. These instructions should be provided at each cycle and 
the site should ensure that the patient understands the instruction. At the beginning of each cycle, 
each patient should be specifically questioned regarding any experience of diarrhea or diarrhea 
related symptoms. If symptoms were experienced, then the site should question the patient 
regarding the actions taken for these symptoms.
Intensive management of diarrhea must be instituted at the first sign of abdominal cramping, 
loose stools or overt diarrhea. Note that all concomitant therapies used for treatment of diarrhea 
must be recorded on the Concomitant Medications/Non-drug Therapies eCRF.
Loperamide is the first-line treatment of diarrhea (any Grade) in this recommended algorithm. 
Persistent symptoms may require the administration of high dose loperamide followed by 
treatment with second-line agents such as opium tincture and octreotide acetate, based on 
severity and duration of diarrhea and related signs/symptoms. Another first-line treatment for 
diarrhea is diphenoxylate hydrochloride/atropine sulfate. This medication may be used in place 
of loperamide however it is important to note that loperamide and diphenoxylate 
hydrochloride/atropine sulfate must not be used in conjunction with one another due to the risk 
of developing paralytic ileus. Upon treatment with any antidiarrheal agents, the patient’s 
response to treatment should be observed and appropriately documented in the source document 
and eCRF.
Treatment of diarrhea CTCAE grade 1 or 2
Diarrhea CTCAE grade 1 or 2 will be treated with standard loperamide (initial at first 
administration 4 mg, then 2 mg every 4 hrs (maximum of 16 mg/day) or after each unformed 
stool).
Diarrhea resolved

Continue instructions for dietary modification

Gradually add solid foods to diet

Discontinue loperamide after 12 hrs diarrhea-free interval


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Diarrhea unresolved
Persisting diarrhea CTCAE grade 1 or 2 will be treated with addition of opium tincture or 
dihydrocodeine tartrate tablets/injections with monitoring of patients condition to rule out 
dehydration, sepsis, ileus) medical check and selected workup if patient does not need 
hospitalization (see section Diarrhea workup and additional test in the particular trial protocol). 
Observe patient for response to antidiarrheal treatment.
Persisting diarrhea CTCAE grade 3 or 4 may be treated with hospitalization, high dose 
loperamide (initial 4 mg, then 2 mg every 2 hrs) and addition of opium tincture (DTO) or 
dihydrocodeine tartrate tablets/injections, start of IV fluids and antibiotics as needed with 
monitoring of patients condition (to rule out dehydration, sepsis, ileus) medical check and 
workup (perform appropriate additional testing). Observe patient for response.
After again 12-24 hrs:
Diarrhea resolved

Continue instructions for dietary modification

Gradually add solid foods to diet

Discontinue loperamide and/or other treatment after 12 hrs diarrhea-free interval
Diarrhea unresolved

If diarrhea still persisting (CTCAE grades 1 and 2), after 2x 24 hrs with high dose 
loperamide and opiates then admit to hospital and employ measures as for CTCAE grade 
3 and 4 until diarrhea resolved.

If diarrhea still persisting and progressed to CTCAE grades 3 and 4, employ measures 
described below.
Treatment of diarrhea CTCAE grade 3 or 4
Severe diarrhea CTCAE grade 3 or 4 may be treated with hospitalization, high dose loperamide 
(initial 4 mg, then 2 mg every 2 hrs and addition of opium tincture or dihydrocodeine tartrate 
tablets/injections, start of IV fluids and antibiotics as needed with monitoring of patients 
condition (to rule out dehydration, sepsis, ileus) medical check and workup (see section 
Diarrhea workup and additional test in the particular trial protocol). Observe patient for 
response.
After 12-24 hrs:

If diarrhea persisting administer s.c. Sandostatin/octreotide (100-500 µg tid)

Continue IV fluids and antibiotics as needed

If diarrhea CTCAE grade 3 or 4 still persists patients should receive opium tincture or 
dihydrocodeine tartrate injections s.c. or i.m.

If diarrhea CTCAE grade 3 or 4 is still persisting s.c. Sandostatin/octreotide (500-1000 µg 
TID) should be administered.

To control and/or resolve diarrhea, next cycle of treatment should be delayed by 1 or 2 
weeks. Treatment should be continued only when diarrhea resolved.


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Diarrhea workup
Perform appropriate tests (Fine et al 1999).
Spot stool analysis

Collect stool separating it from urine (special containers, analysis immediately, 
exceptionally freeze samples)

Blood

Fecal leukocytes (Wright's staining and microscopy) or

Clostridium difficile toxin

Fecal cultures including Salmonella spp., Campylobacter spp., Giardia, Entamoeba, 
Cryptosporidium (which can lead to opportunistic infections in immunosuppressed 
patients), plus Shigella and pathogenic E. coli - enterotoxigenic, enterohemorrhagic etc., 
possibly Aeromonas, Pleisiomonas (if suspected exposure to contaminated water)
Endoscopic examinations
Endoscopic examinations may be considered only if absolutely necessary. The bowel is likely 
to be fragile with evidence of colitis and thus great care and caution must be exercised in 
undertaking these invasive procedures.

Gastroscopy to obtain jejunal fluid - re. bacterial overgrowth for cultures and biopsy of 
proximal jejunum to assess extent of inflammatory jejunitis

Sigmoidoscopy - reassessment of colitis


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14.5
Appendix 5 - Guidelines for the treatment of study drug induced 
stomatitis/oral mucositis
General guidance and management include patient awareness and early intervention. Evaluation 
for herpes virus or fungal infection should be considered.
Patients should be informed about the possibility of developing mouth ulcers/oral mucositis and 
instructed to report promptly any signs or symptoms to their physician,
Patients should be educated about good oral hygiene, instructed to avoid spicy/acidic/salty 
foods, and should follow the following guidelines:

For mild toxicity (grade 1), use conservative measures such as non-alcoholic mouth wash 
or salt water (0.9%) mouth wash several times a day until resolution.

For more severe toxicity (grade 2 in which case patients have pain but are able to maintain 
adequate oral alimentation, or grade 3 in which case patients cannot maintain adequate 
oral alimentation), the suggested treatments are topical analgesic mouth treatments (i.e., 
local anesthetics such as benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 
menthol, or phenol) with or without topical corticosteroids, such as triamcinolone oral 
paste 0.1% (Kenalog in Orabase®).

Agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives may tend to 
worsen mouth ulcers. It is preferable to avoid these agents.
Antifungal agents should be avoided unless a fungal infection is diagnosed as they may interfere 
with alpelisib metabolism (see Section 6.4 and Appendix 1).


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14.6
Appendix 6 - Statistical methodology
14.6.1
Statistical methodology and operating characteristics – PFS futility 
criteria in the PIK3CA mutant cohort
At the time of the futility analysis, the cohort may be stopped for futility if one or both of the 
following criteria are met:
1.
The observed (i.e. nominal) p-value > 0.128
2.
Conditional Probability (HRfinal ≤ 0.6¦ HRinterim) < 0.20
Criterion (2) uses the observed interim data and an assumption regarding the distribution of 
future unobserved data in the two treatment groups conditioned under the alternative hypothesis
(HRHa). Under the alternative hypothesis, the following formula (Jennison and Turnbull 2000 
formula 10.2) can be used to find the futility boundary on the Z-statistic scale (zt) for criterion 
(2) that satisfies:
Φ
⎣
⎢
⎢
⎡
−
1
√1 −
⎝
⎛ −√ −√1 −
−log 


(1 −) ⎠
⎞
⎦
⎥
⎥
⎤
< 0.2
where:
 =
()*+),
)
   with -:1 randomization ratio for treatment and control,
: Total number of PFS events,
:  Information fraction at the futility interim analysis (i.e. 0.4)
.′: Final boundary on Z scale,
: Observed value on Z scale at futility interim
The critical value for the Z-statistic at the futility interim analysis that will ensure criterion (2) 
is satisfied is |zt| = 1.489. The futility boundary in terms of p-value scale is thus calculated as p 
=0.068.
The operating characteristics of the revised futility criteria are provided in Table 14-11.
Table 14-11
Operating characteristics for PFS futility criteria in the PIK3CA mutant 
cohort
Futility Criteria
Probability to be stopped for futility
True HR
Under Criterion 1 only
Under Criterion 2
1.0
86.95%
92.98%
0.6
8.89%
15.31%
Criterion 1: Observed (i.e. nominal) p-value greater than 0.128
Criterion 2: Conditional Probability (HRfinal ≤ 0.6¦ HRinterim) < 0.20
Note: Operating characteristics for criterion 1 performed in East 6.3 with number of simulations = 10,000 
and randomization seed =37275. Operating characteristics for criterion 2 performed in SAS v9.4 with 
10,000 simulations and random seed = 111064


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14.6.2
Statistical design and operating characteristics – PFS in the PIK3CA
non-mutant cohort
A Bayesian double criteria-based design is used to estimate the treatment effect in the PIK3CA
non-mutant cohort, the methodology and operating characteristics based on simulation are 
detailed below.
14.6.2.1 Bayesian methodology for proof of concept criteria
Let θ denote the natural logarithm of the hazard ratio (HR) of PFS (experimental arm vs. control, 
i.e. θ < 0 indicates efficacy in favor of the experimental arm i.e. alpelisib + fulvestrant) and ym
denote the log(HR) estimated from a Cox proportional Hazards model with treatment as 
covariate based on m observed events and then using asymptotic theory of the log hazard ratio 
(Schoenfeld 1981):
Ym~N(θ,4/m)
Further assume θ follows a conjugate normal prior distribution, written as
θ ~N(θ0, 4/n0)
where θ0 is the specified prior mean and the prior variance 4/n0, n0 is the number of events worth 
of prior information.
This results in a posterior distribution of θ as
θ| ym ~ N(ym,+ (1- ) θ0, 4/(m+n0))
where = m/(m+n0) and in this study we consider a non-informative prior with n0=0.
Therefore the posterior distribution is of the following form;
θ| ym ~ N(ym, 4/m)
The cumulative posterior distribution will be used to derive the probability that the true HR is 
less than 1.
14.6.2.2 Proof of concept (PoC) criteria
The following PoC criteria, based on analysis of PFS using Cox proportional Hazards model 
with treatment as covariate, are considered;
a. Estimated HR ≤ 0.6, and
b. Posterior Probability (HR < 1) ≥ 90%
Both criteria need to be met in order to meet primary objective for this part of the study and test 
PFS in this cohort using a stratified log-rank test at one-sided 0.5% level of significance. The 
first criterion is met if the estimated HR is 0.6 or less which is the minimum HR of clinical 
interest. The second criterion provides reasonable evidence that the estimated HR is better than 
the value of no interest (HR=1) and also guarantees a level of precision for the estimate of HR.
14.6.2.2.1
Sample size considerations and simulation details
Based on the assumption that log (HR) is normally distributed, then the minimum number of 
events to satisfy criterion (b) can be calculated (Schoenfeld 1981) as:


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# events = 4 (z1-α + Z1-β)2 / θ2
Taking, θ = log(0.6), and one-sided, α=0.005, β=0.5, then 102 events are required. That is, with 
at least 102 events if the estimated HR is < 0.6 then criterion (b) in Section 14.6.2.2 will be met.
Assuming an enrollment rate of 10 patients during the first 6 months (7 with PIK3CA non-
mutant status), 30 patients up to 12 months (21 with PIK3CA non-mutant status) and 50 patients 
afterwards (35 with PIK3CA non-mutant status) and 10% patients will be lost to follow-up, 220 
patients will be randomized (110 per arm), in order to observe the required 102 events in the 
two arms in approximately 18 months (if the observed HR is 0.6 and the median PFS for the 
control arm is 7.4 months).
The primary analysis to estimate the HR will be performed after approximately 102 PFS events 
have been observed. If the true HR is 1, the probability (obtained by simulation) to obtain a 
positive conclusion is 0.005. If the true HR is 0.60 (reflecting the minimum clinically relevant 
difference), the probability to meet efficacy criteria is 0.491. In addition if the true HR is 0.6 
and the PoC is met, the probability (by simulation) to also observe a positive result with formal 
testing is 0.983.
Table 14-12
Operating characteristics for PoC criteria in PIK3CA non-mutant 
cohort
True 
HR
True Median PFS alpelisib (months)
Probability to meet PoC
0.3
24.67
0.999
0.4
18.50
0.975
0.5
14.80
0.813
0.6
12.33
0.491
0.7
10.57
0.220
0.8
9.25
0.076
0.9
8.22
0.020
1.0
7.4
0.005
Assumes: (1) HR.=0.6, (2) true median PFS for fulvestrant = 7.4 months, (3) protocol planned accr
*Probabilities conditional on PoC criteria being met. Formal testing using log-rank test at a one-side
14.7
Appendix 7: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements
Table 14-13
Liver event and laboratory trigger definitions
 
Definition/threshold
LIVER LABORATORY TRIGGERS
3 x ULN < ALT / AST ≤ 5 x ULN
· 1.5 x ULN < TBL ≤ 2 x ULN
LIVER EVENTS
ALT or AST > 5 × ULN
 
ALP > 2 × ULN (in the absence of known bone 
pathology)


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Definition/threshold
 
TBL > 2 × 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 TBL > 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*
*These events cover the following: Hepatic failure, fibrosis and cirrhosis, and other liver damage-related conditions; 
the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms TBL: total bilirubin; ULN: upper 
limit of normal
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

SAP_003.pdf: 
Clinical Development 
BYL719 (alpelisib) 
Study Number: CBYL719C2301 / NCT02437318 
SOLAR-1: A phase III randomized double-blind, placebo-controlled study 
of alpelisib in combination with fulvestrant for men and postmenopausal 
women with hormone receptor positive, HER2-negative advanced breast 
cancer which progressed on or after aromatase inhibitor treatment 
Statistical Analysis Plan (SAP) 
Author: 
Trial Statistician 
Document type: 
SAP Documentation 
Document status: 
Amendment 6 
Release date: 
08-May-2023
Number of pages: 
102 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous version of SAP. 
Version 
Date 
Changes 
Amendment 
1 
17th October 
2016 
Changes due to Protocol Amendments #1 and #2; new Novartis 
protocol template text; new Novartis SAP template language; new 
Novartis  guidelines for safety analyses; updated Novartis standards 
for data reporting; updated Novartis RECIST guidelines; minor 
clarifications and corrections 
Amendment 
2 
23rd March 
2017 
Design/endpoint changes due to Protocol Amendment 3; Novartis 
guidelines for safety analyses; updated Novartis standards for data 
reporting; minor clarifications and corrections 
Amendment 
3 
27 November 
2017 
Section 2.1.8 Baseline 
• 
Added clarification that tumor assessments (and 
investigator’s overall response) occurring within 7 days 
following treatment start date may considered as the 
baseline RECIST assessment. This allows for the fact that 
subjects have a +/- 7 day window around their scheduled 
tumor assessments 
Section 2.2 Data included in the analysis 
• 
Added clarification on the respective cut-off dates used for 
the efficacy analysis in each cohort: the interim analysis in 
the mutant cohort and final analysis in the non-mutant cohort 
occurred at different time points. The cut-off for safety in 
both cohorts was set at the same time point as the interim 
analysis in the mutant cohort. 
• 
Clarified that any data collected in the clinical database after 
a subject withdraws informed consent from all further 
participation in the trial, will not be included in the analysis or 
analysis data sets 
Section 2.4.5 Determination of missing adequate assessments 
• 
Amended the window for the baseline RECIST assessment, 
given the change regarding baseline definition outlined in 
Section 2.1.8 
Section 3.2.1 Basic demographic and background data 
• 
Analysis using summary statistics updated to use Novartis 
standards 
Section 3.2.4 Prior anti-neoplastic therapy 
• 
Added definition to provide summary of patient population in 
terms of primary & secondary endocrine resistance and 
endocrine sensitivity status 
Section 3.6.1 Duration of study treatment exposure  
• 
Amended study treatment exposure categories 
Section 3.8 Efficacy Evaluation 
• 
Clarified that for central radiology assessments, only the 
final adjudicated data will be listed. 
Section 3.8.1.5 Sensitivity analyses of the primary endpoint 
(Different Censoring Mechanisms) 
• 
Updated the PFS censoring options to match the correct 
option in Table 3-3. 


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Version 
Date 
Changes 
Section 3.8.1.6 Supportive analyses of the primary endpoint (PFS 
assessed by BIRC) 
• 
Clarify that a negative observed differential discordance for 
the EDR or a positive differential discordance for the LDR 
meeting the 15% threshold is required to trigger a full BIRC 
review (per Amit et al, 2011) 
• 
Clarified that the timing of local and central response 
assessment (for subjects with complete agreement of local 
and central sources) will be considered to agree if they 
occur within ±7 days of each other, aligned with the protocol-
specified window for tumor assessments 
Section 3.8.2.5 Overall response rate 
• 
Added new analysis to present ORR in the subset of 
patients with measurable disease at baseline  
Section 3.8.2.6 Clinical benefit rate 
• 
Added new analysis to present CBR in the subset of patients 
with measurable disease at baseline  
Section 3.8.2.9 Patient reported outcomes 
• 
Clarified that data collection for PRO are scheduled up until 
disease progression and not just end of study treatment (as 
per protocol) 
• 
Amended text for inclusion data into statistical model. Model 
fit based on unblinded data will be assessed to decide which 
time points to include 
 
 
 
 
 
 
 
 
 
 
 
 
Section 3.9.1.4 AE summaries 
• 
Removed table for CTC Grade 3 or 4 AEs as this data is 
presented elsewhere 
Section 3.9.3 Vital Signs 
• 
Removed summary statistics for change from baseline to the 
worst post-baseline vital signs value  
Section 3.9.4 ECGs 
• 
RR parameter is not collected in the study 
• 
Removed analysis using summary statistics and shift tables 
• 
Table 3-8: corrected  parameters as per Novartis Oncology 
Guideline for Safety Analyses 
Section 3.10 Pharmacokinetic (PK) analyses 


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Version 
Date 
Changes 
• 
Clarified the use of all available PK samples to derive 
empirical Bayes estimates however reporting C1D15 and 
steady-state assessments only in the summary tables of 
PopPK-derived individual exposures. 
Section 3.10.3 Population PK parameters for alpelisib 
• 
Clarified 3-step procedure to obtain individual exposures 
from PopPK-derived empirical Bayes estimates: 
o 
Use of the most recent version of the Phase I 
PopPK model instead of the model published by de 
Buck et. al. 
o 
Restriction to patients with sparse PK profile 
sampling only 
o 
Specification of the parameters to be derived 
• 
Predicted concentrations will not be reported, only the 
individual parameters (see TFLs) 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 3.13 Subgroup analyses 
• 
Clarified age categories for geriatric subgroups 
• 
Removed gender as a subgroup analysis as number of male 
subjects randomized was too low (one male patient 
randomized in mutant cohort) 
• 
Clarified that CDISC controlled terminology will be used for 
subgroup analyses based on race (and not ethnicity) 


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Version 
Date 
Changes 
• 
Clarified definition of region based on countries with 
randomized patients 
• 
Clarified definition of first and second line therapy groups 
• 
Clarified that prior chemotherapy use is based on the last 
setting prior to study entry 
• 
Added efficacy subgroup analysis in patients with primary- & 
secondary endocrine resistance vs endocrine sensitivity 
Section 3.15 Sample Size Calculation (Overall Survival for Patients 
with PIK3CA non-mutant status (secondary endpoint) 
• 
Corrected reference to primary endpoint for overall survival 
in this cohort 
Section 4.8 Audit-based BIRC assessment of PFS (PhRMA method) 
• 
Clarified that the timing of local and central response 
assessment (for subjects with complete agreement of local 
and central sources) will be considered to agree if they 
occur within ±7 days of each other, aligned with the protocol-
specified window for tumor assessments 
Amendment 
4 
03 July 2018 
Section 3.6.1 Duration of study treatment exposure 
• 
New summaries for treatment exposure are added for 
specific subgroups based on AESI 
Section 3.9.1.5 Adverse Events of Special Interest 
• 
An analysis for time to first onset of CTC Grade 3 or worse is 
added for Hyperglycemia and Rash (AESI) 
Section 3.9.2.1 Blood glucose parameters 
• 
Section added to present new analyses for time to onset and 
time to resolution of hyperglycemia based on plasma 
glucose 
Section 3.10.3 Population PK parameters for alpelisib 
• 
The population PK analysis will be provided in a separate 
report. 
 
 
 
 
 
 
 
 
 
 
 
Section 3.13.1 Safety [subgroups] 
• 
For the AESI of Hyperglycemia only, a subgroup analysis by 
hyperglycemia diagnosis status at baseline per American 
Diabetes Association (ADA) 2017 will be presented  
Section 3.13.2 Efficacy [subgroups] 


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Version 
Date 
Changes 
• 
Subgroup analyses added for the primary endpoint by (i) 
PIK3CA somatic mutation and (ii) PIK3CA somatic mutation 
by location 
Amendment 
5 
28 May 2020 
Amendment 5 introduces several analyses using the cut-off date of 
the final OS analysis to assess the impact of the COVID-19 
pandemic.  
Section 1 Introduction 
• 
Updated wording to broaden the scope of the SAP 
Section 3.3 Protocol deviation summaries 
• 
New protocol deviation summary table for COVID-19 related 
PDs to address the potential impact of COVID-19 pandemic 
Section 3.8.1.5 Sensitivity analyses of the primary endpoint 
• 
Added a sensitivity analysis for PFS censoring to address 
the potential impact of COVID-19 pandemic 
Section 3.8.2.1 Key secondary objective overall survival 
• 
Added a sensitivity analysis for OS censoring to address the 
potential impact of COVID-19 pandemic 
Amendment 
6 
08 May 2023 
Section 2.2 Data included in the analysis.   
• 
Added language that excludes from datasets and analyses, 
laboratory samples that were collected on the date of 
withdrawal of consent, but analyzed by the vendor after this 
date. 
 


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Table of contents 
Table of contents ................................................................................................................. 7 
List of tables ...................................................................................................................... 11 
List of figures .................................................................................................................... 12 
1 
Introduction ....................................................................................................................... 15 
1.1 
Study Design .......................................................................................................... 15 
1.2 
Objectives .............................................................................................................. 16 
2 
Definitions and general methodology ............................................................................... 19 
2.1 
Definitions ............................................................................................................. 19 
2.1.1 
Study drug and study treatment ............................................................. 19 
2.1.2 
Date of first administration of study drug ............................................. 19 
2.1.3 
Date of last administration of study drug .............................................. 19 
2.1.4 
Date of first administration of study treatment ..................................... 19 
2.1.5 
Date of last administration of study treatment ...................................... 20 
2.1.6 
Last date of exposure to study drug/treatment ...................................... 20 
2.1.7 
Study day ............................................................................................... 21 
2.1.8 
Baseline ................................................................................................. 21 
2.1.9 
On-treatment assessment/event ............................................................. 22 
2.1.10 
Last contact date .................................................................................... 23 
2.1.11 
Screening failure ................................................................................... 23 
2.1.12 
Time Units ............................................................................................. 23 
2.2 
Data included in the analysis ................................................................................. 23 
2.2.1 
Pharmacokinetic (PK) data review ........................................................ 24 
2.3 
Analysis sets .......................................................................................................... 24 
2.3.1 
Full analysis set (FAS) .......................................................................... 24 
2.3.2 
Safety set ............................................................................................... 25 
2.3.3 
Per protocol set ...................................................................................... 25 
2.3.4 
Pharmacokinetic (PK) set ...................................................................... 26 
2.3.5 
Patient classification .............................................................................. 26 
2.4 
Implementation of RECIST ................................................................................... 27 
2.4.1 
Overall lesions response for patients with only non-measurable 
lesions at baseline .................................................................................. 27 
2.4.2 
Disease progression ............................................................................... 27 
2.4.3 
Best overall response (BOR) ................................................................. 27 
2.4.4 
Change in imaging modality ................................................................. 29 


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2.4.5 
Determination of missing adequate assessments .................................. 29 
2.4.6 
No baseline tumor assessments ............................................................. 31 
2.4.7 
Construction of waterfall graphs ........................................................... 31 
3 
Statistical methods used in reporting ................................................................................. 33 
3.1 
Enrollment status ................................................................................................... 33 
3.2 
Background and demographic characteristics ....................................................... 33 
3.2.1 
Basic demographic and background data .............................................. 33 
3.2.2 
Diagnosis and extent of cancer ............................................................. 33 
3.2.3 
Medical history...................................................................................... 34 
3.2.4 
Prior anti-neoplastic therapy ................................................................. 34 
 
35 
3.3 
Protocol deviation summaries................................................................................ 35 
3.4 
Groupings for analysis ........................................................................................... 36 
3.5 
Patient disposition .................................................................................................. 36 
3.6 
Study treatment ...................................................................................................... 36 
3.6.1 
Duration of study treatment exposure ................................................... 37 
3.6.2 
Cumulative dose .................................................................................... 38 
3.6.3 
Dose intensity and relative dose intensity ............................................. 38 
3.6.4 
Dose reduction, interruption and permanent discontinuation ............... 39 
3.7 
Concomitant therapy .............................................................................................. 41 
3.7.1 
Concomitant medications with specific impact on the analysis............ 41 
3.8 
Efficacy evaluation ................................................................................................ 42 
3.8.1 
Primary efficacy .................................................................................... 42 
3.8.2 
Secondary efficacy analyses ................................................................. 49 
 
 57 
3.9 
Safety evaluation ................................................................................................... 60 
3.9.1 
Adverse events (AEs) ............................................................................ 60 
3.9.2 
Laboratory data ..................................................................................... 63 
3.9.3 
Vital signs.............................................................................................. 66 
3.9.4 
ECG ....................................................................................................... 67 
3.9.5 
Cardiac imaging (MUGA / ECHO) ...................................................... 68 
3.9.6 
Other safety data ................................................................................... 68 
 
 68 
3.10 
Pharmacokinetic (PK) analyses ............................................................................. 68 
3.10.1 
General principle ................................................................................... 68 
3.10.2 
PK concentrations ................................................................................. 69 


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3.10.3 
Population PK parameters for alpelisib................................................. 69 
 
 69 
3.10.5 
Handling missing and invalid values .................................................... 71 
 
71 
 
72 
 
 72 
 
 73 
 
 73 
 
 74 
 
 74 
 
74 
3.12 
Interim analyses ..................................................................................................... 74 
3.12.1 
Primary endpoint: Progression-free survival ........................................ 74 
3.12.2 
Key Secondary Endpoint: OS in the PIK3CA mutant cohort ............... 76 
3.12.3 
OS in the PIK3CA non-mutant cohort: ................................................. 78 
3.12.4 
Confidentiality of Interim OS results .................................................... 79 
3.13 
Subgroup analysis .................................................................................................. 79 
3.13.1 
Safety..................................................................................................... 79 
3.13.2 
Efficacy ................................................................................................. 80 
 
 82 
3.14 
Sample size calculation.......................................................................................... 83 
3.15 
Power for analysis of key secondary variable ....................................................... 86 
3.16 
Sample size considerations for PK analysis .......................................................... 87 
4 
General Statistical Methodology ....................................................................................... 87 
4.1 
Baseline comparability .......................................................................................... 87 
4.2 
Center pooling ....................................................................................................... 87 
4.3 
One-sided vs. two-sided test .................................................................................. 88 
4.4 
Time-to-event analyses .......................................................................................... 88 
4.4.1 
Analysis of time-to-event data with ties................................................ 88 
4.4.2 
Hypothesis and test statistic .................................................................. 88 
4.4.3 
Kaplan-Meier estimates ........................................................................ 88 
4.4.4 
Hazard ratio ........................................................................................... 89 
 
 89 
4.5 
Group sequential design used in Phase III studies................................................. 90 
4.5.1 
Alpha-spending function ....................................................................... 91 


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4.5.2 
Beta-spending function ......................................................................... 91 
4.5.3 
Calculation of stopping boundaries ....................................................... 91 
4.5.4 
Group sequential design with PFS as a primary endpoint, OS as a 
key secondary endpoint and controlling for multiplicity ...................... 93 
4.6 
Statistical methodology and operating characteristics – PFS futility criteria in 
the PIK3CA mutant cohort..................................................................................... 95 
4.7 
Statistical design and operating characteristics – PFS in the PIK3CA non-
mutant cohort ......................................................................................................... 96 
4.7.1 
Bayesian methodology for proof of concept criteria ............................. 96 
4.7.2 
Proof of concept (PoC) criteria ............................................................. 97 
4.7.3 
Sample size considerations and simulation details ............................... 97 
4.8 
Audit-based BIRC assessment of PFS ................................................................... 99 
5 
References ....................................................................................................................... 100 


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List of tables 
Document History – Changes compared to previous version of SAP. ....................................... 2 
Table 1-1 
Study objectives .................................................................................... 16 
Table 2-1 
Patient classification based on protocol deviations and non-
protocol deviation criteria ..................................................................... 26 
Table 2-2 
Assessments considered for calculation of best percentage change 
for waterfall graphs ............................................................................... 32 
Table 3-1 
Examples of Dose Reduction for alpelisib ............................................ 40 
Table 3-2 
Sources for overall lesion response ....................................................... 42 
Table 3-3 
Options for event dates used in PFS
................... 43 
Table 3-4 
ECOG Performance Scale ..................................................................... 53 
Table 3-5 
Time windows for ECOG PS assessments............................................ 53 
Table 3-6 
Time windows for patient reported outcomes ....................................... 55 
Table 3-7 
Outcome and event/censor dates for PFS2 analysis .............................. 59 
Table 3-8 
Clinically notable ECG values .............................................................. 67 
 
 72 
Table 3-10 
Simulated probabilities to stop for futility or efficacy at the interim 
analysis in the PIK3CA mutant cohort .................................................. 76 
Table 3-11 
Simulated probabilities to stop for efficacy at 1st interim, 2nd 
interim, or final OS analysis in the PIK3CA mutant cohort .................. 77 
Table 3-12 
Simulated probabilities to stop for efficacy at 1st interim, 2nd 
interim, or final OS analysis in the PIK3CA non-mutant cohort .......... 79 
Table 3-13 
Estimated timelines for interim and final PFS analyses in the 
PIK3CA mutant cohort .......................................................................... 84 
Table 3-14 
Operating characteristics for PoC criteria in PIK3CA non-mutant 
cohort..................................................................................................... 85 
Table 3-15 
Estimated timelines for interim and final OS analyses in the 
PIK3CA mutant cohort .......................................................................... 86 
Table 3-16 
Estimated timelines for interim and final OS analyses in the 
PIK3CA non-mutant/ cohort ................................................................. 87 
Table 4-1 
Operating characteristics for PFS futility criteria in the PIK3CA 
mutant cohort ........................................................................................ 96 
Table 4-2 
Operating characteristics for PoC criteria in PIK3CA non-mutant 
cohort..................................................................................................... 98 
Table 4-3 
Local versus central disease progression assessments .......................... 99 
 


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List of figures 
Figure 1-1 
Study design .......................................................................................... 16 
 
 
 


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List of abbreviations 
AE 
Adverse event 
AESI 
Adverse event of Special Interest 
ATC 
Anatomical Therapeutic Chemical 
BIRC 
Blinded Independent Review Committee 
BOR 
Best overall response 
 
 
CI 
Confidence Interval 
CBR 
Clinical benefit rate 
CR 
Complete response 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRS 
Case retrieval strategy 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
ΔQTcF 
Change from baseline in QTcF 
DAR 
Dosage administration Record 
DI 
Dose Intensity 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EORTC QLQ-
C30 
European Organisation for Research and Treatment of Cancer’s core quality 
of life questionnaire 
EOT 
End of treatment 
 
 
FAS 
Full analysis set 
HER2 
Human epidermal growth factor receptor 2 
HR.  
Hazard Ratio 
HRQoL  
Health-Related Quality of Life 


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IRT 
Interactive Response Technology 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI  
Magnetic resonance imaging 
NMQ 
Novartis MedDRA queries 
NSAI 
Non-steroidal aromatase inhibitor  
ORR  
Overall response rate  
OS 
Overall survival  
PAS 
Pharmacokinetic analysis set 
PD 
Progressive disease 
PDI 
Planned dose intensity 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PPS 
Per Protocol Set 
PR 
Partial response 
PRO 
Patient Reported Outcome 
PS 
Performance Status 
PT 
Preferred term 
QTcF 
QT interval corrected by Fridericia method 
RDI 
Relative dose intensity 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SD 
Standard deviation 
SMQ 
Standardized MedDRA queries 
SOC 
System organ class 
TA 
Tumor assessment 
TEAE 
Treatment-emergent adverse event 
UNK 
Unknown 
 


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1 
Introduction 
This document describes the detailed statistical methodology to be used for the Clinical Study 
Report (CSR) for the analysis of study CBYL719C2301. 
The content of this SAP is based on protocol CBYL719C2301 Amendment 5. All decisions 
regarding analysis, as defined in the SAP document, have been made prior to database lock and 
unblinding of the study data. 
This section provides an introduction to the document and describes the study design and 
objectives as outlined in the Clinical Study Protocol. Section 2 provides definitions and the 
general methodology that will be used to analyze data. Section 3 describes the analyses and 
summaries that will be produced. Finally, Section 4 provides more detailed specifications on 
the statistical methodology used. 
CSR deliverables (shells for tables, figures, listings) and further programming specifications 
are described in SAP documents ”Tables, Figures and Listings (TFL) Shells” and 
“Programming Dataset Specifications”, respectively. 
1.1 
Study Design 
This is a phase III, randomized, double-blind, placebo-controlled study of BYL719 (alpelisib) 
or placebo in combination with fulvestrant for the treatment of men and premenopausal women 
with hormone receptor positive, HER2-negative, advanced breast cancer which progressed on 
or after aromatase inhibitor treatment.  
A total of approximately 560 patients will be enrolled; in which approximately 340 and 220 
patients will be enrolled respectively to each of two cohorts: PIK3CA mutant and PIK3CA non-
mutant. Within each of these two cohorts, randomization will be stratified by: 
1. Lung and/or liver metastases (yes versus no) 
2. Previous treatment with any CDK4/6 inhibitor (yes versus no) 
PFS in the PIK3CA mutant cohort, as assessed by the local radiologists/investigators and using 
RECIST 1.1 criteria will be the primary endpoint. PFS in the PIK3CA mutant cohort as assessed 
through Blinded Independent Review Committee (BIRC) using an audit-based approach will 
be used for supportive evidence of the primary efficacy endpoint. 
An independent Data Monitoring Committee (DMC) will monitor semi-blinded safety and 
efficacy data during the trial. A separate DMC SAP specifies the analyses to be performed for 
the DMC reviews.  
One futility interim analysis is planned for the primary efficacy endpoint (PFS) in the PIK3CA 
mutant cohort at the expected time given in Section 3.12.1. There is no intention to stop for 
superiority at this interim analysis. Another interim analysis that allows the study to stop for 
superior efficacy is planned in the PIK3CA mutant cohort, after all patients have been 
randomized and approximately 75% of the total PFS events have been documented, as per 
local assessments. If PFS is statistically significant, interim analyses for OS in the PIK3CA 
mutant cohort will also be conducted as detailed in Section 3.12.2. 
Overall survival in the PIK3CA mutant cohort is a key secondary endpoint in this study and 
will be analyzed provided the primary endpoint PFS is statistically significant.  The type I error 


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rate  for OS will be controlled by using a separate Lan-DeMets (O’Brien-Fleming) alpha 
spending function for OS, independent of the Haybittle-Peto boundary used for the primary 
efficacy analysis of PFS. 
PFS and Overall survival in the PIK3CA non-mutant cohort are secondary endpoints in this 
study. OS will be tested provided the PFS is statistically significant in this cohort. 
The futility and efficacy interim analyses for PFS in the PIK3CA mutant cohort and the final 
PFS analysis in the PIK3CA non-mutant cohort will be performed by an independent statistician 
external to Novartis and the results will be provided to the DMC by the independent statistician. 
Novartis will be unblinded if the study stops early for futility or efficacy in the PIK3CA mutant 
cohort or at the time of the final PFS analysis in the PIK3CA mutant cohort. Further details 
regarding the group sequential design are provided in Section 4.5.  
The study design is summarized in Figure 1-1. 
Figure 1-1 
Study design 
 
 
 
1.2 
Objectives 
The study objectives and corresponding endpoints as specified in the protocol are provided in 
Table 1-1. 
Table 1-1 
Study objectives 
Objective 
Endpoint 
Analysis 
Primary 
 
Refer to Section 
To determine whether treatment with 
alpelisib in combination with fulvestrant 
prolongs PFS compared to treatment with 
placebo in combination with fulvestrant for 
patients with PIK3CA mutant status 
PFS based on local radiology 
assessments and using RECIST 1.1 
criteria in the PIK3CA mutant  cohort  
3.8.1 
Key secondary 
 
Refer to Section 
To determine whether treatment with 
alpelisib in combination with fulvestrant 
OS in the PIK3CA mutant cohort  
3.8.2.1 


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Objective 
Endpoint 
Analysis 
prolongs overall survival (OS) compared to 
treatment with placebo in combination with 
fulvestrant for patients with PIK3CA 
mutant status  
Other secondary 
 
Refer to Section 
To establish proof of concept of treatment 
benefit with alpelisib in combination with 
fulvestrant with respect to PFS for patients 
with PIK3CA non-mutant status 
PFS based on local radiology 
assessments and using RECIST 1.1 
criteria in the PIK3CA non-mutant cohort 
3.8.2.2 
To evaluate the two treatment arms with 
respect to OS for patients with PIK3CA 
non-mutant status 
OS in the PIK3CA non-mutant cohort 
3.8.2.3 
● To evaluate the two treatment arms 
and cohorts of interest with respect to 
overall response rate (ORR), clinical 
benefit rate. 
ORR and CBR in each of the PIK3CA 
mutant and non-mutant cohorts 
 
3.8.2.5 
3.8.2.6 
● To evaluate the two treatment arms 
and cohorts of interest with respect to time 
to deterioration of ECOG performance 
status. 
Time to definitive deterioration of the 
ECOG performance status of the score 
from baseline in each of the PIK3CA 
mutant and non-mutant cohorts 
3.8.2.8 
● To evaluate the safety and tolerability 
of alpelisib in combination with fulvestrant  
- Type, frequency and severity of adverse 
events per CTCAEv4.03 
- Type, frequency and severity of 
laboratory toxicities per CTCAEv4.03 
 
3.9 
● To evaluate change in global health 
status/QOL in the two treatment arms and 
cohorts of interest 
- Time to 10% deterioration in the global 
health status/QOL scale score of the 
EORTC QLQ-C30 
- Change from baseline in the global health 
status/QOL scale score of the EORTC 
QLQ-C30 
in each of the PIK3CA mutant and non-
mutant cohorts 
3.8.2.9 


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Objective 
Endpoint 
Analysis 
● To characterize the pharmacokinetics 
(PK) of fulvestrant and alpelisib when 
given in combination with fulvestrant.  
Summary statistics for PK: plasma 
concentration-time profiles of alpelisib 
given in combination with fulvestrant and 
appropriate individual PK parameters 
based on population PK model 
Summary statistics of fulvestrant trough 
plasma concentrations in each treatment 
arm (alpelisib/placebo) 
3.10 
● 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 and using RECIST 1.1 
criteria for each of (i) patients with PIK3CA 
mutant status and (ii) patients with PIK3CA 
non-mutant status as measured in ctDNA 
at baseline. 
3.8.2.7 
 
 
Refer to Section 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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2 
Definitions and general methodology 
2.1 
Definitions 
2.1.1 
Study drug and study treatment 
Study drug refers to alpelisib, alpelisib matching placebo or fulvestrant.  
Study treatment refers to alpelisib in combination with fulvestrant or alpelisib matching 
placebo in combination with fulvestrant. 
Alpelisib matching placebo will be referred to as “placebo” in the remainder of this document. 
2.1.2 
Date of first administration of study drug 
The date of first administration of study drug is derived as the first date when a non-zero dose 
of study drug (alpelisib/placebo or fulvestrant) is administered.  
For the sake of simplicity, the date of first administration of study drug is referred to start date 
of study drug. Start date of study drug is defined for each drug which is part of study treatment. 
The date of first administration for alpelisib/placebo or fulvestrant is recorded on the 
corresponding “Dosage Administration Record” (DAR) eCRF. 
Note: Dates from “DAR –PK sampling” eCRF will not be used for this derivation. 
2.1.3 
Date of last administration of study drug 
The date of last administration of study drug is defined as the last date when a non-zero dose of 
study drug is administered and recorded on the DAR eCRF.  
This date will also be referred as last date of study drug. Last date of study drug is defined for 
each drug which is part of study treatment. 
The date of last administration for alpelisib/placebo or fulvestrant is recorded on the 
corresponding “DAR” eCRF. 
Note 1: Dates from “DAR –PK sampling” eCRF will not be used for this derivation. 
Note 2: Last date of study drug exposure may not be the same as the last date of study drug (see 
Section 2.1.6). 
2.1.4 
Date of first administration of study treatment 
The date of first administration of study treatment is derived as the first date when a non-zero 
dose of any component of the study treatment (alpelisib/placebo or fulvestrant) is administered  
For the sake of simplicity, the date of first administration of study treatment will also be referred 
as start date of study treatment.  
Note: Dates from ‘DAR – PK sampling’ eCRF will not be used for this derivation. 
For example: if the first dose of alpelisib/placebo is taken on 05JAN2011, and first dose of 
fulvestrant is taken on 03JAN2011, then the date of first administration of study treatment is 
03JAN2011. 


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2.1.5 
Date of last administration of study treatment 
The date of last administration of study treatment is defined as the last date when a non-zero 
dose of any component of the study treatment (alpelisib/placebo or fulvestrant) is administered.  
Note: Dates from ‘DAR – PK sampling’ eCRF will not be used for this derivation. 
For example: if the last dose of alpelisib/placebo is taken on 15APR2011, and the last dose of 
fulvestrant is taken on 17APR2011, then the date of last administration of study treatment is on 
17APR2011. 
2.1.6 
Last date of exposure to study drug/treatment  
The study treatment schedule is organized in cycles of 28 days. 
The last date of exposure to study treatment is derived to be the latest date of the last date of 
exposure to alpelisib/placebo and fulvestrant. The last date of exposure to alpelisib/placebo 
and last date of exposure to fulvestrant will be derived as follows.  
Alpelisib/placebo is administered daily on a continuous once daily dosing schedule. Hence, 
the last date of exposure to alpelisib/placebo is the date of last administration of 
alpelisib/placebo. 
Fulvestrant is administered on  
• Cycle 1 Day 1  
• Cycle 1 Day 15, and  
• The first day of every cycle thereafter (e.g. Cycle 2 Day 1, Cycle 3 Day 1 etc.)  
Due to the irregularly spaced fulvestrant dose administration, the last date of exposure to 
fulvestrant is calculated using a different method depending on the cycle at which fulvestrant 
was discontinued: 
1.  If the patient discontinues fulvestrant between Cycle 1 Day 1 and Cycle 1 Day 14 
inclusive: 
• The last date of exposure to fulvestrant is calculated as (last date of administration of 
fulvestrant) + (length of time interval to next scheduled dose - 1) i.e. [last date of 
fulvestrant administration+ (14-1)]. 
• If the patient died or was lost to follow-up within last date of administration of 
fulvestrant + 13 days, the last date of exposure to fulvestrant is the date of death or the 
date of last contact, respectively. 
2.  If the patient discontinues fulvestrant between Cycle 1 Day 15 and Cycle 2 Day 1: 
• The last date of exposure to fulvestrant is calculated as (last date of administration of 
fulvestrant) + (length of time interval - 1) i.e. [last date of fulvestrant administration+ 
(14-1)]. 
• If the patient died or was lost to follow-up within last date of administration of 
fulvestrant + 13 days, the last date of exposure to fulvestrant is the date of death or the 
date of last contact, respectively. 
3.  If the patient discontinues fulvestrant on or after Cycle 2 Day 1, then: 


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• the last date of exposure to fulvestrant is calculated as (last date of administration of 
fulvestrant) + (length of time interval - 1) i.e. [last date of fulvestrant administration+ (28-
1)]. 
• If the patient died or was lost to follow-up within last date of administration of fulvestrant 
+ 27 days, the last date of exposure to fulvestrant is the date of death or the date of last 
contact, respectively. 
 
‘Date of last administration of study drug’ and ‘Date of last contact’ are defined in sections 
2.1.3 and 2.1.10 respectively. 
2.1.7 
Study day 
The study day, describes the day of the event or assessment date, relative to the reference start 
date (randomization date or start date of study treatment).  
The reference start date is designated as Study Day 1. Study Day –1 is the day that precedes 
Day 1. Study Day 0 is not defined. Study day is not to be used in numerical computations, for 
example in calculating exposure. 
The study day will be calculated as follows: 
• The date of the event (visit date, onset date of an event, assessment date etc.) minus 
reference start date + 1 if the event is on or after the reference start date. 
• The date of the event (visit date, onset date of an event, assessment date etc.) minus 
reference start date if the event precedes the reference start date. 
The reference start date for all safety assessments (e.g. adverse event onset, laboratory 
abnormality occurrence, vital sign measurement, dose interruption etc.) and PK data will be the 
start date of study treatment.  
The reference start date for all efficacy assessments (e.g. tumor assessment, death, ECOG 
performance status, PRO) will be the randomization date.  
For any non-safety screening assessments or events such as baseline disease characteristics or 
medical history (e.g., time since diagnosis of disease) 
 that occurred prior to 
randomization the reference start date will be the randomization date. 
The study day will be displayed in the data listings. 
2.1.8 
Baseline 
Baseline is the result of an investigation describing the “true” uninfluenced state of the patient, 
defined as the period from the date of signing any informed consent document to the start date 
of study treatment or the date of randomization. Assessments, specified to be collected post-
dose on the first date of treatment are not considered as baseline values. 
For efficacy evaluations, the last non-missing assessment, including unscheduled assessments 
on or before the date of randomization is taken as “baseline” value or “baseline” assessment. 
For RECIST-based endpoints including PFS, ORR, CBR,
 a window of 7 days from the start of study treatment will be allowed, i.e. the 


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investigator/BIRC-reported responses will be maintained and baseline considered valid if the 
baseline assessment is within 7 days of treatment start date. In the context of baseline definition, 
the efficacy evaluations also include ECOG performance status and PRO. If a patient has 2 
ECOG PS (or PRO) values at the same date, the worst ECOG PS value will be taken as 
‘baseline’.  
For safety evaluations (i.e. laboratory assessments, ECGs and vital signs), the last available 
assessment, including unscheduled assessments on or before the start date of study treatment 
(Cycle 1 Day 1) as described in Section 2.1.4 is taken as “baseline” value or ‘‘baseline” 
assessment.  
In rare cases, where multiple safety measurements meet the baseline definition, with no further 
flag or label that can identify the chronological order, then the following rule should be applied: 
If values are from central and local laboratories, the value from central assessment should be 
considered as baseline. If multiple values are from the same laboratory (local or central) or 
collected for ECGs or vital signs, then the last value should be considered as baseline. 
If patients have no value as defined above, the baseline result will be missing. 
 
2.1.9 
On-treatment assessment/event 
Safety summary tables and selected summaries of deaths will summarize only on-treatment 
assessments/events.  
An on-treatment adverse event is defined as any adverse event reported in the following time 
interval (including the lower and upper limits): 
• date of first administration of study treatment; date of last administration of study 
treatment + 30 days 
In addition, an AE that started in the screening phase and was ongoing in the treatment phase 
will not be summarized unless it has worsened in severity.   
An on-treatment assessment is defined as any assessment performed after the date of first 
administration of study treatment i.e. assessments performed in the following time interval 
(including the lower and upper limits): 
• date of first administration of study treatment + 1; date of last administration of study 
treatment + 30 days  
If the last date of study treatment is missing, on-treatment assessments/events include any 
assessment/event recorded in the database and which occur after the start date of study 
treatment. 
Data listings will include all assessments/events, flagging those which are not on-treatment 
assessments/events. 
Note: The date of first administration of study treatment and the date of last administration of 
study treatment are defined in sections 2.1.4 and 2.1.5, respectively. 


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2.1.10 
Last contact date 
The last contact date is derived for patients not known to have died at the analysis cut-off date 
based on the latest date among the following: 
• Assessment dates (e.g. laboratory, vital signs, ECOG performance status/PRO, ECG, 
cardiac imaging, tumor imaging, PK assessment, EOT completion etc.). 
• Medication and procedures dates including study medication, concomitant 
medications, surgical and medical procedures, antineoplastic therapies administered 
after study drug discontinuation (with non-missing medication/procedure term). 
• Adverse event start and end dates (with non-missing verbatim AE term present) 
• “Last known date patient alive” collected on the “Survival information” eCRF  
• Study treatment start/end date  
• Randomization date  
The last contact date is defined as the latest complete date from the above list or the cut-off 
date, whichever comes first. The cut-off date will not be used for last contact date, unless the 
patient was seen or contacted on that date. No date post cut-off date will be used. Completely 
imputed dates (e.g. the analysis cut-off date programmatically imputed to replace the missing 
end date of a dose administration record) will not be used to derive the last contact date. Partial 
date imputation is allowed for event (death)/censoring is coming from ‘Survival information’ 
eCRF. 
The last contact date is used for censoring of patients in the analysis of overall survival and 
analyses for time to onset of adverse events.  
2.1.11 
Screening failure 
Screening failures are patients who have signed informed consent and failed screening criteria 
in the study. These patients will not be enrolled into the treatment phase.  
2.1.12 
Time Units 
A month length is 30.4375 days (365.25 / 12). If duration is to be reported in months, duration 
in days is divided by 30.4375.  If duration is to be reported in years, duration in days will be 
divided by 365.25. 
2.2 
Data included in the analysis 
A unique cut-off date will be established after the targeted number of events for each of the 
planned interim and final efficacy analyses has been documented.  
For the primary analysis CSR, all efficacy analyses will be based on separate cut-off dates 
determined for each of the PIK3CA mutant and non-mutant cohorts, based on the target number 
of PFS events specified in Section 3.12 (i.e. final PFS analyses data cut-off date for PIK3CA 
non-mutant cohort; interim efficacy or final PFS analyses data cut-off date for PIK3CA mutant 
cohort). For the primary analysis CSR, all safety analyses for both PIK3CA cohorts will be 
based on the data cut-off date for the interim efficacy or final PFS analysis in the PIK3CA 
mutant cohort. 


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For each of the analyses, all statistical analyses will be performed using all data collected in the 
database up to the data cut-off date. All data with an assessment date or event start date (e.g. 
vital sign assessment date or start date of an adverse event) prior to or on the cut-off date will 
be included in the analysis. Any data collected beyond the cut-off date will not be included in 
the analysis and will not be used for any derivations. 
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘continuing at the cut-off date’. The same rule will be applied to events starting 
before or on the cut-off date and not having documented end date. This approach applies, in 
particular, to adverse event and concomitant medication reports. For these events, the end date 
will not be imputed and therefore will not appear in the listings. 
Interim review of safety data will be provided in each cohort as well as pooled across both 
cohorts, at each DMC meeting where safety data is reviewed. It is planned that the first DMC 
safety review meeting will be based on at least 2 months’ exposure data from approximately 
the first fifty patients, or available data after at least 6 months after the first patient is 
randomized, whichever date occurs first. Subsequent formal safety reviews will be based on 
data available every six months (+/-30 days window) after the first meeting, unless otherwise 
requested by the DMC. 
Withdrawal of Informed Consent 
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis or analysis data sets.  The 
date on which a patient withdraws full consent is recorded in the eCRF. 
In addition, third party data (i.e., laboratory samples) collected on the date of withdrawal of 
consent but analyzed by the local/central laboratory after consent was withdrawn will also be 
excluded from analysis datasets and outputs if local regulations do not permit the usage of such 
data. In this trial, laboratory samples with a collection date on the date of withdrawal consent 
have been identified for patients at sites in Germany, Italy, USA and Hungary.  Per local 
regulations, such samples from patients in Germany and Italy need to be excluded from datasets 
and analyses, whereas those from patients in the USA and Hungary can be included. As the 
laboratory analysis date is not included as a variable in the external data transfer file from the 
laboratory, a conservative approach will be adopted where we assume that, for samples 
collected on the date of withdrawal of consent,  the analysis of the samples was conducted after 
consent was withdrawn and this was confirmed by the central laboratory. 
2.2.1 
Pharmacokinetic (PK) data review 
No PK data review is planned by DMC. 
2.3 
Analysis sets 
2.3.1 
Full analysis set (FAS) 
The Full analysis set (FAS) comprises all patients who were randomized to study treatment 
(alpelisib + fulvestrant or matching placebo + fulvestrant).  According to the intent to treat 
principle, patients will be analyzed according to the cohort, treatment and strata they have been 


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assigned to during the randomization procedure. FAS will be the main population for analyses 
of patient disposition, demographics and other baseline characteristics. The FAS will be the 
primary population for the efficacy analyses. Patients who do not provide main study informed 
consent will be excluded from the FAS. 
2.3.2 
Safety set 
The Safety Set includes all patients who received any study treatment. Patients will be analyzed 
according to the study treatment received, where treatment received is defined as the 
randomized treatment if the patient took at least one dose of that treatment or the first treatment 
received if the randomized treatment was never received.  
2.3.3 
Per protocol set 
The Per-protocol set (PPS) comprises all patients in the FAS for the PIK3CA mutant cohort 
who do not have any protocol deviations that could confound the interpretation of the primary 
analyses conducted on the FAS. The PPS will be used to perform sensitivity analysis for the 
primary efficacy endpoint (i.e. PFS in the PIK3CA mutant cohort) if the primary endpoint is 
statistically significant. Patients with any of the following protocol deviations will be excluded 
from the PPS. 
Exclusion Criteria for Per Protocol Set 
• Patient did not provide main study informed consent  
• Patient does not have HER2 negative breast cancer (Protocol Inclusion Criterion 7) 
• Patient does not have histologically and/or cytologically confirmed diagnosis of ER 
and/or PgR positive breast cancer by local laboratory  (Protocol Inclusion Criterion 6) 
• Patient is female and not post-menopausal (Protocol Inclusion Criterion 4) 
• Patient does not have at least one measureable lesion or at least one predominantly lytic 
bone lesion (Protocol Inclusion Criterion 8) 
• Patient is newly diagnosed with endocrine naive advanced breast cancer (Protocol 
Inclusion Criterion 9) 
• Patient relapsed on/or within 12 months from completion of (neo) adjuvant endocrine 
therapy and then subsequently progressed after one line of endocrine therapy (either an 
antiestrogen or an aromatase inhibitor) for metastatic disease (Protocol Inclusion 
Criterion 9) 
• Patient has no radiological or objective evidence of recurrence or progression (i.e.: 
clinical progression not allowed) (Protocol Inclusion Criterion 5) 
• Patient has no recurrence or progression of disease during or after aromatase inhibitor 
therapy (Letrozole, anastrozole, exemestane) (Protocol Inclusion Criterion 10) 
• Patient does not have an ECOG status of 0 or 1 (Protocol Exclusion Criterion 11) 


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• Patient has symptomatic visceral disease or any disease burden that makes the patient 
ineligible for endocrine therapy per the investigator's best judgment (Protocol Exclusion 
Criterion 1) 
• Patient has received prior treatment with chemotherapy (except for neoadjuvant/ 
adjuvant chemotherapy), or any PI3K, mTOR or AKT inhibitors (Protocol Exclusion 
Criterion 2) 
• Patient is concurrently using other anti-cancer therapy (Protocol Exclusion Criterion 5) 
• Patient is currently receiving any of the following substances and cannot be 
discontinued 7 days prior to Cycle 1 Day 1: Herbal preparations / medications 
• Patient has already been treated by Fulvestrant (Protocol Exclusion Criterion 2) 
Other Criteria 
• Patient enrolled into the wrong cohort, either: 
• Patient with PIK3CA non-mutant status (as per confirmation by Novartis-designated 
laboratory) enrolled into PIK3CA mutant cohort 
• Patient with unknown PIK3CA mutation status (as per confirmation by Novartis-
designated laboratory) enrolled into  the PIK3CA mutant cohort 
• Patient did not take any study treatment 
2.3.4 
Pharmacokinetic (PK) set 
The PK Analysis Set (PAS) will consist of all patients who receive at least one dose of study 
treatment (alpelisib/placebo or fulvestrant) and have at least one post-treatment concentration 
measurement. 
2.3.5 
Patient classification 
Patients may be excluded from the analysis sets defined above based on the protocol deviations 
entered in the database and/or on specific subject classification rules as defined in Table 2-1. 
Table 2-1 
Patient classification based on protocol deviations and non-protocol 
deviation criteria 
Analysis set 
Protocol deviations leading 
to exclusion 
Non-protocol deviation 
criteria leading to exclusion 
FAS  
No written informed consent 
NA 
Safety set 
No written informed consent 
No study treatment taken 
Per Protocol set 
Any major protocol deviation as 
listed in definition of per 
protocol set 
Patient not evaluable for FAS 
 


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2.4 
Implementation of RECIST 
Response and progression evaluation will be performed according to the Novartis RECIST 
guideline (as described in detail in Appendix 3 of the Clinical Study Protocol), which is based 
on the RECIST 1.1 guidelines (Eisenhauer et al 2009). The text below gives instructions and 
rules to provide details needed for programming. 
2.4.1 
Overall lesions response for patients with only non-measurable 
lesions at baseline 
For patients with non-measurable lesions only at baseline, the overall lesion response will be 
based solely on non-target lesion response or an occurrence of a new lesion. Non-measurable 
lesions will be entered as non-target lesions. Therefore, the best overall response is determined 
from non-target lesion response and presence of new lesions (refer to Table 3-1 in Section 3.2.8 
of RECIST Novartis guidelines as described in detail in Appendix 3 of the Clinical Study 
Protocol). 
Patients with at least one predominantly lytic bone lesion but not having measurable disease per 
RECIST 1.1 are allowed to enter the study and the same rules as specified above apply for these 
patients. 
Note: Pathologic fracture, new compression fracture, or complications of bone metastases will 
not be considered as evidence of disease progression, unless there is unequivocal progression 
of existing non-target lesions or a new lesion. 
2.4.2 
Disease progression 
Progressive disease should only be assigned if it is confirmed by an assessment method as per 
RECIST 1.1 guidelines (e.g. radiologic scan, photos for skin lesions, etc.). If a new lesion is 
detected using an objective assessment method other than radiologic scan then it should also be 
entered on the ‘New lesion’ RECIST CRF with appropriate method. Discontinuation due to 
disease progression or death due to study indication, without corresponding supportive data in 
the RECIST CRF (as defined above), will not be considered as progressive disease in the 
calculation of best overall response and in the analysis of PFS. 
2.4.3 
Best overall response (BOR) 
The evaluation of BOR will be assessed using RECIST 1.1. The definitions and the details on 
the derivation of BOR are given in Appendix 3 of the study protocol.  
The best overall response will usually be determined from response assessments undertaken 
while on treatment. In addition, only tumor assessments performed before the start of any 
further anti-neoplastic therapies (i.e. any additional secondary anti-neoplastic therapy with the 
exception of palliative radiotherapy) will be considered in the assessment of BOR. 
Further anti-neoplastic therapies will be identified from the data collected on ‘Antineoplastic 
therapy since discontinuation of study treatment- Medication’ eCRF and “Antineoplastic 
Therapy - Radiotherapy” eCRF.  
Palliative radiotherapy is the only setting of radiotherapy allowed during a study. It will not be 
considered as an antineoplastic therapy for the assessment of BOR.  


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Continuation of fulvestrant monotherapy as 1st new anti-neoplastic therapy after end of 
treatment without prior PD and collected in the ‘antineoplastic therapy since discontinuation of 
study treatment- Medication’ eCRF, will not be considered as an anti-neoplastic therapy for the 
assessment of BOR. 
Since the tumor assessments are performed every 8 weeks (+/- 7 days) after randomization 
during the first 18 months and every 12 weeks (+/- 7 days) thereafter, the standard definition of 
a best overall response evaluation of “stable disease”, “progressive disease” or “unknown” 
given in the Appendix 3 of the study protocol requires an adjustment. Best overall response for 
each patient 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 
• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) 
• SD = at least one SD assessment (or better) > 7 weeks after randomization date (and not 
qualifying for CR or PR).  
• Non-CR/non-PD = at least one non-CR/non-PD assessment (or better) > 7 weeks after 
randomization date (and not qualifying for CR or PR). This applies only for patients 
with non-measurable disease alone at Baseline.  
• PD = progression ≤ 17 weeks after randomization date (and not qualifying for CR, PR, 
SD or non-CR/non-PD). 
UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD or non-
CR/non-PD after more than 7 weeks or early progression within the first 17 weeks). 
Patients with ‘unknown’ BOR will be summarized by reason for having unknown status. The 
following reasons will be used: 
• No valid post-baseline assessment 
• All post-baseline assessments have overall lesion response UNK 
• New anti-neoplastic therapy started before first post-baseline assessment 
• SD or non-CR/non-PD too early   
• PD too late  
Note 1: A SD or Non-CR/Non-PD is considered as “SD too early”’ if the SD or Non-CR/Non-
PD is documented within first 7 weeks after randomization date.  
Note 2: A PD is considered as “PD too late” if the first documentation of PD is recorded more 
than 17 weeks after randomization date with no qualifying CR, PR or SD or Non-CR/Non-PD 
in between.   
Note 3: Special (and rare) cases where BOR is “unknown” due to both too early SD and too 
late PD will be classified as “SD too early”. 


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2.4.4 
Change in imaging modality 
Per RECIST 1.1, 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 change in technique (e.g. from CT 
to MRI, or vice-versa), or a change in any other imaging modality. A change in methodology 
will result by default in an UNK (unknown) calculated overall lesion response assessment. 
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. 
  
2.4.5 
Determination of missing adequate assessments 
The term ‘missing adequate tumor assessment’ is defined as a tumor assessment not done or 
tumor assessment with overall lesion response ‘Unknown’. For the sake of simplicity, a 
‘missing adequate tumor assessment’ will also be referred to as a ‘missing assessment’.  
As described in Table 14-9 in Appendix 3 of the study protocol, the PFS censoring and event 
date options depend on the presence and the number of missing tumor assessments (TAs). In 
the analysis of PFS, an event occurring after two or more missing assessments or non-adequate 
tumor assessments is censored at the last adequate tumor assessment.  
An exact rule to determine whether there is no, one or two missing TAs is therefore needed. 
This rule is based on the time interval between the last adequate tumor assessment (LATA) date 
and the event date. The scheduled date of tumor assessments (in weeks from randomization), 
protocol specified windows for tumor assessments, and the thresholds for LATA to belong to a 
visit can be found in the following table. 
Schedule for tumor assessment and time windows 
Assessment 
schedule 
Scheduled date 
– 1 week 
Scheduled 
date 
(weeks 
from 
randomization) 
Scheduled 
date 
+1 week 
Threshold 
(weeks)* 
Every 8 
weeks 
for 
the 
first 18 
months 
Baseline 
0 
0^ 
1 
n/a 
C3D1 
7 
8 
9 
12 
C5D1 
15 
16 
17 
20 
C7D1 
23 
24 
25 
28 
C9D1 
31 
32 
33 
36 
C11D1 
39 
40 
41 
44 
C13D1 
47 
48 
49 
52 
C15D1 
55 
56 
57 
60 
C17D1 
63 
64 
65 
68 
C19D1 
71 
72 
73 
78 
C22D1 
83 
84 
85 
90 


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Every 
12 
weeks 
after 18 
months 
C25D1 
95 
96 
97 
102 
C28D1 
107 
108 
109 
114 
C31D1 
119 
120 
121 
126 
* The mid-point between current and next visit (except for baseline) and the upper limit for LATA to 
be matched to a certain scheduled assessment, e.g. if LATA is at week 13, this is after threshold for 
C3D1 and before that for C5D1, so the matching scheduled assessment is C5D1. 
^ Day of randomization is taken as 0. 
 
To calculate the number of missing tumor assessments, the LATA before an event is matched 
with a scheduled tumor assessment using the time window in the table above (essentially 
whichever scheduled assessment it is closest to). 
 Two additional thresholds, D1 and D2 are calculated for that scheduled assessment based on 
the protocol-specified schedule and windows. 
• The threshold D1 is defined as the protocol-specified time interval between the TAs plus 
2x the protocol-allowed time window around the assessments. 
• The threshold D2 is defined as twice the protocol-specified time interval between the 
TAs plus 2x the protocol-allowed time window around the assessments (except when 
the matched scheduled tumor assessment is C17D1, in which case D2 is defined in Rule 
2 below). 
Since there is a change of schedule for tumor assessments after 18 months, D1 and D2 are 
defined differently depending on when LATA occurs.   
Rule 1: if LATA happens within 60 weeks from randomization (the matched scheduled tumor 
assessment is C15D1 or before). For example, D1=8+2=10 weeks and D2=2*8+2=18 weeks. 
Rule 2: if LATA happens after 60 weeks but within 68 weeks from randomization (the matched 
scheduled tumor assessment is C17D1). For example, D1=8+2=10 weeks and D2=8+12+2=22 
weeks. 
Rule 3: if LATA happens after 68 weeks from randomization (the matched scheduled tumor 
assessment is C19D1 or later). For example, D1=12+2=14 weeks and D2=2*12+2=26 weeks. 
The number of missing events is defined as: 
• An event after LATA+D1 weeks will be considered as having >=1 missing assessment 
• An event after LATA+D2 weeks will be considered as having >=2 missing assessments 
. 
The same definition of D2 will be used to determine the PFS censoring reason.  If there is no 
post-baseline adequate tumor assessment available (before an event or a censoring reason 
occurred), the randomization date will be used to compute the interval.  
If the time interval between the last adequate TA date and the earliest of the following dates is 
smaller or equal to D2 days: 


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Analysis cut-off date  
Date of consent withdrawal 
Visit date of study treatment discontinuation due to lost to follow-up or end of post-treatment 
follow-up discontinuation due to lost to follow-up. 
Then the PFS censoring reason will be respectively: 
• ‘Ongoing’ 
•  ‘Withdrew consent’  
• ‘Lost to follow-up’ 
However if the time interval is larger than D2 days with no event then the PFS censoring reason 
will always default to ‘Adequate assessment no longer available’.  If the time interval between 
the last adequate tumor assessment date and the PFS event date is larger than D2 then the patient 
will be censored and the censoring reason will be 'Event documented after two or more missing 
tumor assessments'. 
2.4.6 
No baseline tumor assessments 
As specified in Table 14-9 in Appendix 3 of the study protocol, since the timing of disease 
progression cannot be determined for patients with missing baseline tumor assessment, these 
patients are censored in the PFS analysis at the date of randomization. This rule, however, only 
applies to the ‘progressive disease’ component of the PFS assessment. 
Patients without any baseline tumor assessment who die within D2 time interval (Section 2.4.5) 
from date of randomization will be counted as having an event in the analysis of PFS at the date 
of death. All deaths will be counted in the overall survival analysis regardless of presence or 
absence of the baseline tumor assessment. 
2.4.7 
Construction of waterfall graphs 
Waterfall graphs will be used to depict the anti-tumor activity. These plots will display the best 
percentage change from baseline in the sum of diameters of all target lesions for each patient. 
Only patients with measurable disease at baseline will be included in the waterfall graphs. 
Special consideration is needed for assessments where the target lesion response is CR, PR or 
SD, but the appearance of a new lesion or a worsening of non-target lesions results in an overall 
lesion response of PD. As a conservative approach, such assessments will not be considered for 
display as bars in the graph, since the percentage change in the sum of diameters of target lesions 
reflects the non-PD target lesion response, but the overall lesion response is PD. A patient with 
only such assessments will be represented by a special symbol (e.g. ) in the waterfall graph. 
Assessments with “unknown” target lesion response and assessments with unknown overall 
response will be excluded from the waterfall plots. Patients without any valid assessments will 
be completely excluded from the graphs. 
The total number of patients displayed in the graph will be shown and this number will be used 
as the denominator for calculating the percentages of patients with tumor shrinkage and tumor 
growth. Footnote will explain the reason for excluding some patients (due to absence of any 
valid assessment). 


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All possible assessment scenarios are described in Table 2-2. 
Table 2-2 
Assessments considered for calculation of best percentage change 
for waterfall graphs 
Case 
Target response 
Overall lesion 
response 
Calculate % change from baseline 
in sum of diameters? 
1 
UNK 
Any 
No, exclude assessment 
2 
Any 
UNK 
No, exclude assessment 
3 
CR/PR/SD 
PD 
No, flag assessment with  
4 
PD 
PD 
Yes 
5 
CR/PR/SD 
CR/PR/SD 
Yes 
Based on the above considerations, the following algorithm will be used to construct the graph: 
1. Select “valid” post-baseline assessments to be included, i.e. for each patient and each 
assessment repeat the following four steps. 
1.1. Check the target lesion response and overall lesion response. If at least one of them is 
UNK then exclude the whole assessment. Otherwise, go to step 1.2. 
1.2. Check the overall lesion response. If it is PD then go to step 1.3. Otherwise go to step 
1.4. 
1.3. Check target response. If it’s PD then go to step 1.4. Otherwise flag the assessment 
with  . 
1.4. Calculate the % change from baseline in target lesions.  
2. For each patient, go through all valid assessments identified in step 1 and find the 
assessment with best % change from baseline in target lesions. The “best” means best for 
the patient, i.e. the largest shrinkage or if a patient only has assessments with tumor 
growth take the assessment where the growth is minimal. 
3. Construct the waterfall graph displaying the best % change from baseline for each patient. 
Patients having only  flagged assessment(s) will be displayed separately.  
The graph will be constructed using the data from the investigator/local radiologist assessments. 
The best overall response (BOR) will be shown above each of the displayed bars in the graph, 
if the number of patients displayed in the graph is small enough for the labels to be legible. 
The order of the display from left to right will be as follows:  
1. Bars under the horizontal axis representing tumor shrinkage 
2. Bars above the horizontal axis representing tumor growth 
3. “Zero” bars with  symbol.   
For each of the 3 categories above, n (%) (where % uses the total number of patients displayed 
in the graph) will be displayed. If there are any patients with zero change they will be as a 
separate category following patients with tumor shrinkage. 


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3 
Statistical methods used in reporting 
3.1 
Enrollment status 
The following summaries will be provided in each cohort separately for the FAS overall, and 
for both treatment groups: 
1. Number (%) of patients who were randomized 
2. Number (%) of patients who received at least one dose of study treatment after 
randomization 
Number (%) of patients screened will be summarized by country and center.  In addition, the 
number (%) of patients randomized will be summarized by country, center and treatment group.  
For patients who are screen failures, the reasons for not completing screening will be 
summarized based on “Screening Phase Disposition” eCRF. 
3.2 
Background and demographic characteristics 
The FAS will be used for all baseline disease characteristics and demographic summaries and 
data listings. Summaries will be presented in each cohort separately for the FAS overall and for 
both treatment groups to assess baseline comparability. No inferential statistics will be 
provided. 
3.2.1 
Basic demographic and background data 
Descriptive statistics (mean, median, standard deviation, minimum, maximum) will be 
presented for continuous variables. The number and percentage of patients in each category will 
be presented for categorical variables.  This analysis will include the following: Age, gender, 
race, ethnicity, body mass index (BMI) and ECOG performance status at baseline.  
BMI at Baseline will be calculated using the following formula, i.e., BMI (kg/m2) = weight (kg) 
/ (height (cm)/100)**2) using weight at Baseline.  
A breakdown of the age distribution according to EUDRACT required categories will be 
provided: Adolescents (12-17 years), Adults (18-64 years), Elderly (>= 65 years). 
3.2.2 
Diagnosis and extent of cancer 
This analysis will include the following: primary site of cancer, predominant 
histology/cytology, histological grade, stage at initial diagnosis, stage at time of study entry, 
time since initial diagnosis of primary site, time from initial diagnosis to first 
recurrence/progression, time since most recent relapse/progression (where last treatment was in 
the (neo-)adjuvant or advanced disease settings), presence/absence of target and non-target 
lesions, number of metastatic sites, metastatic sites, HER2 receptor status, estrogen receptor 
(ER) status, progesterone receptor (PgR) status and hormone receptor (ER and/or PgR) status. 
Note: The variables ‘presence/absence of target and non-target lesions’ will be based on the 
data collected on target/non-target lesion assessment according to RECIST 1.1 (Appendix 3 of 
the protocol) and documented in the eCRF. 


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3.2.3 
Medical history 
Medical history and ongoing conditions, including cancer-related conditions, will be 
summarized and listed. Separate summaries will be presented for ongoing and historical 
medical conditions. The summaries will be presented by system organ class and preferred term. 
Medical history/current medical conditions are coded using the latest version of Medical 
Dictionary for Regulatory Activities (MedDRA) terminology available at the time of the 
analyses. The MedDRA version used for reporting will be specified in the CSR and as a footnote 
in the applicable tables/listings. 
3.2.4 
Prior anti-neoplastic therapy 
The number (%) of patients receiving prior anti-neoplastic medication, prior anti-neoplastic 
radiotherapy and prior anti-neoplastic surgery respectively will be summarized. 
Prior anti-neoplastic therapy will be summarized for each treatment group by therapy type 
(surgery, radiotherapy, chemotherapy, hormonal therapy etc.), disease setting, last therapy 
before study entry and its outcome (type of therapy, setting, and best response). Number of lines 
of prior medication therapy, prior chemotherapy, and prior hormonal therapy will be 
summarized by treatment group in any setting and in the metastatic setting. In addition, number 
of lines of prior chemotherapy in the neo-/adjuvant setting will also be summarized by treatment 
group.  
In addition, number (%) of patients who received any hormonal therapy (irrespective of given 
in combination with chemotherapy or biologic or targeted therapy), any aromatase inhibitors, 
any hormonal therapy other than aromatase inhibitors in any setting and in the metastatic 
setting, any prior CDK4/6 inhibitors will be summarized by treatment group. 
Patients exhibiting primary & secondary endocrine resistance will be summarized based on the 
ESMO (ref) definition, vs patients exhibiting endocrine sensitivity: 
• Primary resistance = Relapse < 24 months while on ET in adjuvant setting or 
progression < 6 months while on ET in metastatic setting 
• Secondary resistance = Relapse ≥ 24 months while on ET in adjuvant setting or relapse 
<12 months after end of ET in adjuvant setting or progression ≥ 6 months while on ET 
in metastatic setting 
• Endocrine sensitive = Relapse ≥ 12 months after end of ET in adjuvant setting or 
progression ≥ 12 months after end of ET in metastatic setting 
 
The patient population will be summarized additionally by presenting the number (%) of 
patients with: 
• relapsed with documented evidence of progression more than 12 months from 
completion of (neo)adjuvant endocrine therapy with no treatment for metastatic 
disease 
• relapsed with documented evidence of progression more than 12 months from 
completion of (neo)adjuvant endocrine therapy and then subsequently progressed with 


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documented evidence of progression while on or after only one line of endocrine 
therapy for metastatic disease 
• relapsed with documented evidence of progression while on (neo) adjuvant endocrine 
therapy or within 12 months from completion of (neo)adjuvant endocrine therapy with 
no treatment for metastatic disease 
• newly diagnosed advanced breast cancer, then relapsed with documented evidence of 
progression while on or after only one line of endocrine therapy 
The medication therapy type of any combination therapy will be classified based on the 
following order: chemotherapy, biologic therapy, targeted therapy, hormonal therapy. For 
example, a combination therapy of chemotherapy and hormonal therapy will be classified as 
chemotherapy. 
Last hormonal therapy prior to study entry will be summarized by type of aromatase inhibitors, 
anti-estrogen therapy, disease setting, duration of hormonal therapy in adjuvant setting and best 
overall response at last hormonal therapy in the metastatic setting.   
Last hormonal therapy refers to hormonal medication received in the last regimen. If multiple 
hormonal therapy medications are given as part of last regimen, then last hormonal therapy 
medications are selected based on the latest start date among the hormonal therapy medications. 
Standard imputation rules will be applied for dates of prior anti-neoplastic therapy (medication, 
radiotherapy and surgery). 
Separate listings will be produced for prior anti-neoplastic medications, radiotherapy, and 
surgery. 
 
 
 
3.3 
Protocol deviation summaries 
The number and percentage of patients in the FAS with any protocol deviation will be 
summarized by deviation category (as specified in the Study Specification Document). 
Protocol deviations leading to the exclusion from the Per Protocol Set will also be summarized.  
All protocol deviations will be listed. Summaries will be presented in each cohort separately 
for the FAS overall and for both treatment groups. 
Additional protocol deviation summaries will be provided to address the potential impact of 
COVID-19 pandemic in each cohort. The number and percentage of patients in the FAS with 
any protocol deviation with one of the following relationships will be summarized by deviation 
category: COVID-19 health status related, COVID-19 situation: Site issue, COVID-19 
situation: Lockdown / Quarantine of patient, COVID-19 situation: Patient concern, COVID-19 
situation: Drug supply issue and COVID-19 situation: Other. 


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3.4 
Groupings for analysis 
The number and percentage of patients in each analysis set (definitions are provided in Section 
2.3) will be summarized in each cohort separately, by treatment arm and randomization stratum 
(presence of lung and/or liver metastases, previous treatment with any CDK4/6 inhibitor based 
on data obtained from the IRT system).  
Discrepancies between stratum recorded in IRT at the time of randomization and actual stratum 
recorded in the clinical database will be summarized. 
3.5 
Patient disposition 
The FAS will be used for the patient disposition summaries, which will be summarized in each 
cohort separately overall, and for both treatment groups. 
Based on the ‘End of Treatment Disposition’ and ‘End Post Trt Phase Disposition’ CRF there 
will be one combined by-treatment summary showing: 
1. Number (%) of patients who are still on-treatment (based on the absence of the ‘End 
of Treatment Disposition’ eCRF) 
2. Number (%) of patients who discontinued study treatment (based on the ‘End of 
Treatment Disposition’ eCRF) 
3. Reasons for study treatment discontinuation (based on ‘End of Treatment Disposition’ 
eCRF) 
4. Number (%) of patients who entered the post-treatment evaluations (based on ‘End of 
Treatment Disposition’ eCRF) 
5. Number (%) of patients who discontinued from the post-treatment evaluations (based 
on the ‘End Post Trt Phase Disposition’ eCRF) 
6. Reasons for discontinuation from the post-treatment evaluations phase (based on ‘End 
of post treatment follow up disposition’ eCRF). 
3.6 
Study treatment 
Duration of study treatment exposure, cumulative dose, dose intensity (DI) and relative dose 
intensity (RDI) will be summarized by treatment. The number of patients with dose 
reductions/interruptions, and the reasons, will be summarized and listed. Details of the 
derivations and summaries are provided in the following sections. 
Summaries will be presented for the Safety set by treatment arm, in each cohort separately as 
well as both cohorts combined. 
Data handling  
The following rule should be used for the imputation of date of last administration (please refer 
to Section 2.1.3) for a given study treatment component:  
Scenario 1: If the date of last administration is completely missing and there is no EOT eCRF, 
the subject is considered as on-going:  
The subject should be treated as on-going and the cut-off date should be used as the last dosing 
date.  


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Scenario 2: If the date of last administration is completely or partially missing and the EOT 
eCRF is available (prior to any death date or withdrawal of consent date, if available):  
Case 1: The date of last administration is completely missing, and the EOT visit date is 
complete, then this latter date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Use Dec31yyyy  
Case 3: Only Year(yyyy) of the dose end date is available and yyyy = the year of EOT date:  
Use EOT date  
Case 4: Both Year(yyyy) and Month (mm) are available for the date of last administration, and 
yyyy = the year of EOT date and mm < the month of EOT visit:  
Use last day of the Month (mm).  
After imputation, compare the imputed date with the start date of that specific record, if the 
imputed date is < start date of that record  
Use the start date of that record.  
Subjects with missing start dates are to be considered missing for all study treatment component 
related calculations described in Section 3.6 and no imputation will be made. If the date of first 
administration is missing, then the date of last administration should not be imputed. 
3.6.1 
Duration of study treatment exposure 
Duration of exposure to study drug (for alpelisib/placebo and fulvestrant) is defined 
according to dosing regimen for each study drug as outlined in Section 2.1.6. 
Duration of exposure (days) = (last date of exposure to study drug) – (date of first administration 
of study drug) + 1 
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to each study drug: 
Duration of exposure (days) = (last date of exposure to study treatment) – (date of first 
administration of study treatment) + 1, 
The duration includes the periods of temporary interruption. ‘Date of first administration of 
study drug/treatment’ and ‘last date of exposure to study drug/treatment’ are defined in Sections 
2.1.2/2.1.4 and 2.1.6 respectively. 
Duration of exposure to study drug/treatment will be categorized into time intervals (<1 month, 
at least1 month, at least 2 months etc.). In addition, summary statistics will be displayed. 
Note: If the last record in DAR CRF is a zero dose, this record will not be used in the analyses.  
To assess the impact of specific adverse events of special interest on exposure to study treatment 
the following summaries are added: 
• Duration of exposure to study drug for patients who developed hyperglycemia during 
the study 


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• Duration of exposure to study drug for patients who developed hyperglycemia during 
the study and started anti-diabetic medication  
• Duration of exposure to study drug for patients who developed hyperglycemia during 
the study and started anti-diabetic medication by hyperglycemia diagnosis status 
• Duration of exposure to study drug for patients who developed rash during the study 
• Duration of exposure to study drug for patients who developed rash during the study 
and started anti-rash medication 
Patients who developed hyperglycemia [rash] during the study are defined as those patients 
with any on-treatment CTC Grade 1 or higher AESI. Hyperglycemia diagnosis status is defined 
in Section 3.13.1. Anti-diabetic medications are defined by medications where ATC code=A10 
[Drugs used in diabetes].  Anti-rash medications are defined by medications where ATC codes 
in the following categories: 
• R06A [Antihistamines for systemic use] 
• D07 [Topical dermatological corticosteroids] 
• H02 [Corticosteroids systemic] 
3.6.2 
Cumulative dose  
Cumulative dose for any component of study treatment is defined as the total dose of the 
medication given during the study treatment exposure.    
Cumulative dose will be summarized using descriptive statistics by treatment arm for each 
component of study treatment. For patients who do not receive any drug the cumulative dose 
will be set to zero. 
The cumulative dose is defined according to the type of dosing schedule and is calculated from 
the DAR eCRF. It is expressed in mg for alpelisib/placebo and fulvestrant. 
Alpelisib/placebo 
Cumulative dose (mg) = Sum of doses of the study drug administered to the patient from the 
start date to the last date of study drug. 
Fulvestrant 
The cumulative dose for fulvestrant with cyclic administration should be defined based on the 
days when the subject is assumed to have taken a non-zero dose during dosing periods. 
3.6.3 
Dose intensity and relative dose intensity 
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows.  
DI (dosing unit / unit of time) = Cumulative dose (dosing unit) / Duration of exposure (unit of 
time). 
For patients who did not take any drug the DI is equal to zero. Planned dose intensity (PDI) is 
the assigned dose by unit of time planned to be given to patients as per protocol in the same 


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dose unit and unit of time as that of the Dose Intensity. DI, PDI and Relative dose intensity 
(RDI) is defined as: 
For alpelisib/placebo: 
• DI (mg/day) = Cumulative dose (mg) / duration of exposure (days) 
• PDI is 300 mg/day 
• RDI (%) = DI (mg/day) / PDI (mg/day) *100 
For fulvestrant: 
• DI (mg/day) = Cumulative dose (mg) / duration of exposure (days) 
Categorical summaries of alpelisib RDI and the continuous summaries of RDI (i.e. mean, 
standard deviation etc.) will be presented. 
3.6.4 
Dose reduction, interruption and permanent discontinuation 
The number (%) of patients with dose reductions or interruptions and permanent 
discontinuations, and associated reasons, will be summarized separately for each study drug 
(alpelisib/placebo and fulvestrant).  In addition, reasons for permanent discontinuation from the 
study drug will be summarized for both alpelisib/placebo and fulvestrant. 
Dose administered (mg) and dosing frequency from the DAR eCRF will be used to determine 
the dose reductions and interruptions. 
‘Dose permanently discontinued’ ticked box from the DAR eCRF will be used to determine 
permanent discontinuation.  
Dose interruption  
For alpelisib/placebo, an interruption is defined as a zero dose on one or more days between 
two non-zero doses.   
Any two or more consecutive zero doses of alpelisib (e.g. in the sequence 300 mg daily, 0 mg, 
0 mg, 300 mg daily) or fulvestrant will be counted as 1 interruption if the reasons for these two 
consecutive dose interruption are the same. It will be counted as two different interruptions only 
if the reasons are different. 
For fulvestrant, an interruption is defined as a zero dose on one or more days between two non-
zero doses. 
For example, a 500mg dose on C1D1, a zero dose on C1D15 and a 500mg dose on C2D1 will 
constitute a single interruption. 
The number (%) of dose interruptions along with reasons will be summarized.  
Note: The last zero dose of alpelisib/placebo or fulvestrant is not considered as a dose 
interruption.  


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Dose reduction  
For alpelisib/placebo, a dose reduction is defined as a decrease in dose from the protocol 
planned starting dose (e.g. from 300 mg daily to 250 mg daily) even if the dose decrease has 
been directly preceded by an interruption.  On the other hand, if the dose decrease is followed 
by an interruption, with the dose resuming at the same level prior to the interruption (e.g. in the 
sequence 300 mg daily – 0 mg - 300 mg daily), the second dose decrease or change in dosing 
frequency will not be counted as dose reduction. 
If, due to a dosing error, a patient receives a higher than planned starting dose and moves down 
to the planned starting dose then this is not considered a dose reduction. However if the dose 
change is from a higher than planned starting dose down to a lower than protocol planned 
starting dose, then this is considered a dose reduction (e.g. in the sequence: 350 mg daily, 300 
mg daily, 250 mg daily; 250 mg is considered a dose reduction). 
If, due to a dosing error, a patient receives a lower than previous non-zero dose and resumes 
later at the protocol specified dose reduction, then the lower dose received due to dosing error 
and protocol specified dose reduction are dose reductions (e.g. in the sequence 300 mg daily – 
200 mg daily - 250 mg daily, then 200 mg and 250 mg are considered dose reductions). 
If, due to a dosing error, a patient receives a lower than previous non-zero dose and resumes 
later at a lower than previous non-zero dose, then 2 dose reductions will be counted (e.g. in the 
sequence 300 mg daily - 250 mg daily – 200 mg daily, 250 mg and 200 mg are dose reductions).  
Table 3-1 
Examples of Dose Reduction for alpelisib 
Sequence 
Reduction 
With dose change 
300 mg daily - 250 mg daily – 0 mg - 250 mg daily  1 reduction (the 1st 250 mg) 
300 mg daily – 300 mg daily – 0 mg - 250 mg daily 1 reduction (250 mg) 
300 mg daily – 0 mg – 250 mg daily 
1 reduction (250 mg) 
With interruption  
300 mg daily – 0 mg - 300 mg daily  
0 reductions  
With dosing error 
300 mg daily – 250 mg daily – 200 mg daily*  
2 reductions (250 mg, 200 mg) 
300 mg daily – 200 mg daily* - 300 mg daily 
1 reduction (200 mg) 
300 mg daily – 200 mg daily* - 250 mg daily 
2 reductions (200 mg, 250 mg) 
300 mg daily – 400 mg daily* - 350 mg daily* 
0 reductions since 400 mg and 350 mg 
are dose escalations not reduction 
300 mg daily – 150 mg daily* - 300 mg daily 
1 reduction (150 mg) 
With dosing error at the 1st administration 
150 mg daily* - 300 mg daily 
1 reduction (150 mg) 


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Sequence 
Reduction 
150 mg daily* - 0 mg – 150 mg*- 300 mg daily 
1 reduction (150 mg) 
150 mg daily* - 300 mg daily – 0 mg - 250 mg daily 2 reductions (150 mg and 250 mg) 
*dosing error 
There is no planned dose reduction for fulvestrant; in addition the reason for fulvestrant dose 
reduction is not collected in the eCRF. No analysis for fulvestrant will be done on the number 
of, and reasons for, reductions. 
3.7 
Concomitant therapy 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
besides the study treatment that were administered to a patient, coinciding with the study 
assessment period.  
Concomitant therapy include medications (other than study drugs) starting on or after the start 
date of study treatment or medications starting prior to the start date of study treatment and 
continuing after the start date of study treatment.  
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference  Listing  (DRL)  dictionary  that  employs  the  WHO  Anatomical  Therapeutic 
Chemical (ATC) classification system and summarized by lowest ATC class and preferred term 
using frequency counts and percentages. Surgical and medical procedures will be coded using 
MedDRA and summarized by SOC and preferred term. 
Concomitant medications, concomitant medications with specific impact on the analysis (See 
Section 3.7.1), procedures and significant non-drug therapies taken concurrently with study 
treatment will be listed and summarized by ATC class/SOC using frequency counts and 
percentages. Any prior medications, procedures or significant non-drug therapies starting and 
ending prior to the start date of study treatment will be listed. Analysis will be based on Safety 
set.  
3.7.1 
Concomitant medications with specific impact on the analysis 
According to study protocol Table 14-1, the following medications are either prohibited during 
the treatment period in this study, or to be used with caution: 
• CYP3A4, CYP2C8, CYP2C9 or CYP2C19 substrates 
• Medications with a known risk of QT prolongation 
• QT prolonging drugs to be used with caution 
• BCRP inhibitors to be used with caution 
A corresponding list for programming purposes will be saved in a separate document. 
However, some patients may take these substances during the treatment period so these 
concomitant medications will be selected via programming and tabulated and listed in the 
Clinical Study Report. 
  


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3.8 
Efficacy evaluation 
The efficacy endpoints based on the tumor assessments will be derived according to the 
RECIST guideline version 1.1 (see Section 2.5 and Appendix 3 of the Clinical Study Protocol 
for details). The tumor endpoint derivation is based on the sequence of overall lesion responses 
at each assessment/time point. However, the overall lesion response at a given assessment/time 
point may be provided from different sources as illustrated in Table 3-2. 
Table 3-2 
Sources for overall lesion response 
Source 1 
Investigator (local radiology) reported overall lesion response 
Source 2 
Novartis-calculated overall lesion response based on raw (i.e. individual 
lesion) measurements from investigator (local radiology) 
Source 3 
Final central radiology review committee reported overall lesion response 
The primary efficacy analysis will be based on the investigator/local radiology review. The 
investigator reported overall lesion response at each assessment/time point (Source 1 in Table 
3-2) will be used to derive the efficacy endpoints.  
Source 2 will be listed against Source 1 and discrepancies between calculated and assigned 
responses will be identified for data review purposes. 
Data from Source 3 will be used for selected supportive efficacy analyses. For central radiology, 
the final adjudicated data will be listed. Differences in overall responses between local 
radiology (Source 1) and central radiology (Source 3) will be listed. 
3.8.1 
 Primary efficacy 
The primary objective of the study is to determine whether treatment with alpelisib in 
combination with fulvestrant prolongs PFS compared to treatment with placebo in combination 
with fulvestrant in men and postmenopausal women with HR+, HER2-negative advanced breast 
cancer which progressed on or after AI treatment for patients with PIK3CA mutant status as 
measured in tissue. 
PFS based on local radiology assessment is the primary efficacy variable in this study. PFS is 
defined as the time from the date of randomization to the date of the first documented disease 
progression or death due to any cause. If a patient has not progressed or died at the analysis 
cutoff date, PFS will be censored at the time of the last adequate tumor assessment before the 
cut-off date. Definitions and further details on PFS can be found in Appendix 3 of the study 
protocol. 
Discontinuation due to disease progression (collected on the ‘End of Treatment Disposition’ 
and ‘End Post Trt Phase Disposition’ eCRF) without supporting objective evidence (as defined 
in Section 2.4.2) satisfying progression criteria per RECIST will not be considered disease 
progression for PFS derivation. 
3.8.1.1 
Primary analysis 
The primary analysis of PFS will be based on the local radiological assessments (Source 1 in 
Table 3-2) up until the cut-off date defined in Section 2.2. The analysis will be performed on 
the FAS and will use the default censoring and event date options from Table 3-3, with the 


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exception of the rules for new antineoplastic therapy given, i.e. event/censoring rules will be 
based on options A(1), B(1), C1(1), C2(1), D(1), E(1), and F(1). In particular, PFS will be 
censored at the last adequate tumor assessment if a patient didn’t have an event or the event 
occurred after two or more missing tumor assessments (see Section 2.4.5). In the primary 
analysis in this study PFS will not be censored if a new antineoplastic therapy is started; instead, 
an ITT approach will be used and this new antineoplastic therapy will be ignored for the 
purposes of PFS derivation (and tumor assessments will continue), i.e. option F(1) in Table 3-
3 will be used. A sensitivity analysis will be performed censoring PFS at the last adequate tumor 
assessment prior to start of new antineoplastic therapy, i.e. using option F(2).  Discontinuation 
of study treatment (for any reason) will not be considered as a reason for censoring. 
Table 3-3 
Options for event dates used in PFS
 
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 assessment
2 
Progressed 
Progressed 
C1 
Progression or death after exactly one 
missing assessment 
(1) Date of progression (or death) 
(2) Date of next scheduled assessment
2 
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 
 
 
1.=Definitions can be found in Protocol Appendix 3 Section 14.3.25 
2.=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Protocol Appendix 
3 Section 14.3.25. 
3.=The rare exception to this is if the patient 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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3.8.1.2 
Hypothesis and test statistic 
The overall Type I error for the trial is one-sided 2.5%. The primary efficacy analysis of PFS 
based on the population of patients with PIK3CA mutant status will be performed at a one-sided 
2.0% level of significance. A secondary efficacy analysis of PFS based on the population of 
patients with PIK3CA non-mutant status will be performed at a one-sided 0.5% level of 
significance (see Section 3.8.2.2). This approach guarantees the protection of the overall type I 
error at 2.5% (based on a Bonferroni adjustment). 
The primary efficacy analysis will be the comparison of PFS between the two treatment arms 
using a stratified log-rank test at a one-sided 2.0% level of significance for the PIK3CA mutant 
cohort. The strata information will be based on the data obtained from the IRT system that was 
utilized for randomization. 
Assuming proportional hazards model for PFS for the PIK3CA mutant cohort, the following 
statistical hypotheses will be tested at the one-sided 2.0% level of significance: 
H01: θ1 ≥ 0 vs. Ha1: θ1 < 0 
where θ1 is the log-hazard ratio (alpelisib + fulvestrant treatment arm vs. placebo+fulvestrant 
treatment arm) of PFS.  
3.8.1.3 
Kaplan-Meier estimates 
The survival distribution of PFS will be estimated using the Kaplan-Meier method. The results 
will be plotted graphically (Kaplan-Meier curves) by treatment arm. The plots will display the 
number of patients at risk at equidistant time points. The median, 25th and 75th percentiles for 
PFS for each treatment arm will be provided with associated 95% confidence intervals. The 
survival probabilities at 6, 12, 18 months, and the associated 95% confidence intervals will be 
summarized by treatment arm. Kaplan-Meier estimates will be obtained using PROC 
LIFETEST with method=KM option in SAS. The loglog option available within PROC 
LIFETEST will be used to compute the confidence intervals. 
The purpose of the two-sided 95% CI is to give an estimate of the respective treatment effect 
together with a comparable measure of reliability but not for reconstructing the test decisions. 
3.8.1.4 
Hazard Ratio 
The PFS hazard ratio with two-sided 95% confidence interval will be derived from the stratified 
Cox proportional hazards model for each cohort. In this analysis the baseline hazard function 
will be allowed to vary across strata. SAS PHREG procedure with ties=EXACT option will be 
used to carry out this analysis in which the model statement will include treatment arm variable 
as the only covariate and the STRATA statement will include the stratum information as 
obtained via IRT. 
3.8.1.5 
Sensitivity analyses of the primary endpoint 
Sensitivity analyses are performed only if the analysis of primary endpoint in the PIK3CA 
mutant cohort shows statistically significant results. Subgroup analyses to explore the intrinsic 
consistency of any treatment effect found overall are specified in Section 3.13.2. 


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Per protocol Population 
The PPS will be used to perform sensitivity analysis for the primary efficacy endpoint (i.e. PFS) 
if the primary endpoint is statistically significant. 
Different Censoring Mechanisms 
Depending on the statistical significance of the primary efficacy endpoint, the following 
sensitivity analyses will be performed to address the impact of tumor assessment features and 
censoring rules on primary analyses. The primary efficacy analyses in each cohort; i.e. the 
stratified log-rank test, Kaplan-Meier estimates, estimate of the median PFS along with 95% 
confidence interval, and hazard ratio obtained using the Cox proportional hazards model, will 
be repeated (as appropriate) based on the data obtained: 
1. If more than 10% patients have two or more consecutive missing assessments prior to 
PFS event, primary PFS analyses will be repeated using investigator/local assessment 
(Source 1 in Table 3-2) on the FAS and taking the event whenever it occurs - even after 
two or more missing tumor assessments. The following options from Table 3-3 will be 
used: A(1), B(1), C1(1), C2(3), D(1), E(1) and F(1). In the summary table, this approach 
is referred as ‘Actual event PFS analysis’ 
2. If more than 10% patients have two or more consecutive missing assessments prior to 
PFS event, primary PFS analyses will be repeated using investigator/local assessment 
(Source 1 in Table 3-2) on the FAS and backdating events occurring after missing tumor 
assessments. The following options from Table 3-3 will be used: A(1), B(1), C1(2), 
C2(2), D(1), E(1), and F(1). In the summary tables, this approach is referred as 
‘Backdating PFS analysis’ where, the date of next scheduled assessment is defined as 
the date of the last adequate tumor assessment plus the protocol specified time interval 
for assessments. 
3. Using investigator/local assessment (Source 1 in Table 3-2) on the FAS and censoring 
all PFS events that occur after the start of new anti-neoplastic therapy to the time of last 
adequate tumor assessment done prior to the therapy start date. 
4. If there are any COVID-19 related deaths, an additional sensitivity analysis will be 
performed to address the potential impact of the COVID-19 pandemic, using 
investigator/local assessment (Source 1 in Table 3-2) on the FAS and censoring all death 
events related to COVID-19 at the time of the event. 
Unstratified Analysis 
As a sensitivity analysis to assess the impact of stratification, the two treatment groups will be 
compared using the unstratified log-rank test. The HR together with the associated 95% 
confidence interval obtained using the unstratified Cox regression model will also be presented. 
Baseline Demographic and Disease Characteristic factors 
If the primary endpoint is statistically significant, a multivariate stratified Cox regression model 
for PFS will be fitted to evaluate additionally the effect of other baseline demographic or disease 
characteristics on the estimated hazard ratio. This model will include the following key 


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prognostic factors: ECOG performance status (0 vs. 1), bone lesions only at baseline (yes or 
no), number of prior lines of therapy in any setting (1st line vs 2nd line) and region (see Section 
3.13.2 for definitions). 
All covariates will be included in the model regardless of their observed significance (p-value 
for given covariate). Forest plots for these factors will be provided, please see Section 3.13.2. 
3.8.1.6 
Supportive analyses of the primary endpoint 
The following analyses will be conducted in the PIK3CA mutant cohort to support the 
interpretation of the primary endpoint, regardless of the outcome in the primary endpoint. 
• If there is a high rate of discrepancy (>10%) between the strata classifications 
constructed using CRF data and those obtained from the IRT (considering also 
PIK3CA mutation status), a sensitivity analysis will be performed in which a stratified 
Cox regression model will be used to estimate the treatment hazard ratio and the 
associated 95% confidence interval based on the CRF-derived strata.   
• Number of patients with a PFS event and number of patients censored for the PFS 
analysis will be summarized. In addition, a summary of reasons for PFS censoring will 
be provided by treatment arm based on the reasons defined in Section 2.4.5.  
The following summaries on censoring reasons will be produced for PFS by investigator 
radiology and central radiology. The censoring patterns will be compared between investigator 
and central review (in patients selected for BIRC assessment). 
• Comparison of PFS event type/censor between local radiology review and central 
radiology review 
• Summary for the difference in days to progression as per local radiology review and as 
per central radiology review 
PFS assessed by Blinded Independent Review Committee (BIRC) will serve as supportive 
evidence of the primary endpoint in the PIK3CA mutant cohort.  
For studies with PFS based on local radiology assessment as the primary endpoint, PFS 
assessment done centrally has generally been used as a secondary or supportive analysis of the 
treatment effect observed in the primary efficacy analysis. Although 100% central review of 
scans has been performed in many trials, there is a growing body of evidence that an audit based 
approach for central evaluation is sufficient (Zhang et al, 2012, FDA ODAC 2012). 
An audit (sample) based approach will therefore be implemented for the BIRC assessment of 
PFS, whereby all assessments for a randomly selected subset of randomized patients will be 
assessed by BIRC. An independent random sampling process, implemented by the third party 
IRT vendor, will select approximately 50% of randomized patients. This random allocation will 
be stratified by randomized treatment arm and the strata used for the randomization of patients 
to treatment arms. 
The distribution of PFS based on audit BIRC sample will be estimated using the Kaplan-Meier 
method for the FAS. The median along with two-sided 95% confidence intervals (CI) will be 
presented by treatment group. Kaplan-Meier figure will also be displayed. A stratified Cox 
regression will be used to estimate the hazard ratio (HR), along with two-sided 95% CI based 
on the audit BIRC sample. 


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Two additional methods will be used to summarize the data from the BIRC assessment in order 
to decide whether a 100% BIRC review should be conducted.  
• The NCI (National Cancer Institute) method (Dodd et al. 2011), uses an auxiliary 
variable estimator of the log-hazard ratio that combines information from patient-level 
investigator assessment from all patients in the PIK3CA mutant cohort and the BIRC 
assessment of these patients randomly selected for central review (see Section 4.8 for 
methodological details). This estimate and its one-sided 95% CI will be provided.  The 
NCI method will be used for audit sample size determination (see Section 3.14) and 
summary of treatment effect (HR, 95% confidence intervals) based on the supportive 
BIRC assessment. 
• The data from the BIRC assessment generated following the sampling scheme as above 
will also be summarized using the method proposed by Amit et al. 2011, referred to as 
the PhRMA (Pharmaceutical Research and Manufacturers in America) method, based 
on the early discrepancy rate (EDR) and late discrepancy rate (LDR). 
The EDR quantifies the frequency with which the investigator declares progression 
early relative to BIRC within each arm as a proportion of the total number of investigator 
assessed PDs. The LDR quantifies the frequency that the investigator declares 
progression later than BIRC as a proportion of the total number of discrepancies within 
the arm. If the distribution of discrepancies is similar between the arms this suggests the 
absence of evaluation bias favoring a particular arm.  (see Section 4.8 for details on the 
calculations). With this approach, the differential discordance (DD) of the early 
discrepancy rate (EDR) and late discrepancy rate (LDR) between the two arms will be 
estimated as the rate on the alpelisib+fulvestrant arm minus the rate on the 
placebo+fulvestrant arm. The EDR and LDR results will also be summarized by 
treatment arm.   
If the analysis of primary endpoint in the PIK3CA mutant cohort shows a statistically significant 
treatment effect, a full BIRC review may be conducted. 
The following thresholds based on the NCI and PhRMA methods will be used to define the 
trigger for a full BIRC review: 
• If the upper-bound of the one-sided 95% confidence interval for BIRC-based log-
hazard ratio exceeds zero (i.e. HR>1) based on the NCI  method 
and/or 
• If ≥ 15% differential discordance is observed in EDR or LDR based on the PhRMA 
method (a negative observed differential discordance for the EDR or a positive 
differential discordance for the LDR) 
Cross-tabulation of ‘PFS by central radiology’ vs. ‘PFS by investigator’ by PFS event type (i.e. 
‘death’, ‘PD’, ‘censor’ for each of the two sources) and by treatment will be constructed to 
investigate discordance between the two sources (in patients selected for BIRC assessment). 
The discrepancy rate between central radiology  and  investigator  will  be calculated and 
presented as % as follows: 100 × (n13 + n23  + n31 + n32 )/ N by treatment arm. 


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A cross-tabulation will be produced displaying the PFS timings for the local investigators’ 
assessment compared to the BIRC assessment (in patients selected for BIRC assessment). For 
progression assessments, the frequency and percent of subjects with complete agreement 
[occurring on the same date plus or minus 7 days of each other], progression later, progression 
earlier, and cases where progression was called by one method and censored by the other will 
be displayed. Similarly, if censoring was recorded, the frequency and percent of subjects with 
complete agreement, censoring called later, censoring called earlier, and cases where censoring 
was called by one method and progression was called by the other method will be displayed.  
3.8.1.6.1 Missing tumor assessments 
The number of patients with at least one missing/unknown TA based on local assessment will 
be presented together with the following breakdown categories: number of patients with 1, 2, 
3, 4, 5, >5 missing/unknown TAs. The purpose of this analysis is to gain an insight as to whether 
the TAs have been carried out in accordance with the protocol and to understand if any 
meaningful discrepancies exist between the pattern of missing assessments by treatment arms. 
Since the planned tumor assessments are every 8 weeks in the first 18 months and every 12 
weeks thereafter, the following time windows (in weeks) will be constructed for each patient: 
(note the open parenthesis such as (12, 20] indicates that week 12 doesn’t belong to this interval 
and week 12+1 day belongs to that interval) 
• Until ~18 months post randomization  [0, 12], (12, 20], (20, 28], …(60, 68], (68, 76] 
• After ~18 months post randomization (76, 90], (90, 102], (102, 114], … 
where ‘0’ is the patient’s date of randomization. Every time-window (with the exception of the 
initial, broader one) is centered at the scheduled time of a TA, i.e., around week 16, week 24 
for second and third window respectively, etc. A patient will be considered ‘at risk’ of missing 
his/her TA for any one of these time-windows if he/she either: 
• is ‘on study’ for at least the first 4 weeks of the time-window  for the first 18 months 
(8 weeks for the first time window), or at least the first 6 weeks of time-window 
thereafter, i.e., if the patient is ongoing at the time of the scheduled TA, or 
• discontinued treatment due to documented disease progression within the specific time 
window. 
For example, if a patient discontinued due to documented disease progression during Week 24, 
then he/she would have been ‘at risk’ of a missing/unknown TA for the [20, 28] week time-
window. 
For the purpose of this analysis, ‘unknown’ TAs (i.e., evaluations with an overall lesion 
response of ‘unknown’) will be considered to be missing. However, a clear distinction between 
‘truly missing’ and ‘present but unknown’ needs to be made in the derived dataset to allow for 
both a combined analysis, i.e. missing and unknown treated the same, and separate analyses. 
TAs performed after a documented disease progression will not be considered. In other words, 
the final time-window for which a patient would be at risk of a missing/unknown scan would 
be that during which the documented progression occurred. 


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For patients without documented progression, all TAs are considered up to the earliest of the 
following dates: death, the analysis cut-off, disease progression, withdrawal of consent or loss 
to follow-up. 
  
 
 
 
 
 
 
 
3.8.2 
Secondary efficacy analyses 
The analysis of all secondary efficacy endpoints will be performed, where appropriate, based 
on the FAS for i) cohort of patients with PIK3CA mutant status, and ii) cohort of patients with 
PIK3CA non-mutant status.   
3.8.2.1 
Key secondary objective: overall survival 
The key secondary objective of the study are to determine whether treatment with alpelisib in 
combination with fulvestrant prolongs OS compared to treatment with placebo in the PIK3CA 
mutant cohort.  
In the PIK3CA mutant cohort, a hierarchical testing procedure will be adopted and OS will be 
tested between the two treatment groups, provided the primary endpoint PFS is statistically 
significant favouring alpelisib.  
OS is defined as the time from date of randomization to date of death due to any cause. If a 
patient is not known to have died by the date of analysis cut-off, then OS will be censored at 
the last contact date (see Section 2.1.10). 
Assuming proportional hazards model for OS, the following statistical hypothesis for OS will 
be tested using a stratified log-rank test (according to randomization stratification factors) at the 
one-sided level of significance of 2.0%: 
H02: θ2 ≥ 0 vs. Ha2: θ2 < 0 
where θ2 is the log-hazard ratio (alpelisib-fulvestrant treatment arm vs. placebo-fulvestrant 
treatment arm) of OS. 
The analysis for OS will be based on the FAS population according to the treatment arm patients 
were randomized to and the strata they were assigned to at randomization. 
The final OS analysis will not be performed at the time point of the final PFS analysis in the 
PIK3CA mutant cohort, but after additional follow-up. Therefore, a three-look group sequential 
design is considered for OS, see Section 3.12.2 for further details.  
The type I error probability will be controlled by using a separate Lan-DeMets (O’Brien-
Fleming) alpha spending function independent of the Haybittle-Peto boundary used for the 


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primary efficacy analysis of PFS at a 2.0% level of significance. This guarantees the protection 
of the overall type I error (α = 2.5%) across all hypotheses and the repeated testing of the OS 
hypotheses at the interim and the final analyses (Glimm 2010). This includes hypotheses 
associated with the secondary endpoints PFS and OS in the PIK3CA non-mutant cohort (PFS 
in the non-mutant cohort will be tested at a 0.5% level of significance if PoC is established). 
The OS distribution will be estimated using the Kaplan-Meier method, and Kaplan-Meier 
curves, medians and 95% confidence intervals of the medians along with the proportion of 
patients alive at 12, 24, 36, and 48 months 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 using the same stratification factors as the log-rank test. The purpose of the two-
sided 95% CI is to give an estimate of the respective treatment effect together with a comparable 
measure of reliability but not for reconstructing the test decisions. 
Supportive Analyses 
If the key secondary endpoint OS is statistically significant, a multivariate stratified Cox 
regression model will be fitted to evaluate the effect of other baseline demographic or disease 
characteristics on the estimated hazard ratio. This model will include the following key 
prognostic factors: ECOG performance status (0 vs. 1), bone lesions only at baseline (yes or 
no), number of prior lines of therapy in any setting (1st line vs 2nd line) and region (see Section 
3.13.2 for definitions). 
All covariates will be included in the model regardless of their observed significance (p-value 
for given covariate). 
If the analysis for OS is statistically significant, subgroup analyses of OS will be performed to 
explore homogeneity of the treatment effect across relevant patient subsets. See details in 
Section 3.14.2. 
The pattern of censored data will be examined between the treatment arms: reasons for 
censoring (‘Alive’ or ‘Lost to follow-up’) and death cause will be summarized by treatment 
arm. Survival status, reason for censoring and death cause will be listed. Patients not known to 
have died will be censored for ‘Loss to follow-up’ if the time between their last contact date 
and the analysis cut-off date is longer than 12 + 2 weeks = 98 days (i.e. the planned interval 
between two OS follow-up visits plus the 1 week window on either side).  
If there are any COVID-19 related deaths, an additional sensitivity analysis on the FAS will be 
performed to address the potential impact of COVID-19 pandemic, censoring all deaths related 
to COVID-19 at the time of the event. The efficacy analyses for the key secondary endpoint OS 
in the PIK3CA mutant cohort; i.e. the stratified log-rank test, Kaplan-Meier estimates, estimate 
of the median OS along with 95% confidence interval, and hazard ratio obtained using the 
stratified Cox proportional hazards model, will be repeated. 
 
Handling missing month/day in date of death 
For rare cases when either day is missing or both month and day are missing for the date of 
death, the follow imputation rules will be implemented: 


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- If only day is missing, then impute max [(1 mmm-yyyy), min (any valid date from data 
base used for deriving last contact date +1, cutoff date)].  
- If both day and month are missing, then impute max [(1 Jan-yyyy, min (any valid date 
from data base used for deriving last contact date +1, cutoff date)].  
3.8.2.2 
PFS in patients with PIK3CA non-mutant status measured in tissue 
PFS in the PIK3CA non-mutant cohort will be analyzed at a single look based on the FAS 
population according to the treatment arm patients were randomized to and the strata they were 
assigned to at randomization. Refer to Section 2-2 for the cut-off date for efficacy. 
PFS treatment effect in this cohort will be considered to be clinically relevant via a Bayesian 
decision rule if: 
• The estimated HR (stratified according to presence of lung and/or liver metastasis and 
previous treatment with CDK4/6 inhibitor) ≤ 0.60 
and 
• The posterior probability (HR < 1) ≥ 90% 
The posterior probability in the second criterion will be derived from the Bayesian posterior 
distribution of the HR. Assuming a non-informative prior distribution, the distribution of the 
HR will be updated with all available data from the patients included in the FAS in this cohort. 
The cumulative posterior distribution will be used to derive the probability that the true HR is 
less than 1. 
If both these criteria are met then the comparison of PFS between the two treatment arms in this 
cohort using a stratified log-rank test at a one-sided 0.5% level of significance, will be made. 
Assuming proportional hazards model for PFS, the following statistical hypotheses will be 
tested at the one-sided 0.5% level of significance: 
 
H01: θ1 ≥ 0 vs. Ha1: θ1 < 0 
where θ1 is the log-hazard ratio (alpelisib + fulvestrant treatment arm vs. placebo+fulvestrant 
treatment arm) of PFS. 
The median PFS along with 95% confidence intervals will be presented by treatment arm. 
3.8.2.3 
OS in patients with PIK3CA non-mutant status measured in tissue 
OS analyses will be performed only if the secondary efficacy endpoint, PFS, in this cohort meets 
the PoC criteria given in Section 3.8.2.2 and is statistically significant. A hierarchical testing 
procedure will be adopted. Assuming proportional hazards model for OS, the following 
statistical hypotheses will be tested at the one-sided 0.5% level of significance: 
 
H01: θ1 ≥ 0 vs. Ha1: θ1 < 0 
where θ1 is the log-hazard ratio (alpelisib + fulvestrant treatment arm vs. placebo+fulvestrant 
treatment arm) of OS. 
The analysis for OS will be based on the FAS population according to the treatment arm patients 
were randomized to and the strata they were assigned to at randomization. 


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The final OS analysis will not be performed at the time point of the final PFS analysis in the 
PIK3CA non-mutant cohort, but after additional follow-up. Therefore, a three-look group 
sequential design is considered for OS, see Section 3.12.3 for further details. 
OS will be estimated using the Kaplan-Meier method. The median OS along with 95% 
confidence intervals will be presented by treatment arm. Stratified Cox regression will be used 
to estimate the HR of OS, along with 95% confidence interval. The pattern of censored data 
will be examined between the treatment arms as described in Section 3.8.2.1. 
3.8.2.4 
PFS in patients where PIK3CA mutation status is measured in ctDNA 
An analysis of PFS based on local radiology assessments and using RECIST 1.1 criteria for 
each of (i) patients with PIK3CA mutant status and (ii) patients with PIK3CA non-mutant status 
as measured in ctDNA at baseline will be conducted using the same analytical conventions as 
the primary analysis. 
3.8.2.5 
Overall response rate 
ORR is defined as the proportion of patients with best overall response of confirmed complete 
response (CR) or confirmed partial response (PR) according to RECIST 1.1 (see Appendix 3 of 
the study protocol). ORR will be calculated based on the FAS using investigators’ review of 
tumor assessment data for each cohort. Patients with only non-measurable disease at baseline 
will be part of the analysis and will be included in the numerator only if a complete response 
was observed.  
ORR will be presented along with the exact binomial two-sided 95% confidence interval 
(Clopper 1934) by treatment arm for the PIK3CA mutant and non-mutant cohorts. 
In addition, ORR in the subset of patient with measurable disease at baseline will be presented.  
As a supportive analysis, ORR will also be summarized based on the central radiology review 
of tumor data, if the BICR moves to a 100% audit.  
3.8.2.6 
Clinical benefit rate 
Clinical benefit rate is defined as the proportion of patients with a best overall response of CR 
or PR or SD or Non-CR/Non-PD lasting 24 weeks or more based on local investigator 
assessment according to RECIST 1.1 criteria. 
A patient will be considered to have SD for 24 weeks or longer if a SD response is recorded at 
24-1=23 weeks or later from randomization, allowing for the ±1 week visit window for tumor 
assessments. Patients with only non-measurable disease at baseline will be part of the analysis 
and will be included in the numerator only if they achieve a complete response or have a ‘Non-
CR/Non-PD’ response 23 weeks or more after randomization.  
CBR will be presented along with the exact binomial two-sided 95% confidence interval 
(Clopper 1934) by treatment arm for the PIK3CA mutant and non-mutant cohorts. 
In addition, CBR in the subset of patient with measurable disease at baseline will be presented.  
As a supportive analysis, CBR will also be summarized based on the central radiology review 
of tumor data, if the BICR moves to a 100% audit.  


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3.8.2.7 
Clinical response in patients with PIK3CA mutant status measured in 
ctDNA 
An analysis of ORR, CBR based on local radiology assessments and using RECIST 1.1 criteria; 
and OS for (i) patients with PIK3CA mutant status and (ii) patients with PIK3CA non-mutant 
status as measured in ctDNA at baseline will be conducted using the same analytical 
conventions as the endpoint where mutation status is defined in tissue. 
3.8.2.8 
ECOG performance status 
The ECOG PS scale (Table 3-4) will be used to assess physical health of patients, ranging from 
0 (most active) to 5 (least active): 
Table 3-4 
ECOG Performance Scale 
Score 
Description 
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 
The following intervals will be used to group the ECOG PS data over time. Day in columns 2 
and 3 is defined as date of ECOG PS assessment date – randomization date + 1. The 
corresponding Day in column 1 assumes that a patient is treated on the day of randomization; 
however the definition of Day in columns 2 and 3 still applies if this is not the case, i.e. 
randomization date is taken as the reference for the windows. 
Table 3-5 
Time windows for ECOG PS assessments 
Assessment 
Target day of assessment 
Time Interval 
Baseline 
 
 
Day 1 (if ECOG PS 
assessment is not available, 
use the one performed at 
screening) 
Cycle 2 Day 1 
29 
Day 2 to day 42  
Cycle k Day 1 (k≥3) 
d=(k-1)*28+1 
Day d-14 to day d+13 
End of Treatment 
 
Assessment taken at the end 
of treatment visit 
If 2 assessments within a time window are equidistant from the target date (or if the closest 
assessment to the target date has two ECOG filled out on the same date), then the worst ECOG 
PS value will be used. 
Time windows are applicable for descriptive summary of ECOG data by visit only. For time to 
deterioration analysis described hereafter all post-baseline assessments will be considered. 


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Frequency counts and percentages of patients in each score category will be provided by 
treatment arm and time point.  
Time to definitive deterioration of the ECOG PS is the number of days between the date of 
randomization and the date of the assessment at which definitive deterioration is seen. The 
ECOG PS deterioration is considered definitive if there is an increase in the performance status 
by at least one category relative to the baseline or death due to any cause and if no improvement 
in ECOG PS is observed subsequent to the deterioration. 
Baseline is the last available assessment on or before date of randomization. If a patient has 2 
ECOG PS values at the same date, the worst ECOG PS value will be taken as ‘baseline’. 
Example: If the ECOG PS is 1 at baseline and then 1, 2, 1, 2, 3 at D28, D57, D83, D115, and 
D150 respectively, then the time to definitive worsening is D115. 
Example: if the ECOG PS is 1 at baseline and then 1, 1, 2 at D28, D57, and D83 respectively, 
with no assessment of the ECOG PS after D83 then the time to definitive worsening is 83 days. 
If a definitive deterioration is observed after any missing assessments, this event will be 
backdated to the first of the missing assessments before the deterioration. The first missing 
assessment date is calculated as the last available assessment before the definitive deterioration 
plus X, where X corresponds to the planned scheduled time point for ECOG PS (28 days). 
For example, if a patient has an assessment at week 6, misses the following two assessments on 
weeks 10 and 14 and a definitive deterioration is observed on week 15, then the event will be 
backdated to week 6+28 days. 
In addition, death is considered as a worsening of performance status if it occurs close to the 
last available assessment, where “close” is defined as twice the planned (i.e. protocol scheduled) 
period between two assessments. This avoids overestimating the time to definitive worsening 
in patients dying after an irregular assessment scheme. Patients who die after more than twice 
the planned period between two assessments are censored at the date of their last available 
assessment of the performance status.  
For example, if the last assessment is at week 6 and the patient dies at week 10, the definitive 
deterioration date will be week 10. On the other hand, if the last assessment is at week 6 and 
the patient dies at week 16, which is after more than twice the planned period between two 
assessments since the last assessment (week 6), then the definitive deterioration date will be 
week 6. 
Patients receiving any further anti-neoplastic therapy before definitive worsening will be 
censored at the date of their last assessment before the start date of the therapy. Patients that 
have not worsened as of the cutoff date will be censored at the date of their last assessment 
before the cutoff. 
Patients without baseline ECOG PS or without any post-baseline ECOG PS will be censored at 
the date of randomization with censoring reason being ‘No baseline score’ or ‘No post-baseline 
score’, respectively. However, patients without post-baseline ECOG PS who die within 62 days 
after date of randomization  will be counted as having a definitive deterioration of the ECOG 
PS at the date of death. 


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This threshold corresponds to twice the protocol defined ECOG assessment interval plus twice 
the time window around each assessment: (2 x 28 days)+( 2 x 3 days), i.e. 62 days. 
Kaplan-Meier estimates will be constructed for each treatment arm in each cohort. The median, 
25th and 75th percentiles for time to definitive deterioration for each treatment group will be 
obtained along with 95% confidence intervals. 
3.8.2.9 
Patient reported outcomes 
The European Organisation for Research and Treatment of Cancer’s core quality of life 
questionnaire (EORTC-QLQ-C30, version 3.0)
will be used to evaluate patient-reported outcome measures of health-related 
quality-of-life,
The PRO instruments are planned to be administered during screening and every 8 weeks after 
randomization in the first 18 months, and every 12 weeks thereafter (including at EOT) until 
disease progression, death, withdrawal of consent, loss to follow-up or subject/guardian 
decision. 
The following time based intervals will be used to group the PRO data over time. Day is defined 
as date of PRO assessment date – randomization date + 1.  
Table 3-6 
Time windows for patient reported outcomes 
Assessment 
Time Interval 
Baseline 
 
Screening assessment 
 
Cycle 3, 5, 7, 9 until 
cycle 19 
+/- 4 weeks centered around the planned assessment date (except for 
the first window and the last window): 
i.e. days (1, 85] for Day 1 of cycle 3 (2nd assessment) 
      days (85, 141] for Day 1 of cycle 5 (3rd assessment) 
      days (k*56-27; k*56+29] for (k+1th assessment) 
     days (477, 547] for 10th assessment on Day 1 cycle 19 
Cycle 22, 25, 28, … 
+/- 6 weeks centered around the planned assessment date: 
i.e. days (547, 631] for 11th assessment 
    days (631, 715] for 12th assessment 
   days (715, 799] for 13th assessment 
If more than one assessment is done within the same time window, the assessment performed 
closest to the target date will be used. If 2 assessments within a time window are equidistant 
from the target date, then the assessment obtained prior to target date will be used. 
The global health status/QoL scale score of the EORTC QLQ-C30 is identified as a primary 
PRO variable of interest. The physical functioning, emotional functioning and social 
functioning sub-scale scores of the EORTC QLQ-C30, 
 
are identified as secondary PRO 
variables of interest.    


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The number of patients completing PRO questionnaires and the number of patients 
missing/expected to have PRO assessments will be summarized by treatment arm for scheduled 
assessment time points (the number of ongoing patients will be used as denominator). 
Furthermore, the amount and the pattern of missing data may be explored by treatment arm and 
over time using summary statistics. The following categories will be used to describe whether 
the questionnaire was completed at a specific time point: 
- yes, fully completed 
- yes, partly completed 
- no. 
Scoring of raw data and methods for handling missing items or missing assessments will be 
handled according to scoring manuals for each respective patient questionnaire (Fayers 2001; 
Oemar and Janssen 2013; Cleeland 2009). 
Descriptive statistics (n, mean, median, SD, min, max) will be used to summarize the
 
 scores from the EORTC QLQ-C30
at each scheduled assessment 
time point. Additionally, change from baseline in the
scores at the time of each 
assessment will be summarized. 
 
Patients with an evaluable baseline 
score and at least one evaluable post baseline score during the treatment period will be included 
in the change from baseline analyses. 
A repeated measures model for longitudinal data will be used to compare the two treatment 
arms in sub-scales obtained from EORTC QLQ-C30 
 over 
time. This longitudinal model will include terms for treatment, the randomization stratification 
factors (presence of lung and/or liver metastases [yes versus no] and previous treatment with 
any CDK4/6 inhibitor [yes versus no]), time (duration in weeks counting from the time of 
baseline measurement to the time of a particular post baseline measurement) and baseline value 
as main effects, as well as an interaction term for treatment by time. Time will be explored as 
both a continuous and categorical variable to assess the best model fit. As a first approach, an 
unstructured correlation matrix will be used to model the correlation within patients. The 
structure of the correlation matrix will be investigated and simplified using likelihood ratio tests 
if appropriate. The differences in least square means between treatment and control group, and 
the corresponding 2-sided 95% CI at selected time points will be presented.  Data collected 
under treatment (i.e. while the patient is treated) and during post-treatment follow-up up until 
documented progression will be included. If the model fit based on unblinded data does not 
achieve convergence then fewer time points for inclusion may be considered.   
Time to 10% deterioration in the global health status/
 
will be assessed in each cohort. 10% deterioration is 
defined as a worsening in score by at least 10% compared to baseline, with no later 
improvement above this threshold observed during the treatment period, or death due to any 
cause.  Time to deterioration is the number of days between the date of randomization and the 
date of the assessment at which deterioration is seen.  If a patient has not had an event prior to 
analysis cut-off, start of new anti-neoplastic therapy, lost to follow-up, or withdrawal of 


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consent, the time to deterioration will be censored at the date of the last evaluation before the 
earliest of these dates. If deterioration is observed after two or more missing assessments, time 
to deterioration will be censored at the date of the last assessment prior to the deterioration. 
Patients with no baseline data will be censored at Day 1. Death is considered as an event when 
it occurs within a period of time defined by 2 times the period between two assessments as 
planned in the study protocol. This avoids overestimating the time to definitive worsening in 
patients dying after an irregular assessment scheme. Patients who die after more than twice the 
planned period between two assessments since the last assessment are censored at the date of 
their last available questionnaire. 
Time to 10% deterioration will be compared between the two treatment arms using a stratified 
log-rank test (strata based on IRT data) and the survival distributions will be presented 
descriptively using Kaplan-Meier curves. Summary statistics from the Kaplan-Meier 
distributions will be determined, including the median time to 10% deterioration and the 
proportions of patients without 10% deterioration at 6, 12, 18 months. Both point estimates and 
95% CIs will be presented. A stratified Cox regression model will be used to estimate the hazard 
ratio (HR) of time to deterioration, along with 95% confidence interval. Sensitivity analysis of 
time to definitive deterioration with different cut-off definitions (e.g. 5%, 15%) may also be 
considered if the number of events per arm is judged sufficient to draw relevant conclusions. 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 


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3.9 
Safety evaluation 
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory/ECG values that fall outside of pre-determined ranges. Other safety data 
(e.g. vital signs and special tests) will be considered as appropriate. 
All safety outputs will use the safety set and be presented by treatment arm for the PIK3CA 
mutant and non-mutant cohorts individually as well as combined. The safety summary tables 
will include only ‘on-treatment’ events/assessments, i.e. those collected on or after the first date 
of study treatment and collected no later than 30 days after the date of last study treatment 
administration. The AEs started before the first dose but worsening during the treatment period 
are also considered as ‘on-treatment’ events. All safety events/assessments will be listed and 
those collected outside of the on-treatment window will be flagged. 
3.9.1 
Adverse events (AEs) 
3.9.1.1 
Coding of AEs 
Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
3.9.1.2 
Grading of AEs 
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0.3. 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE v4.0.3 grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. 
If CTCAE grading does not exist for an adverse event, grades 1 – 4 corresponding to the severity 
of mild, moderate, severe, and life-threatening will be used. CTCAE grade 5 (death) will not be 
used in this project; if an AE results in death it will be documented in the outcome (“fatal”). 
Information on deaths will also be collected on the ‘Death’ CRF.  
3.9.1.3 
General rules for AE Reporting 
AE summaries will include all AEs starting on or after study Day 1 (i.e. on or after the day of 
the first intake of study treatment) and starting no later than 30 days after the last administration 


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of study treatment (see Section 2.1.5). All AEs will be listed. AEs starting prior to study Day 1 
and AEs starting later than 30 days after the last treatment date will be flagged in the listings. 
AEs will be summarized by presenting the number and percentage of patients having at least 
one AE, having at least one AE in each system organ class, and for each preferred term using 
MedDRA coding. A subject with multiple occurrences of an AE will be counted only once in 
the AE category. 
Separate AE summaries will be presented by system organ class, preferred term, and maximum 
CTC grade. A patient with multiple CTC grades for an AE will be summarized under the 
maximum CTC grade recorded for the event. In the summaries presented by grade, all AEs will 
be pooled regardless of whether they are CTC gradable or not.  AE with missing CTCAE grade 
will be included in the ‘All grades’ column of the summary tables. 
The frequency of CTC grade 3 and 4 AEs will be summarized separately. 
Any information collected (e.g. CTC grades, relationship to study treatment, action taken etc.) 
will be summarized and listed as appropriate. 
3.9.1.4 
AE summaries 
The following adverse event summaries will be produced: 
• AEs by SOC, PT, maximum CTCAE grade 
• Most frequent AEs, regardless of study treatment relationship by PT, maximum 
CTCAE grade (at least 5% incidence) 
• Treatment-related AEs by SOC, PT, maximum CTCAE grade 
• Most frequent treatment-related AEs by PT, maximum CTCAE grade (at least 5% 
incidence) 
• On-treatment deaths by primary SOC and PT   
• On-treatment deaths and SAEs with fatal outcome by PT 
• All deaths by SOC, PT. (All deaths (on-treatment + post treatment) are included) 
• Serious adverse events  by SOC, PT, maximum CTCAE grade 
• Treatment-related serious adverse events by SOC, PT, maximum CTCAE grade 
• Most frequent SAEs by PT and maximum CTCAE grade 
• Most frequent treatment-related SAEs by PT and maximum CTCAE grade 
• AEs leading to study drug discontinuation by SOC, PT and maximum CTCAE grade 
• Treatment-related AEs leading to study drug discontinuation by SOC, PT and 
maximum CTCAE grade 
• AEs requiring dose adjustment and/or interruption by SOC, PT, maximum CTCAE 
grade. 
• AEs requiring medication or therapies by SOC, PT, maximum CTCAE grade.  
AEs of special interest will also be summarized. See Section 3.9.1.5 for the grouping details. 


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3.9.1.5 
Adverse Events of Special Interest 
Specific groupings of Adverse Events of Special Interest (AESI) will be considered and the 
number of patients with at least one event in each grouping will be reported. Such groups consist 
of AEs for which there is a specific clinical interest in connection with alpelisib treatment (i.e. 
where alpelisib may influence a common mechanism of action responsible for triggering them) 
or AEs which are similar in nature (although not identical). The groups are defined according 
to the MedDRA terms defined in the program Case Retrieval Strategy (CRS) document and 
will be summarized. The latest version of the CRS document available at the time of the 
analyses will be used. 
All AESI groupings are defined through the use of Preferred Terms (PT), High Level Terms 
(HLT) or System Organ Classes (SOC) or through a combination of these three components. 
An Excel file with the exact composition of the AEs groupings is to be used to map reported 
AEs to the AESI groupings. This file may be updated (i.e. it is a living document) based on 
review of accumulating trial data. Note that certain AEs may be reported within multiple 
groupings. Final deliverables will be aligned with the final excel file. A listing of all grouping 
levels down to the MedDRA preferred terms used to define each AESI will be generated. 
Groupings for Adverse Events of Special Interest 
AESI grouping* 
Definition* 
Hyperglycemia 
SMQ Hyperglycaemia /new onset diabetes mellitus (narrow) 
Rash 
NMQ Rash (BYL719) 
Pneumonitis 
SMQ Interstitial lung disease (narrow) 
GI Toxicity Nausea, Vomiting, 
Diarrhea 
HLT Diarrhoea (excl infective) 
HLT Nausea and Vomiting symptoms 
* At the time of the analyses, MedDRA-defined (SMQ) or Novartis-defined (NMQ) groupings for all 
identified and potential risks as described in the latest version of the CRS document available will be 
used 
Standard data of analysis for AESI will be conducted as follows: 
• The number (%) of patients with AESI will be reported by AESI grouping, maximum 
CTCAE grade and by treatment group. 
• All AEs of special interest will be listed. 
• Depending on the observed number of events, the time to first occurrence of any CTC grade 
≥ 2 AESI may be summarized using Kaplan-Meier methods for each of the groupings in the 
table above. Median time to onset and 95% CI will be summarized. Ascending Kaplan-
Meier plots will be generated. Please refer to Section 3.9.1.5.1 for definitions. For the AESI 
of ‘Hyperglycemia’, ‘Rash’ and ‘GI Toxicity Nausea, vomiting and Diarrhea’, additional 
analyses for time to first occurrence of any CTC grade ≥ 3 AESI will be presented. 
3.9.1.5.1 Time to onset of any CTC grade > 2 [> 3] event 
Time to onset of CTC grade > 2 [> 3] event will be summarized using the Kaplan-Meier 
method. Median time to onset and 95% CI will be provided. In addition, Ascending Kaplan-
Meier plots will be generated. 


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Time to onset of CTC grade > 2 [>3] event is defined as the time from the start of treatment to 
the start date of the first incidence of an event of CTC grade > 2 [>3] i.e. time in days is 
calculated as (start date of first occurrence of the event) – (date of first dose of study treatment) 
+1.  
In the absence of an event during the on-treatment period, the censoring date applied will be the 
earliest of the following dates: 
•  end date of on-treatment period (end of study treatment + 30 days). 
• death date 
• start date of new antineoplastic therapy (with the exception of palliative radiotherapy or 
fulvestrant monotherapy) before experiencing any CTC grade > 2 [>3] event.  
• data cut-off date. 
• withdrawal of informed consent date 
3.9.2 
Laboratory data 
On analyzing laboratory data, data from all sources (central and local laboratories) will be 
combined. The summaries will include all laboratory assessments collected no later than 30 
days after the last administration of study treatment. All laboratory assessments will be listed 
and those collected later than 30 days after the last treatment date will be flagged in the listings. 
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of laboratory 
CTC grades will be based on the observed laboratory values only, clinical assessments will not 
be taken into account. The criteria to assign CTC grades are given in the document “Novartis 
internal criteria for CTC grading of laboratory parameters”. The latest available version of the 
document based on the underlying CTCAE version 4.03 at the time of analysis will be used. 
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges. 
The following summaries will be produced for the laboratory data (by laboratory parameter): 
• Worst post-baseline CTC grade (regardless of the baseline status). Each subject will be 
counted only for the worst grade observed post-baseline   
• Shift tables using CTC grades to compare baseline to the worst post-baseline value will 
be produced for hematology and biochemistry laboratory parameters with CTC grades. 
• For laboratory parameters where CTC grades are not defined, shift tables to the worst 
post-baseline value will be produced using the low/normal/high classifications based on 
laboratory reference ranges. 
3.9.2.1 
Blood Glucose parameters 
HbA1c, fasting plasma glucose and fasting C-peptide data will be summarized in tables by time 
point and treatment. Summary statistics include number of patients with available data, mean, 
standard deviation, median, minimum and maximum. Figures of mean glucose/C-peptide levels 


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with two-sided 95% confidence intervals over time by treatment may also be produced to view 
the trends over time. 
For plasma glucose only, the following summaries will be provided: 
• Time to first occurrence of CTC Grade >=2 hyperglycemia  
• Time to first occurrence of CTC Grade >=3 hyperglycemia  
• Time to resolution of CTC Grade >=2 hyperglycemia  
• Time to resolution of CTC Grade >=3 hyperglycemia  
Note that CTC Grade 3 and 4 hyperglycemia events use both fasting and non-fasting plasma 
glucose laboratory values. Median time to onset, duration and 95% CI will be summarized. In 
addition, ascending Kaplan-Meier plots will be generated. In addition, median and range of time 
to event will be summarized.  
A plot of baseline HbA1c vs. worst post-baseline HbA1c (%) will be presented. 
Time to first occurrence of Grade ≥ 2 [≥ 3] lab event 
Time to onset of first grade 2 [≥ 3] or worse toxicity is defined as the time from the start of 
treatment to the start date of the first incidence of grade 2 [≥ 3] or worse toxicity i.e. time in 
days is calculated as (start date of first occurrence of grade 2 [≥ 3] or worse toxicity) – (date of 
first dose of study treatment) +1.  
In the absence of grade 2 [≥ 3] or worse toxicity during the on-treatment period, the censoring 
date will be the earliest date from the following dates: last date of administration of study 
treatment + 30 days, analysis cut-off date, new anti-cancer therapy start date, death date, 
withdrawal of informed consent date and last non-missing assessment for the lab parameter if 
the event is lab based).  
Note: patients who have grade 2 [≥ 3] or worse toxicity at the baseline will be excluded from 
this analysis. 
Time to resolution (i.e. duration) of Grade ≥ 2 [≥ 3] lab event 
Time (days) to resolution of an event is defined as time from first onset to the date of resolution 
of the event: (date of resolution of event) – (date of first onset of event) + 1. Resolution of an 
event means that there is a lab value returning to grade ≤ 1. The following lab parameters will 
be analyzed: 
• Grade 2 or worse Hyperglycemia  
• Grade 3 or worse Hyperglycemia  
Time to resolution of an event will be presented for the subset of the Safety Set who experienced 
the event. 
In the absence of a resolution during the on-treatment period, the censoring date is the earliest 
of the following dates: end of treatment + 30 days, analysis cut-off, new anticancer therapy start 
date, death date, withdrawal of informed consent date and last non-missing assessment for the 
lab parameter. 
Ascending Kaplan-Meier curves will be constructed by treatment arm. Medians together with 
95% confidence intervals will be presented for each treatment arm. 25th percentile and 75th 


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percentile may be considered as well. In addition, the median and range of time to resolution 
for patients with an event will also be summarized. 
The following listings will be produced for the laboratory data: 
• Listing of patients with CTC grade 3 or 4 laboratory abnormalities; 
• Listing of all laboratory data with values flagged to show the corresponding CTC 
grades and the classifications relative to the laboratory reference ranges. 
• Urinary parameters for all patients 
 
In order to summarize labs parameters as applicable, collected over time (including 
unscheduled visits), the assessments will be time-slotted. 
 
Time windows for laboratory parameters 
 
Assessment (1) 
Target 
day 
of 
assessment 
Time Interval 
Baseline 
 
≤ Day 1 
Cycle 1 Day 8 
8 
Day 2 to Day 11 
Cycle 1 Day 15 
5 
Day 12 to Day 18 
Cycle 2 Day 1 
29 
Day 26 to day 35 
Cycle 2 Day 15 
43 
Day 36 to day 49 
Cycle 3 Day 1 
57 
Day 50 to day 70 
Cycle 4 Day 1 
85 
Day 71 to day 98 
Cycle k Day 1 (k≥5) 
=(k-1)*28+1 
Day d-14 to day d+13 
End of Treatment 
 
Assessment taken at the EOT visit 
(1) HbA1c is measured on-treatment at Cycle 3 Day 1 and EOT and same rule applies. 
For laboratory parameters, all scheduled/unscheduled assessments should be assigned to time 
windows. In case of multiple values per window, the one closest to the planned visit date should 
be used. If 2 values are equidistant to the planned visit date, the selection should be made by 
selecting the one assessed by central (if any) and otherwise - for multiple central assessments 
equidistant to the planned visit - the last value. 
Further derivation of laboratory parameters might be required for CTCAE grading. For 
instance, corrected calcium can be derived using the reported total calcium value and albumin 
at the same assessment using the following formula: 
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4] 


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3.9.2.2 
Liver function parameters 
Liver function parameters of interest for alpelisib are total bilirubin (TBIL), ALT, AST and 
alkaline phosphatase (ALP). 
The number (%) of patients with worst post-baseline values (maximum post-baseline values) 
as per Novartis Liver Toxicity guidelines will be summarized: 
• ALT or AST > 3xULN 
• ALT or AST > 5xULN 
• ALT or AST > 10xULN 
• ALT or AST > 20xULN 
• ALP > 1.5xULN 
• TBL > 1.5xULN 
• TBL > 2xULN 
• ALT or AST > 3xULN & TBL > 2xULN (without time window) 
• ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN (without time window)*    
*Potential Hy’s Law events (candidates) are defined as those patients with AST or ALT > 
3xULN and TBL > 2xULN and ALP < 2xULN at any visit during the on-treatment period.  
A figure displaying time course of hepatic function tests (ALT, AST, TBL, ALP) in patients 
with potential Hy’s law cases will be displayed. 
Additional categories may be added to the above list based on any updates to the internal 
guidelines on collection, analysis, and presentation of liver safety data. 
For lab events the censoring date will be the date of the last scheduled/unscheduled lab 
assessment with a non-missing value for the lab parameter of interest that was collected prior 
to the time of occurrence of the censoring reason. 
3.9.3 
Vital signs 
Vital signs assessments are performed in order to characterize basic body function. The 
parameters expected to be collected include: height, weight, body temperature, heart rate, and 
systolic and diastolic blood pressure. 
The criteria for clinically notable abnormalities are defined as follows: 
Clinically notable elevated values 
• Systolic BP: ≥ 180 mmHg and an increase ≥ 20 mmHg from baseline 
• Diastolic BP: ≥ 105 mmHg and an increase ≥ 15 mmHg from baseline. 
• Body temperature: ≥ 39.1°C 
• Pulse rate:  >=100 and increase from baseline of >25% 
• Weight: Increase ≥ 10% from baseline 
Clinically notable below normal values 


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• Systolic BP: ≤ 90 mmHg and a decrease ≥ 20 mmHg from baseline 
• Diastolic BP: ≤ 50 mmHg and a decrease ≥ 15 mmHg from baseline 
• Pulse rate:  <=50 and decrease from baseline of >25% 
• Weight: Decrease ≥ 10% from baseline 
The following summaries will be produced for each vital sign parameter: 
• Number and percentage of patients with at least one post-baseline vital sign 
abnormality (in both directions, i.e. both elevated and below normal values). 
In addition, the following two listings will be produced by treatment arm: 
• Patients with clinically notable vital sign abnormalities. 
• All vital sign assessments will be listed by patient and vital sign parameter. 
In both listings, the clinically notable values will be flagged and also the assessments collected 
later than 30 days after the last treatment date will be flagged. 
3.9.4 
ECG 
All analyses of ECG data will be based on the average of all available replicate ECGs assessed 
by the central reader at each scheduled time point for each patient. ECG data will be summarized 
by presenting summary statistics of the raw data and change from baseline by treatment arm 
and time point. The following parameters will be assessed: QT, QTcF,  PR, and QRS intervals 
in ms, heart rate (bpm), and the overall interpretation if clinically significant abnormalities are 
present. The number and percentage of patients with notable abnormalities will be summarized. 
Individual listings will be provided by subject.  
Table 3-8 
Clinically notable ECG values 
ECG parameter (unit)  
Clinically notable criteria  
QT, QTcF (ms)  
New value of > 450 and ≤ 480 ms 
New value of > 480 and ≤ 500 ms 
New value of > 500 ms 
Increase from Baseline > 30 to ≤ 60 ms 
Increase from Baseline > 60 ms 
PR duration (ms) 
Increase > 25% from baseline and to PR duration > 200  
New value of > 200 ms 
QRS duration (ms) 
Increase > 25% from baseline and to QRS duration > 120 ms 
New value of > 120 ms  
Heart Rate (bpm)  
Decrease from Baseline of > 25% and to a value < 50 bpm 
Increase from Baseline of > 25% and to a value > 100 bpm 
A newly occurring ECG abnormality is defined as an abnormal post-baseline ECG finding that 


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is not present at Baseline. Baseline is defined as the last ECG measurements taken during the 
screening phase. The percentage of patients having notable ECG interval values is based on the 
number of patients at risk for the change with a value at baseline and post-baseline. 
3.9.5 
Cardiac imaging (MUGA / ECHO) 
Note: If there is any change in the methodology used throughout the study compared to baseline, 
the post-baseline values for which the methodology differs from baseline will be discarded in 
the tables presenting comparisons to baseline. 
For left ventricular ejection fraction (LVEF) a shift table using CTC grades for ’Ejection 
fraction - decrease’ as defined per CTCAE version v4.03 to compare baseline to the worst on-
treatment value will be provided.  
A listing of patients with newly occurring clinically significant abnormality will be produced 
by treatment arm. 
3.9.6 
Other safety data 
Other safety data (e.g. data relating to liver events) will be listed in the safety set. 
Data from other tests will be listed, notable values will be flagged, and any other information 
collected will be listed as appropriate. 
All assessments collected later than 30 days after the last treatment date will be flagged in the 
listings. 
Any statistical tests performed to explore the data will be used only to identify any interesting 
comparisons that may warrant further consideration. 
 
 
 
 
 
 
 
 
 
3.10 
Pharmacokinetic (PK) analyses 
3.10.1 
General principle 
All PK analyses for alpelisib and fulvestrant will be based on the PK Analysis set.  However, 
only samples taken within the following time windows around the scheduled time points and at 
steady state will be used for summary tables and profiles which are summarized by time point: 
• Pre-dose: prior to dosing on the assessment day and collected at approximately 24 ± 2 
hours after the last dose 


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• 1 h post-dose: within ± 10 minutes of the scheduled time point 
• 2, 4, 6 or 8 h post-dose: within ± 30 minutes of the scheduled time point 
In addition the following criteria for alpelisib samples considered at steady state must be met: 
• assessments with at least 3 continuous days of daily dosing at the planned dose (dose 
assigned at study entry) prior to the day of alpelisib PK assessment; 
• no vomiting occurs within the first 4 hours of the last dose (pre-dose trough samples); 
• no vomiting occurs within the first 4 hours of the current and last dose (post-dose sparse 
samples).  
All samples regardless of time window or steady state status will be used for the individual time 
profile figures. 
3.10.2 
PK concentrations 
Trough PK concentrations of alpelisib and fulvestrant will be summarized by visit and treatment 
group. Alpelisib sparse PK concentrations will be reported at Cycle 1 Day 15. 
Descriptive statistics of concentrations will be provided using steady state concentrations only 
and include n, number of non-zero concentrations, arithmetic mean, geometric mean, median, 
SD, coefficient of variation CV (%), geometric CV (%), minimum and maximum. Coefficient 
of variation CV (%) is calculated as follows from non-zero values: 100*(SD/arithmetic mean). 
Geometric CV (%) is calculated as follows from non-zero values:  
( )
(
) 1
ˆ
exp
100
%
CV
2 −
σ
⋅
=
                                       
where 
2ˆσ  denotes the variance of the log-transformed values. 
Geometric mean and arithmetic mean (SD) plots will also be graphically presented for trough 
concentration-time data.  Individual concentration-time profiles will be displayed graphically 
for trough concentrations (alpelisib and fulvestrant) and sparse concentrations (alpelisib only) 
separately. All PK concentration data will be listed as appropriate. 
3.10.3 
Population PK parameters for alpelisib 
The population PK analysis will be conducted in a separate report. 
 
 
 
 
 
 
  
 


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The relationship between alpelisib PK exposure and selected AESI as defined in Section 3.9.1.5 
 
 
 
 
 
 
3.10.5 
Handling missing and invalid values 
The lower limits of quantitation (LLOQ) are currently 5.0 ng/mL for alpelisib and 1.0 ng/mL 
for fulvestrant. Values below the assay LLOQ will be reported as 0 ng/mL. All concentrations 
below the LLOQ will be displayed in listings as zero with a flag and handled as zero in any 
calculations of summary statistics, but handled as missing for the calculation of the geometric 
means and their CV. Any missing PK parameter data will not be imputed.  
Invalid concentrations will be flagged in the PK concentration data set by the CP expert after 
the merge of clinical and bioanalytical data has taken place. Flagged values will not be included 
in summaries and will be listed only. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.12 
Interim analyses 
3.12.1 
Primary endpoint: Progression-free survival 
PIK3CA mutant cohort: 
Two interim analyses are planned after approximately 97 and 185 of the 243 targeted PFS 
events (40% and 76% information fractions respectively) have been documented. These 


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analyses are expected to take place around 19 and 25 months from the date of first patient 
randomized in the study. Approximately 243 patients are expected to be randomized when the 
97th PFS event occurs at the time of the first interim analysis if H0 is true (HR.=1). The primary 
intent of the first interim analysis is to allow the cohort to stop early for lack of efficacy (futility). 
There is no intent to carry out an analysis to declare superior efficacy at the time of the first 
interim analysis. The second interim analysis will allow the study to stop early for outstanding 
efficacy. The second interim analysis will only be carried out after all patients have been 
randomized in the PIK3CA mutant cohort and approximately 76% of the 243 targeted PFS 
events have been observed. 
The assessment of futility will be guided based on two criteria. 
A user-defined gamma spending function (γ=5) will be used as a beta-spending function to 
determine the non-binding futility boundary. One important feature of the design is that the 
efficacy stopping boundaries will not be affected by the presence of non-binding futility 
stopping boundaries. 
Based on the choice of α-spending and β-spending function described above, the futility 
boundary in terms of p-value scale at the interim is calculated as p =0.128 (or Z=1.134; hazard 
ratio=0.794). The observed (i.e. nominal) p-value has to be greater than 0.128 to conclude 
futility according to this criterion at the time of the first interim analysis.  
In addition to the stopping boundary based on the β-spending function described above, DMC 
members will be instructed to include in their recommendation whether the conditional 
probability of observing a clinically relevant PFS treatment effect at the final PFS analysis is 
less than 0.20, i.e.: 
Conditional probability (HRfinal ≤ 0.6¦ HRinterim) < 0.20 
This criterion uses the observed interim data and an assumption regarding the distribution of 
future unobserved data at the final analysis, conditioned under the alternative hypothesis 
(HR.=0.6). The futility boundary for this criterion in terms of p-value scale at the interim is 
calculated as p=0.068 (or |Z|=1.489; hazard ratio=0.739). Thus the observed (i.e. nominal) p-
value has to be greater than the p-value scale futility boundary = 0.068 to conclude futility 
according to this criterion. 
Details of the methodology as well as the operating characteristics for the futility criterion based 
on conditional probability is described in Section 4.7. 
Therefore at the time of the futility analysis, the PIK3CA mutant cohort may be stopped for 
futility if one or both of the criteria are met. 
In addition, the predictive probability of success based on the final planned number of PFS 
events will be calculated given the interim data, and provided to the DMC at the time of the 
futility interim analysis as supportive information. 
A Haybittle-Peto stopping boundary (as implemented in East 6.3) will be used for interim and 
final PFS analyses. At the second interim analysis, the observed p-value has to be less than or 
equal to 0.0001 (or Z=3.719) in order to conclude superior efficacy. If the study continues to 
final analysis, the p-value that will be used to declare statistical significance at the final analysis 
will be 0.0199 (Z=2.054). 


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Since the observed number of events at the interim analyses may not be exactly equal to the 
planned number of events, the efficacy and futility boundaries will need to be re-calculated (or 
updated) based on the actual number of observed events using the pre-specified Haybittle-Peto 
boundary and β-spending functions. Therefore, the observed p-values at the interim analyses 
will be compared with the updated boundaries. 
If the study continues to final analysis, the p-value that will be used to declare statistical 
significance at the final analysis will be based on the actual number of PFS events documented 
at the cut-off date for the final analysis and the alpha already spent at the interim analysis. 
Therefore, if the interim analyses were carried out after exactly 40% and 76% of the planned 
number of events, and the cohort continued until the final analysis, the observed p-value will 
have to be less than 0.0199 to declare statistical significance. If the number of events in the final 
analysis deviates from the expected number, the final analysis criteria will be determined so 
that the significance level is maintained at 0.02 in this cohort. 
Statistical properties of the group sequential design in this cohort are summarized in 
Table 3-10. 
 
Table 3-10 
Simulated probabilities to stop for futility or efficacy at the interim 
analysis in the PIK3CA mutant cohort 
Scenario 
Look 
# PFS 
events 
Simulated cumulative 
probabilities (%) 
Simulated incremental 
probabilities (%) 
Stop for 
efficacy 
Stop for 
futility 
Stop for 
efficacy 
Stop for 
futility 
Under H0 (HR=1) 
Interim 1 
97 
0 
92.98 
0  
92.98 
 
Interim 2 
185 
0.02 
- 
0.02 
- 
 
Final 
243 
0.98 
- 
0.96 
- 
Under Ha (HR=0.6) 
Interim 1 
97 
0.34 
15.31 
0.34 
15.31 
 
Interim 2 
185 
38.50 
- 
38.50 
- 
 
Final 
243 
83.95 
- 
45.45 
- 
Note: The study will not stop for outstanding efficacy at the first (futility) interim analysis. Simulation is 
performed in SAS v9.4 with number of simulations = 10,000 and randomization seed =111064 
 
3.12.2 
Key Secondary Endpoint: OS in the PIK3CA mutant cohort 
OS will be compared between the two treatment groups, provided the primary endpoint PFS is 
statistically significant favouring alpelisib. A hierarchical testing procedure will be adopted in 
this study and OS will be tested only if the primary efficacy endpoint PFS is statistically 
significant. A maximum of three analyses are planned for OS: 
• The first potential time point for OS analysis will be at the time of the PFS efficacy interim 
analysis after approximately 37% of the expected deaths are observed, at which point 
approximately 66 deaths are expected. If PFS is not statistically significant at this stage, 
then OS will not be tested, in which case the next potential time point for OS analysis will 
be at the time of the final PFS analysis after approximately 57% of the expected deaths are 


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observed, at which point approximately 101 deaths are expected to have been recorded in 
the clinical database. 
• If OS is not statistically significant at the first interim analysis, the 2nd OS analysis will be 
planned after approximately 85% of the expected deaths are observed, at which point 
approximately 151 deaths have been recorded in the clinical database. If OS is not 
statistically significant at this stage, a final analysis is planned at the time approximately 
178 deaths have been recorded. 
• If PFS is not statistically significant at the final analysis for PFS, then OS will not be tested. 
The type I error probability will be controlled by using a separate Lan-DeMets (O’Brien-
Fleming) alpha spending function independent of the Haybittle-Peto boundary used for the 
primary efficacy analysis of PFS at a 2.0% level of significance for the PIK3CA mutant cohort. 
This guarantees the protection of the overall type I error (α = 2.5%) across all hypotheses and 
the repeated testing of the OS hypotheses at the interim and the final analyses (Glimm 2010). 
This includes hypotheses associated with the secondary endpoints PFS and OS in the PIK3CA 
non-mutant cohort (PFS in the non-mutant cohort will be tested at a 0.5% level of significance 
if PoC is established). The trial allows for the stopping of a cohort for a superior OS result, 
provided the primary endpoint PFS has already been shown to be statistically significant 
favouring the alpelisib arm. Further, the exact nominal p-values that will need to be observed 
to declare statistical significance at the time of these analyses for OS will depend on the number 
of OS events that have been observed at the time of these analyses and the α for OS already 
spent at the time of earlier analyses. 
Given the hierarchical testing strategy of PFS and OS, the design concerning OS analyses will 
have the following characteristics based on simulations in East 6.3. The probabilities shown in 
Table 3-11are conditional probabilities (conditional on PFS being statistically significant) not 
marginal probabilities. 
At the final PFS analysis in the PIK3CA mutant cohort: 
• The cumulative probability to show efficacy on OS (alternative hypothesis Ha is true) by 
the final analysis is 71.57%; while the cumulative type I error (rejecting the null 
hypothesis H0 if H0 is true) is 1.91%. 
• The cumulative probability to detect efficacy on OS if the alternative hypothesis Ha is true 
is 19.14% at the first interim analysis, 56.60% at the second interim analysis and 71.57% 
at the final PFS analysis. 
Statistical properties the PIK3CA mutant cohort are summarized in Table 3-11. 
Table 3-11 
Simulated probabilities to stop for efficacy at 1st interim, 2nd interim, 
or final OS analysis in the PIK3CA mutant cohort 
Scenario 
Look 
# deaths 
Simulated 
cumulative 
probabilities (%)* 
Simulated incremental 
probabilities (%)* 
Stop for efficacy 
Stop for efficacy 
Scenario 1: The first IA for OS is performed at the time of the PFS IA for efficacy 
Under H0 (HR.=1) 
1st Interim 
66 
0.01 
0.01 


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Scenario 
Look 
# deaths 
Simulated 
cumulative 
probabilities (%)* 
Simulated incremental 
probabilities (%)* 
Stop for efficacy 
Stop for efficacy 
 
2nd Interim 
151 
1.11 
1.09 
 
Final OS 
178 
1.89 
0.79 
Under Ha (HR.=0.67) 
1st Interim 
66 
1.94 
1.94 
 
2nd Interim 
151 
57.01 
55.07 
 
Final OS 
178 
71.62 
14.61 
Scenario 2: The first IA for OS is performed at the time of the final PFS analysis 
Under H0 (HR.=1) 
1st Interim 
101 
0.17  
0.17  
 
2nd Interim 
151 
1.12  
0.95  
 
Final OS 
178 
1.91  
0.79  
Under Ha (HR.=0.67) 
1st Interim 
101 
19.14  
19.14  
 
2nd Interim 
151 
56.60  
37.46  
 
Final OS 
178 
71.57  
14.97  
Note: Simulations are performed in East 6.3 with number of simulations = 10,000 and randomization seed 
=37059. 
* Probabilities are reported as if OS was tested alone, regardless the testing strategy with PFS. The true 
probabilities should take into account the probability of PFS at each look. Simulated probabilities shown based 
on the alpha allocated for testing (p=0.02).  
At the time of final PFS analysis in this cohort, both PFS and interim OS analysis will be 
performed by the Sponsor's clinical team. Investigators and patients will remain blinded to 
study treatment and all patients will continue to be followed for OS until the final OS analysis 
(or earlier if OS reaches statistical significance at any of the interim analyses). 
3.12.3 
OS in the PIK3CA non-mutant cohort: 
OS will be compared between the two treatment groups, provided the PFS is statistically 
significant favouring alpelisib, in the PIK3CA non-mutant cohort. A hierarchical testing 
procedure will be adopted in this study and the OS analyses will be tested only if PFS is 
statistically significant. A maximum of three analyses are planned for OS: 
• at the time of the final analysis for PFS (provided PFS is statistically significant) when 
approximately 29% of the expected deaths are observed, at which point approximately 36 
deaths in the PIK3CA non-mutant cohort have been recorded (after approximately 18 
months from the first patient to be randomized in this cohort); 
• at the time when approximately 87% of the expected deaths are observed, at which point 
approximately 109 deaths in the PIK3CA non-mutant cohort have been recorded (after 
approximately 45 months from the first patient to be randomized in this cohort); 
• a final analysis for OS when approximately 125 deaths in the PIK3CA non-mutant cohort 
have been recorded (approximately 54 months from date of first patient to be randomized 
in this cohort). 
An α-spending function according to Lan-DeMets (O’Brien-Fleming will be used to maintain 
the overall type I error probability (Lan and DeMets 1983). The exact nominal p-values that 
will need to be observed to declare statistical significance at the time of these analyses for OS 


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will depend on the number of OS events that have been observed at the time of these analyses 
and the α for OS already spent at the time of earlier analyses. 
Given the hierarchical testing strategy of PFS and OS, the design concerning OS analyses will 
have the following characteristics based on simulations in East 6.3. The probabilities shown in 
Table 3-12 are conditional probabilities (conditional on PFS being statistically significant) not 
marginal probabilities. 
Table 3-12 
Simulated probabilities to stop for efficacy at 1st interim, 2nd interim, 
or final OS analysis in the PIK3CA non-mutant cohort 
Scenario 
Look 
# 
deaths 
Simulated cumulative 
probabilities (%)* 
Simulated incremental 
probabilities (%)* 
Stop for efficacy 
Stop for efficacy 
Under H0 (HR.=1) 
1st Interim 
36 
<0.001 
<0.001 
 
2nd Interim 
109 
0.31 
0.31 
 
Final OS 
125 
0.59 
0.28 
Under Ha 
(HR.=0.67) 
1st Interim 
36 
0.001 
0.001 
 
2nd Interim 
109 
24.59 
24.58 
 
Final OS 
125 
36.74 
12.15 
Note: Simulations are performed in East 6.3 with number of simulations = 10,000 and randomization 
seed =60030. 1st Interim analysis will be conducted at the time of final analysis for PFS 
* Probabilities are reported as if OS was tested alone, regardless the testing strategy with PFS. The 
true probabilities should take into account the probability of PFS at each look. Simulated 
probabilities shown based on the alpha allocated for testing (p=0.005). 
At the time of final PFS analysis in this cohort, both PFS and interim OS analysis will be 
performed by  the independent statistical group for the DMC. The Novartis Clinical team will 
remain blinded to study treatment allocations up until such point the PIK3CA mutant cohort 
can be unblinded. Investigators and patients will remain blinded to study treatment and all 
patients will continue to be followed for OS until the final OS analysis (or earlier if OS reaches 
statistical significance at any of the interim analyses). 
3.12.4 
Confidentiality of Interim OS results 
At the time of final PFS analysis in the PIK3CA mutant cohort, both PFS and interim OS 
analysis will be performed by the Sponsor’s clinical team. Investigators and patients will remain 
blinded to study treatment and all patients will continue to be followed for OS until the final 
OS analysis (or earlier if OS reaches statistical significance at any of the interim analyses). 
3.13 
Subgroup analysis 
3.13.1 
Safety 
The objective for carrying out these subgroup analyses is to identify potential safety issues that 
may be limited to a subgroup of patients, or safety issues that are more commonly observed in 
a subgroup of patients 
The main safety analyses will be repeated in the following subgroups of patients: 


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• Age >=65 vs age <65 years  
• Age >=75 vs age <75 years  
• Race (white vs Asian vs black or African American vs other) 
 
These main safety analyses include: 
• AEs, by SOC, PT, maximum CTCAE grade 
• Treatment-related AEs  by SOC, PT, maximum CTCAE grade 
• Serious adverse events (SAE) by  SOC, PT, maximum CTCAE grade 
•  
• For the AESI of Hyperglycemia only, a subgroup analysis by hyperglycemia diagnosis 
status at baseline per American Diabetes Association (ADA) 2017 will be presented:  
• Diabetic: FPG ≥ 7.0 mmol/l or 126 mg/dl or HbA1c ≥ 6.5 % vs.  
• Pre-diabetic: FPG 5.6- <7.0 mmol/l or 100-125 mg/dl or HbA1c 5.7- <6.5% vs.  
• Normal: [FPG <5.6 mmol/l or <100 mg/dl] and HbA1c <5.7% 
3.13.2 
Efficacy 
 
  
If the primary analysis for PFS is statistically significant in a cohort, subgroup analyses will be 
performed on the FAS with the same statistical model used for the point estimate in the full 
cohort. Analyses will be performed for each subgroup one by one, i.e. fitting a model using only 
patients available in the subgroup of consideration.  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


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3.14 
Sample size calculation 
The median TTP for fulvestrant in first line post-menopausal advanced breast cancer patients 
with endocrine sensitive disease is estimated to be between 8 months (Howell 2004) and 23 


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months in FIRST trial (Robertson 2014). For sample size calculation, it is assumed that 
approximately 8% patients in the PIK3CA mutant cohort and 15% of patients in the PIK3CA 
non-mutant cohort  will comprise these patients with an expected median PFS for fulvestrant of 
18 months. 
Two main studies have been reported assessing fulvestrant in relapsed advanced breast cancer: 
SoFEA trial with a median PFS of 4.8 months (Johnston 2013) and CONFIRM trial with a 
median PFS of 6.5 months (Di Leo 2010). However, in the SoFEA study after a first induction 
with fulvestrant at 500 mg, the dose of fulvestrant continued at 250 mg; in CONFIRM 
fulvestrant was given at 500 mg throughout. Approximately 92% patients in the PIK3CA 
mutant cohort and 85% of patients in the PIK3CA non-mutant cohort enrolled in the current 
study will have similar clinical features to the population treated in CONFIRM trial, therefore 
for sample size calculation, the median PFS for fulvestrant in this group is assumed to be 6.5 
months. 
For the overall population in the PIK3CA mutant cohort, the median PFS in the control arm 
(fulvestrant + placebo) is estimated via simulation to be around 7.0 months. 
For the overall population in the PIK3CA non-mutant cohort, the median PFS in the control 
arm (fulvestrant + placebo) is estimated via simulation to be around 7.4 months. 
It is expected that treatment with alpelisib + fulvestrant in both cohorts will result in a 40% 
reduction in the hazard rate (corresponding to an increase in median PFS from 7.0 months to 
11.67 months in the PIK3CA mutant cohort and from 7.4 months to 12.33 months in the 
PIK3CA non-mutant cohort, under the exponential model assumption). 
Patients with PIK3CA mutant status: 
If the true hazard ratio is 0.6 (under alternative hypothesis), a total of 243 PFS events are 
required to have 83.80% power at an one-sided overall 2.0% level of significance to reject the 
null hypothesis (HR.=1) using a log-rank test for a 3-look group sequential design using a 
Haybittle-Peto boundary to determine the efficacy boundary along with (i) a gamma spending 
function (γ = 5) and (ii) a conditional probability function to determine the non-binding futility 
boundaries. Assuming that 40% of the patients will have a PIK3CA mutant status, an enrollment 
rate of 12 patients per month during the first 6 months (5 per month with PIK3CA mutant status), 
35 patients per month up to 12 months (14 per month with PIK3CA mutant status) and 59 
patients per month afterwards (24 per month with PIK3CA mutant status) and 10% patients will 
be lost to follow-up for PFS final analysis, a total of 340 patients will need to be randomized in 
this cohort to the two treatment arms in a 1:1 ratio. Given the above assumptions, it is estimated 
that the 243rd PFS event will be observed at approximately 32 months from the date of first 
patient randomized in the cohort. 
The estimated timelines for interim and final PFS analyses are provided in Table 3-13. 
Table 3-13 
Estimated timelines for interim and final PFS analyses in the PIK3CA 
mutant cohort 
Look 
Months after 
randomization 
of the first 
patient 
Number of PFS events 
Number of patients expected to 
be randomized (HR.=1). 


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Interim 1 (futility) 
19 
97 
271 
Interim 2 (efficacy) 
25 
185 
340 
Final 
32 
243 
340 
Patients with PIK3CA non-mutant status: 
The proof of concept criteria require: 
(a) an estimate for PFS HR reaching a critical value i.e. HR ≤ 0.60 
(b) strong evidence that the treatment results in a HR that is better than the value of no interest. 
i.e. Posterior Probability (HR < 1) ≥ 90% 
Based on the dual criteria a minimum of 102 PFS events are required (please refer to Section 
3.8.2.2). Assuming an enrollment rate of 12 patients per month during the first 6 months (7 per 
month with PIK3CA non-mutant status), 35 patients per month up to 12 months (21 per month 
with PIK3CA non-mutant status) and 59 patients per month afterwards (35 per month with 
PIK3CA non-mutant status) and 10% patients will be lost to follow-up, 220 patients will be 
randomized (110 per arm), in order to observe the required 102 PFS events in approximately 
18 months (if the observed HR is 0.60 and the median PFS for the control arm is 7.4 months). 
The primary analysis to estimate the HR will be performed after approximately 102 PFS events 
have been observed. If the true HR is 1, the probability (obtained by simulation) to obtain a 
positive conclusion is 0.005; if the true HR is 0.50, the probability to meet efficacy criteria is 
0.813. If the true HR is 0.60 (reflecting the minimum clinically relevant difference), the 
probability to meet efficacy criteria is 0.491. Simulation results are provided in Table 3-14. 
Table 3-14 
Operating characteristics for PoC criteria in PIK3CA non-mutant 
cohort 
True HR 
True Median PFS 
alpelisib (months) 
Probability to PoC 
Expected duration 
of cohort (months) 
0.3 
24.67 
0.999 
21.0 
0.4 
18.50 
0.975 
19.7 
0.5 
14.80 
0.813 
18.7 
0.6 
12.33 
0.491 
18.0 
0.7 
10.57 
0.220 
17.4 
0.8 
9.25 
0.076 
16.9 
0.9 
8.22 
0.020 
16.5 
1.0 
7.4 
0.005 
16.0 
Assumes: (1) HR.=0.6, (2) true median PFS for fulvestrant = 7.4 months, (3) protocol 
planned accrual rates, (4) Analysis after 102 PFS events have been observed 
 
Audit size for BIRC assessed PFS in the PIK3CA mutant cohort 
The audit size of the sample-based BIRC assessment will be 50% of all randomized patients in 
the PIK3CA mutant cohort. Based on the audit size calculation approach proposed by Dodd, et 
al (2011), assuming investigator and BIRC assessments are similar and the estimated log of 


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investigator-based HR is -0.51 (i.e. HR.=0.60), the audit size of 50% will ensure that the upper 
bound of a one-sided 95% CI for BIRC-based log-hazard ratio has 94% probability of being 
below 0 (i.e. HR. < 1) if the correlation between investigator assessment and BIRC assessment 
is 0.65 (the estimated correlation based on data from the Bolero-2 [CRAD001Y2301] study in 
metastatic breast cancer). 
3.15 
Power for analysis of key secondary variable 
For first line patients no phase III data are available with single agent fulvestrant. Data from 
phase III studies have been reported with letrozole showing a median OS of 34 months 
(Mouridsen 2003) and with anastrozole showing a median OS of 38 months (Bergh 2012). OS 
data with fulvestrant alone in first line setting have been recently presented within the phase II 
study FIRST. In that study the median OS for fulvestrant was 54 months (Robertson 2014). 
Therefore, for sample size calculation, median OS for fulvestrant alone in the current study for 
patients with progression more than 12 months from completion of (neo)adjuvant endocrine 
therapy is assumed to exceed 50 months. 
Median OS for fulvestrant in relapsed post-menopausal advanced breast cancer patients is 
estimated to be between 19 months (SoFEA trial, Johnston 2013) and 26 months (CONFIRM 
trial, Di Leo 2013). For sample size calculation, the median OS for fulvestrant in second line is 
thus assumed to be 26 months. 
Based on the expected split of the patient population as mentioned in Section 3.14, the median 
OS of control arm is estimated via simulation to be approximately 30 months. It is hypothesized 
that adding alpelisib to fulvestrant will result in a 33% reduction in the hazard rate for OS 
(corresponding to an increase in median survival to 44.8 months). 
Patients with PIK3CA mutant status: 
OS will be compared between the two treatment groups, provided that the primary endpoint 
PFS is statistically significant in this cohort of patients. If the true hazard ratio is 0.67 (under 
alternative hypothesis), a total of 178 deaths are needed to be observed to have 72% power at 
an one-sided overall 2.0% level of significance to reject the null hypothesis (HR.=1) using a 
log-rank test and a 3-look group sequential design. Based on the same number of patients that 
are planned to be enrolled in this study to detect the primary endpoint and assuming 5% dropout 
rate by the time of the OS final analysis, it is estimated that these 178 deaths will be observed 
at approximately 54 months from the date of first patient to be randomized in this cohort. 
The estimated timelines for interim and final OS analyses are provided in Table 3-15. 
Table 3-15 
Estimated timelines for interim and final OS analyses in the PIK3CA 
mutant cohort 
Look 
Months after randomization of the first 
patient 
Number of OS events 
1st OS Interim at time of 
interim PFS analysis 
25 
66 
1st OS Interim at time of 
final PFS analysis 
32 
101 
2nd Interim 
45 
151 


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Final 
54 
178 
Patients with PIK3CA non-mutant status (secondary endpoint): 
OS will be compared between the two treatment groups, provided that the endpoint PFS is 
statistically significant in this cohort of patients. The final analysis of OS for the PIK3CA non-
mutant cohort will be performed at approximately 54 months from the date of first patient to be 
randomized in the PIK3CA non-mutant cohort. Based on the same number of patients that are 
planned to be enrolled in the PIK3CA non-mutant cohort and assuming 5% dropout rate by the 
time of the OS final analysis, it is estimated that approximately 125 deaths will be observed. If 
the true hazard ratio is 0.67 (under alternative hypothesis), a total of 125 deaths will allow 
36.1% power at a one-sided overall 0.5% level of significance to reject the null hypothesis 
(HR.=1) using a log-rank test and a 3-look group sequential design. 
The power calculations were conducted with software package East 6.3. 
The estimated timelines for interim and final OS analyses are provided in Table 3-16. 
Table 3-16 
Estimated timelines for interim and final OS analyses in the PIK3CA 
non-mutant/ cohort 
Look 
Months after randomization of the first 
patient 
Number of OS events 
1st Interim 
18 
36 
2nd Interim 
45 
109 
Final 
54 
125 
 
3.16 
Sample size considerations for PK analysis 
Sample size for PK analysis was based on feasibility only. 
4 
General Statistical Methodology 
4.1 
Baseline comparability 
Appropriate descriptive summary statistics of baseline variables (see Section 3.2) will be 
provided as in-text tables in the core CSR and also in Section 14 in the post-text tables. The 
summaries will be provided by cohort and grouped by treatment arms, but no p-values will be 
provided.  
4.2 
Center pooling 
All study centers will be combined for the analysis unless otherwise specified. No center effect 
will be assessed due to expected small size of centers. 


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4.3 
One-sided vs. two-sided test 
One-sided tests will be used in this study for the primary endpoint (PFS) and key secondary 
endpoint (OS) at the alpha levels specified in Section 3.8. Confidence intervals will be estimated 
as two-sided. 
4.4 
Time-to-event analyses 
The following sections present a general methodology to be used to analyze the following time-
to-event variables. 
4.4.1 
Analysis of time-to-event data with ties 
The STRATA statement in LIFETEST procedure will be used to analyze time to event data 
with ties. The PHREG procedure in SAS with option TIES=EXACT will be used to fit the Cox 
proportional hazards model.  
4.4.2 
Hypothesis and test statistic 
For the primary, key-secondary and secondary efficacy endpoints, the comparison between the 
two treatment groups will be performed using a stratified log-rank test at levels α described in 
Section 3.8. 
The stratified log-rank test (strata information will be based on the data obtained from IRT that 
was utilized for randomization) will be implemented as follows:  
General SAS code for the stratified log-rank test 
PROC LIFETEST data=dataset METHOD=KM; 
BY stratum; 
TIME survtime*censor(1); 
STRATA trt; 
RUN; 
/* stratum represents stratum variable (to be included for stratified analysis only);  
survtime represents variable containing event/censor times;  
censor represents censoring variable (1=censored, 0=event);  
trt represents treatment arm variable; */ 
For each of the K=2 strata, the LIFETEST procedure will be run with the STRATA statement 
including only the treatment variable. The TIME statement will include the survival time and a 
(right) censoring variable. 
4.4.3 
Kaplan-Meier estimates 
The survival function in each treatment arm will be estimated using the Kaplan-Meier (product-
limit) method as implemented in PROC LIFETEST (see examples above). Median survival for 
each treatment arm will be obtained along with 95% confidence intervals calculated from PROC 
LIFETEST output using the loglog option available within PROC LIFETEST, Kaplan-Meier 
estimates with 95% confidence intervals at specific time points will be summarized.  


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The Kaplan-Meier graphs will be constructed using Splus software. The statistics (test statistics, 
p-value, hazard ratio etc.) displayed on the graph will, however, be obtained from the SAS 
software. 
4.4.4 
Hazard ratio 
The hazard ratio as a measure of treatment effect will be derived from the Cox proportional 
hazards model using SAS procedure PHREG with TIES=EXACT option in the MODEL 
statement. The stratified unadjusted Cox model will be used (where the baseline hazard function 
is allowed to vary across strata) for the primary analysis, i.e. the MODEL statement will include 
only the treatment arm variable as a covariate and the STRATA statement will include 
stratification variable(s). The strata information will be based on the data obtained from IRT 
that was utilized for randomization. 
General SAS code for the stratified Cox model 
PROC PHREG data=dataset; 
MODEL survtime*censor(1)=trt / TIES=EXACT; 
STRATA stratum 1 stratum 2; 
RUN; 
/* survtime represents variable containing event/censor times; 
censor represents censoring variable (1=censored, 0=event); 
trt represents treatment arm variable; 
stratum 1 and stratum 2 represent IRT stratification variables */ 
Hazard ratio with two-sided 95% confidence interval will be based on Wald test. 
Note: Ideally, the hazard ratio and the confidence interval should be derived by a method 
consistent with the p-value calculation, i.e. in this case with log-rank test. This requirement 
would lead to the score test based intervals. However, score test-based confidence intervals are 
not available in SAS procedure PHREG therefore Wald test based intervals will be used instead. 
 
 
 
 
 
 
 
 
 
 
 
 


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4.5 
Group sequential design used in Phase III studies 
The statistical methodology for the interim analyses will be based on group sequential 
methodology. 
Since the exact number of events available for interim and final analyses cannot be predicted 
exactly in the clinical trial setting, the group sequential design will be implemented using the 
α- and β-spending function approach. This approach is flexible in dealing with any deviations 
from the targeted event totals, or unexpected changes to the plan. 
If the exact number of events observed at the interim and final analyses deviates from the target 
numbers described in the protocol, the actual critical boundaries will be derived using the pre-
specified error spending functions and the actual numbers of events observed.  
• At interim analyses, information fractions will be computed as the ratio of the number 
of events observed at the considered interim analysis relative to the number targeted 
for the final analysis, as described in the sample size section of the protocol.  
• At the final analysis in the PIK3CA mutant cohort, the critical value will be calculated 
using the exact number of observed events at the final cut-off date, considering the α-
levels spent at interim analyses and considering the actual correlation among the test 
statistics, in order to achieve a cumulative type I error smaller than the desired 


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significance level (i.e. smaller than 2.0% for a one-sided test in the PIK3CA mutant 
cohort). 
It is recognized that circumstances (that are either internal or external to the trial) may require 
changes in the scheduling of the interim analyses. In case an additional unscheduled interim 
analysis is requested (e.g. the DMC might request this analysis if the study duration is much 
longer than expected) the procedure to calculate stopping boundaries needs to be adapted 
accordingly. An adaptation is also required if the interim analysis is skipped, e.g. if recruitment 
is much faster than planned and an early efficacy comparison cannot be performed or is not 
considered necessary anymore. Both scenarios can be implemented without inflating the type-
I error, thanks to the error spending approach used for the group sequential design. The 
calculation of stopping boundaries needs to be adapted accordingly. 
4.5.1 
Alpha-spending function 
The stopping boundaries to be used for the efficacy test will be calculated using the α-spending 
function approach described in Lan and DeMets (Lan and DeMets, 1983). The spending 
function for one-sided test has the following functional form: 
 
This function generates stopping boundaries that closely resemble the O’Brien-Fleming 
boundaries (O’Brien and Fleming, 1979). 
4.5.2 
Beta-spending function 
The stopping boundaries to be used for the futility test will be calculated using the Gamma 
family β-spending function approach (Hwang et al, 1990). The spending function for one-sided 
test has the following functional form:  
β(t) = β (1 – e–γt) / (1 – e–γ), where t represents the information fraction  
A non-binding user-defined beta-spending function will be used to determine the futility 
boundary. The futility boundary will be constructed so that the critical value will be determined 
based on the gamma function (γ=5). The choice of non-binding nature of the futility stopping 
boundary ensures that the efficacy stopping boundaries are not affected. 
Negative values of γ yield convex spending functions that increase in conservatism as γ 
decreases, while positive values of γ yield concave spending functions that increase in 
aggressiveness as γ increases.  
4.5.3 
Calculation of stopping boundaries 
The stopping boundaries for PFS in the PIK3CA mutant cohort were calculated at the design 
stage by selecting a nominal p-value that met the high threshold of the efficacy criteria as 
determined in the protocol. 
The following description applies to the PIK3CA mutant cohort with 2 interim analyses 
allowing stopping for futility and outstanding efficacy and assumes a 1-sided test. For this study 
since there is no futility assessment in the second interim analysis, the formula is altered to fit 
the particular case.  
)
/
(
2
2
)
(
2
/
t
Z
t
α
α
Φ
−
=


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Let u(t1), u(t2), uF denote the upper critical boundaries for efficacy to be used for the test 
statistics Z1, Z2  and ZF at the 1st  interim, the 2nd interim and the final analysis, respectively, 
and let l(t1) denote the lower futility boundaries at the  1st interim analysis (note: lF = uF  by 
construct, i.e., the boundaries meet at the final look, thereby ensuring that a decision about the 
2nd hypotheses will indeed be made). Let P0 denote probabilities determined under the null 
hypothesis, and Pa denote probabilities under the alternative hypothesis (used for the sample 
size or power calculation). Furthermore, α(t) and β(t) are the predefined spending functions 
for efficacy and futility, respectively, and the desired overall significance level is α = 0.02 
(since a 1-sided test is assumed). 
The critical values u(t1) and l(t1) for the 1st interim analysis are obtained such that 
P0(Z1 ≥ u(t1)) = α(t1) and Pa(Z1 ≤ l(t1)) = β(t1), 
where α(t1)  and  β(t1), denote the  α-level and  β-level,  respectively, spent  at 
informationfraction t1  and determined from the corresponding spending functions (t1  is 
calculated using the actual number of events observed at 1st interim and assuming the final 
number of PFS events is 243). 
Critical boundaries for the second interim and the final analysis are calculated recursively 
such that efficacy boundaries do not depend on the futility boundaries. Given that the 
boundaries for the 1st interim analysis have been computed, the critical boundary for the 2nd 
interim analysis u(t2) is calculated such that 
α(t1) + P0(Z1 < u(t1), Z2 ≥ u(t2) ) = α(t2) 
(where t2  is  again calculated using the actual number of events observed at 2nd interim and 
assuming the final number of PFS events is 243). 
The boundary for the final efficacy analysis is calculated such that 
α(t2) + P0(Z1 < u(t1), Z2 < u(t2), ZF ≥ uF )= α = 0.02, 
where α is the cumulative alpha spent up to the final analysis. 
As a practical matter it is rather unlikely that the last analysis can be performed at the precise 
time point that the planned maximum information is attained. If the number of events in the 
final analysis deviates from the expected number, the final analysis criteria will be determined 
using the above formula, taking into account the alpha actually spent at each of the interim 
analyses and the actual correlation among the three test statistics Z1, Z2 and ZF, in such a way 
that the overall significance level across all analyses is maintained at 0.02. 
In practice, the calculation of the final analysis boundaries will be implemented in EAST 
Version 6.3 by the use of “Interim Monitoring” sheet associated with the study design which 
allows entering of cumulative events at the interim analysis and at the final analysis. 


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4.5.4 
Group sequential design with PFS as a primary endpoint, OS as a key 
secondary endpoint and controlling for multiplicity 
This statistical testing method described below addresses multiplicity issues arising from using 
a group sequential design when there are multiple endpoints involved. In this study, the primary 
endpoint is PFS in the PIK3CA mutant cohort and the key secondary endpoint is OS in the 
PIK3CA mutant cohort. There are also interim analyses that allows the PIK3CA mutant cohort 
to stop for futility (in the first interim) and for outstanding PFS efficacy (in the second interim 
analysis). Therefore, there are 2 sources of multiplicity: 
• Multiplicity arising due to the group sequential nature of the study design 
• Multiplicity arising due to testing two endpoints PFS and OS 
There is yet another complexity that arises due to the fact that the PFS events are expected to 
accrue faster than the OS events.  Since in most situations, there will be some delay between 
the PFS events and the OS events, the number of deaths expected at interim analysis as well as 
at the time of final PFS analysis might not be sufficient to have at least reasonable chance (i.e. 
statistical power) to achieve statistical significance for the key secondary endpoint. Therefore, 
it seems reasonable to perform (and pre-specify) the final analysis of overall survival at a later 
time point, when sufficient survival events have been observed. Since the final analysis for the 
key secondary endpoint may potentially happen after the primary analysis for PFS has been 
conducted, there may be up-to 3 analyses for OS. 
An intuitive hierarchical testing strategy is to test for the key secondary endpoint only if the 
primary endpoint is found to be significant, using the same level of significance α that was used 
to test the primary endpoint. However, as shown [Hung et al, 2007] this hierarchical strategy 
when applied in a group sequential design does not control the overall type I error rate (or the 
family-wise type I error probability) in the strong sense. It has been demonstrated that the 
correlation between the two endpoints and the effect size of the primary endpoint are two 
nuisance parameters that determine the level of the type I error probability of falsely concluding 
a positive effect on the secondary endpoint.  
The above multiplicity issues will be addressed by the use of a Haybittle–Peto boundary and an 
alpha spending function  δ(t) for PFS and OS respectively (note: these are two different 
spending functions on two different information fraction scales), and by implementing the 
following testing strategy. Notations used in the Table are defined as follows:  
PIK3CA Mutant Cohort 
• Let H0PFSmut and H0OSmut denote the null hypotheses for testing PFS and OS 
respectively in the PIK3CA mutant cohort.  
• Let αmut(t) and δmut(t) denote the alpha-spending functions for PFS and OS, 
respectively. 
• Let s1mut <s2mut < s3mut<s4mut<s5mut denote the time points for:  
 First interim (futility) analysis (driven by PFS events), 
 Second interim analysis (driven by PFS events, first OS interim analysis) 
 Planned final analysis of PFS when targeted number of PFS events is expected to 
be observed  (first OS interim analysis, if not tested at s2) 


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 Planned second interim analysis of OS.  
 Planned final analysis of OS 
• Let tPFS(s1mut), tPFS(s2mut), tPFS(s3mut)  represent information fractions for PFS at time 
points s1mut, s2mut, s3mut, respectively. 
• Let tOS(s2mut), tOS(s3mut), tOS(s4mut), tOS(s5mut) represent information fractions for OS at time 
points s2mut, s3mut, s4mut, s5mut, respectively. 
• umut(tk) and vmut(tk) are the efficacy stopping boundaries for PFS and OS, respectively, 
at information fraction tk. 
• lmut(t(PFS(s1mut))) is the futility stopping boundaries for PFS at the first interim analysis 
Using the following testing strategy, the overall type-I error rate can be controlled: 
1. During the first PFS interim analysis, test PFS at αmut(tPFS(s1mut)):  
o If the futility boundary for PFS, lmut(tPFS(s1mut)) is crossed then stop the study 
for futility, otherwise go to step 2.  
o Note there is no intent to test OS at the first PFS interim analysis. 
2. During the second PFS interim analysis, test PFS at α=0.0001:  
o If the PFS efficacy boundary umut(tPFS(s2mut)) is crossed then test OS at 
δmut(tOS(s2mut)).  
o If the OS efficacy boundary vmut(tOS(s2mut)) is also crossed then we will stop the 
study for superior efficacy, and no more testing will be done for either PFS or 
OS.  
o If umut(tPFS(s2mut)) is crossed but vmut(tOS(s2mut)) is not crossed then we will stop 
testing for PFS, however OS will be tested as planned at s4mut (Step 4).  
o If umut(tPFS(s2mut)) is not crossed then OS will not be tested during the second 
interim analysis; and go to step 3. 
3. During the final PFS analysis, test PFS at α=0.0199: 
o If the PFS efficacy boundary umut(tPFS(s3mut)) is crossed then test OS at 
δmut(tOS(s3mut)).  
o If the OS efficacy boundary vmut(tOS(s3mut)) is also crossed then no more testing 
for either PFS or OS.  
o If umut((tPFS(s3mut)) is crossed but vmut(tOS(s3mut)) is not crossed then we will 
continue test OS as planned (go to step 4).  
o If umut(tOS(s3mut)) is not crossed then OS will not be tested; and no more testing 
on either PFS or OS. 
4. During the planned second OS interim analysis, test OS at δmut(tOS(s4mut)). If the OS 
efficacy boundary vmut(tPFS(s4mut)) is crossed then no more testing. If not then go to 
step 5. 
5. During the planned final OS analysis, test OS at δmut(tOS(s5mut)). The study will be 
stopped at this step regardless of the outcome. 
PIK3CA Non-mutant Cohort 
 


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• Let H0OSnonmut denote the null hypotheses for testing OS in the PIK3CA non-mutant 
cohort.  
• Let δnonmut(t) denote the alpha-spending function for OS. 
• Let s1nonmut <s2nonmut < s3nonmut denote the time points for:  
 Planned final analysis of PFS when targeted number of PFS events is expected to 
be observed  (first OS interim analysis) 
 Planned second interim analysis of OS.  
 Planned final analysis of OS 
• Let tOS(s1nonmut), tOS(s2nonmut), tOS(s3nonmut) represent information fractions for OS at time 
points s1nonmut, s2nonmut, s3nonmut respectively. 
• vnonmut(tk) are the efficacy stopping boundaries for OS, at information fraction tk. 
Using the following testing strategy, the overall type-I error rate can be controlled: 
1. During the final PFS analysis, test PFS at 0.005: 
o If the PFS efficacy boundary is crossed then test OS at δnonmut(tOS(s1nonmut)).  
o If the OS efficacy boundary vnonmut(tOS(s1nonmut)) is also crossed then no more 
testing for OS.  
o If the PFS efficacy boundary  is crossed but vnonmut(tOS(s1nonmut)) is not crossed 
then we will continue to test OS as planned (go to step 2).  
2. During the second OS interim analysis, test OS at δnonmut(tOS(s2nonmut)). If the OS 
efficacy boundary vnonmut(tPFS(s2nonmut)) is crossed then no more testing. If not then 
go to step 3. 
3. During the planned final OS analysis, test OS at δnonmut(tOS(s3nonmut)). The study 
will be stopped at this step regardless of the outcome. 
4.6 
Statistical methodology and operating characteristics – PFS 
futility criteria in the PIK3CA mutant cohort 
At the time of the futility analysis, the cohort may be stopped for futility if one or both of the 
following criteria are met: 
• The observed (i.e. nominal) p-value >  0.128   
• Conditional Probability (HRfinal ≤ 0.6¦ HRinterim) < 0.20 
Criterion (2) uses the observed interim data and an assumption regarding the distribution of 
future unobserved data in the two treatment groups conditioned under the alternative hypothesis 
(HRHa). Under the alternative hypothesis, the following formula (Jennison and Turnbull 2000 
formula 10.2) can be used to find the futility boundary on the Z-statistic scale (zt) for criterion 
(2) that satisfies: 
Φ
⎣
⎢
⎢
⎡
−
1
√1 −𝑡𝑡
⎝
⎛𝑧𝑧𝛼𝛼′ −√𝑡𝑡𝑧𝑧𝑡𝑡−√1 −𝑡𝑡   −log  𝐻𝐻𝐻𝐻𝐻𝐻𝑎𝑎  
ට൬
𝑎𝑎
𝐷𝐷(1 −𝑡𝑡)൰⎠
⎞
⎦
⎥
⎥
⎤
< 0.2 
where: 


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𝑎𝑎 = 
(𝑟𝑟+1)2
𝑟𝑟 
   with 𝑟𝑟:1 randomization ratio for treatment and control, 
𝐷𝐷: Total number of PFS events, 
𝑡𝑡:  Information fraction at the futility interim analysis (i.e. 0.4) 
𝑧𝑧𝛼𝛼′: Final boundary on Z scale, 
𝑧𝑧𝑡𝑡: Observed value on Z scale at futility interim 
The critical value for the Z-statistic at the futility interim analysis that will ensure criterion (2) 
is satisfied is |zt| = 1.489. The futility boundary in terms of p-value scale is thus calculated as p 
=0.068. 
The operating characteristics of the revised futility criteria are provided in Table 4-1. 
Table 4-1 
Operating characteristics for PFS futility criteria in the PIK3CA mutant 
cohort 
Futility Criteria 
Probability to be stopped for futility 
True HR 
Under Criterion 1 only 
Under Criterion 2 
1.0 
86.95% 
92.98% 
0.6 
8.89% 
15.31% 
Criterion 1: Observed (i.e. nominal) p-value greater than 0.128 
Criterion 2: Conditional Probability (HRfinal ≤ 0.6¦ HRinterim) < 0.20 
Note: Operating characteristics for criterion 1 performed in East 6.3 with 
number of simulations = 10,000 and randomization seed =37275. 
Operating characteristics for criterion 2 performed in SAS v9.4 with 10,000 
simulations and random seed = 111064 
 
4.7 
Statistical design and operating characteristics – PFS in the 
PIK3CA non-mutant cohort 
A Bayesian double criteria-based design is used to estimate the treatment effect in the PIK3CA 
non-mutant cohort, the methodology and operating characteristics based on simulation are 
detailed below. 
4.7.1 
Bayesian methodology for proof of concept criteria 
Let θ denote the natural logarithm of the hazard ratio (HR) of PFS (experimental arm vs. control, 
i.e. θ < 0 indicates efficacy in favor of the experimental arm i.e. alpelisib + fulvestrant) and ym 
denote the log(HR) estimated from a Cox proportional Hazards model with treatment as 
covariate based on m observed events and then using asymptotic theory of the log hazard ratio 
(Schoenfeld 1981): 
 
Ym~N(θ,4/m) 
Further assume θ follows a conjugate normal prior distribution, written as 
 
θ ~N(θ0, 4/n0) 


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where θ0 is the specified prior mean and the prior variance 4/n0, n0 is the number of events worth 
of prior information. 
This results in a posterior distribution of θ as 
 
θ| ym ~ N(φ ym,+ (1- φ ) θ0, 4/(m+n0)) 
where φ = m/(m+n0) and in this study we consider a non-informative prior with n0=0. 
Therefore the posterior distribution is of the following form; 
 
θ| ym ~ N(ym, 4/m) 
The cumulative posterior distribution will be used to derive the probability that the true HR is 
less than 1. 
4.7.2 
Proof of concept (PoC) criteria 
The following PoC criteria, based on analysis of PFS using Cox proportional Hazards model 
with treatment as covariate, are considered; 
• Estimated HR ≤ 0.6, and 
• Posterior Probability (HR < 1) ≥ 90% 
Both criteria need to be met in order to meet primary objective for this part of the study and test 
PFS in this cohort using a stratified log-rank test at one-sided 0.5% level of significance. The 
first criterion is met if the estimated HR is 0.6 or less which is the minimum HR of clinical 
interest. The second criterion provides reasonable evidence that the estimated HR is better than 
the value of no interest (HR=1) and also guarantees a level of precision for the estimate of HR. 
4.7.3 
Sample size considerations and simulation details 
Based on the assumption that log (HR) is normally distributed, then the minimum number of 
events to satisfy criterion (b) can be calculated (Schoenfeld 1981) as: 
# events = 4 (z1-α + Z1-β)2 / θ2 
Taking, θ = log(0.6), and one-sided, α=0.005, β=0.5, then 102 events are required. That is, with 
at least 102 events if the estimated HR is < 0.6 then criterion (b) in Section 4.7.2 will be met. 
Assuming an enrollment rate of 10 patients during the first 6 months (7 with PIK3CA non-
mutant status), 30 patients up to 12 months (21 with PIK3CA non-mutant status) and 50 patients 
afterwards (35 with PIK3CA non-mutant status) and 10% patients will be lost to follow-up, 220 
patients will be randomized (110 per arm), in order to observe the required 102 events in the 
two arms in approximately 18 months (if the observed HR is 0.6 and the median PFS for the 
control arm is 7.4 months). 
The primary analysis to estimate the HR will be performed after approximately 102 PFS events 
have been observed. If the true HR is 1, the probability (obtained by simulation) to obtain a 
positive conclusion is 0.005. If the true HR is 0.60 (reflecting the minimum clinically relevant 
difference), the probability to meet efficacy criteria is 0.491. In addition if the true HR is 0.6 
and the PoC is met, the probability (by simulation) to also observe a positive result with formal 
testing is 0.983. 


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Table 4-2 
Operating characteristics for PoC criteria in PIK3CA non-mutant 
cohort 
True HR 
True Median 
PFS alpelisib 
(months) 
Probability to meet PoC 
Probability formal testing is 
positive given PoC is met* 
0.3 
24.67 
0.999 
0.999 
0.4 
18.50 
0.975 
0.999 
0.5 
14.80 
0.813 
0.994 
0.6 
12.33 
0.491 
0.983 
0.7 
10.57 
0.220 
0.972 
0.8 
9.25 
0.076 
0.970 
0.9 
8.22 
0.020 
0.956 
1.0 
7.4 
0.005 
0.940 
Assumes: (1) HR.=0.6, (2) true median PFS for fulvestrant = 7.4 months, (3) protocol planned accrual rates,  
(4) Analysis after 102 PFS events have been observed 
* Probabilities conditional on PoC criteria being met. Formal testing using log-rank test at a one-sided,  
α=0.005 
 


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4.8 
Audit-based BIRC assessment of PFS 
NCI method 
The auxiliary variable estimator of the NCI audit-based method (Dodd et al. 2011) has the form 
𝜃𝜃෨𝐶𝐶= 𝜃𝜃෠𝐶𝐶𝐶𝐶+ 𝜆𝜆̂൫𝜃𝜃෠𝐿𝐿𝐴𝐴̅ −𝜃𝜃෠𝐿𝐿𝐿𝐿൯, 
where 𝜃𝜃෠𝐶𝐶𝐶𝐶, 𝜃𝜃෠𝐿𝐿𝐴𝐴̅ and 𝜃𝜃෠𝐿𝐿𝐿𝐿 are estimators of the log-hazard ratio based on the central assessment 
in the audited subset of patients, the local assessment in the nonaudited subset of patients, and 
the local assessment in the audited subset, respectively. 𝜆𝜆̂ is defined as 𝜌𝜌ො√𝛿𝛿(1 −𝛿𝛿)√(𝑉𝑉෠𝐶𝐶𝐶𝐶/𝑉𝑉෠𝐿𝐿),  
where 𝑉𝑉෠𝐶𝐶𝐶𝐶 and 𝑉𝑉෠𝐿𝐿 are variance estimators of  𝜃𝜃෠𝐶𝐶𝐶𝐶 and 𝜃𝜃෠𝐿𝐿 (the estimator of log-HR based on the 
local assessment in all patients) respectively, 𝛿𝛿 is the proportion of patients in the audited subset, 
and 𝜌𝜌ො is an estimator of the correlation between 𝜃𝜃෠𝐿𝐿𝐿𝐿 and 𝜃𝜃෠𝐶𝐶𝐶𝐶. For the latter, a bootstrap approach 
will be used:  
• Within the audited subset of size m, m patients will be sampled with replacement. 
Using this sample of m patients, the log-hazard ratio will be estimated based on the 
local and central assessments separately;  
• This procedure will be repeated 1000 times, giving rise to 1000 pairs (local and 
central) of estimates of the log-HR;  
• The sample correlation coefficient between these pairs of estimates will be used for 𝜌𝜌ො. 
The log-hazard ratio estimates contributing to the auxiliary variable estimate and corresponding 
variance estimates will be based on stratified Cox proportional hazards models, with 
stratification based on the randomization stratification factors. The upper bound of a 95% CI 
for 𝜃𝜃𝐶𝐶 will be calculated assuming asymptotic normality of 𝜃𝜃෨𝐶𝐶 and using the variance estimator 
for 𝜃𝜃෨𝐶𝐶 provided in Dodd et al., 2011, i.e. 𝑉𝑉෠𝐶𝐶𝐶𝐶{1 − 𝜌𝜌ො2(1 −𝛿𝛿)}. 
PhRMA method 
The early discrepancy rate (EDR) and late discrepancy rate (LDR) will be calculated using the 
equations below together with information in Table 4-3. 
EDR = (b + a3)/(a + b); 
LDR = (c + a2)/(b + c + a2 + a3). 
Table 4-3 
Local versus central disease progression assessments 
 
Central 
Local 
PD 
No PD 
PD 
a = a1 + a2 + a3 
b 
No PD 
c 
d 
a1: number of agreements on timing and occurrence of PD 
a2: number of times local PD declared later than central PD 
a3: number of times local PD declared earlier than central PD  
The timing of local and central response assessment (for subjects with complete agreement of 
local and central sources) will be considered to agree if they occur within ±7 days of each other, 
aligned with the protocol-specified window for tumor assessments. 


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5 
References 
Amit O, Mannino F, Stone AM, Bushnell W, Denne J, Helterbrand J and Burger HU. Blinded 
independent central review of progression in cancer clinical trials: results from a meta-
analysis. European Journal of Cancer 2011; 47: 1772-1778 
Bergh J, Jönsson PE, Kerstin Lidbrink E,Trudeau et al (2012) FACT: An Open-Label 
Randomized Phase III Study of Fulvestrant and Anastrozole in Combination Compared With 
Anastrozole Alone As First-Line Therapy for Patients With Receptor-Positive 
Postmenopausal Breast Cancer. J.Clin.Oncol.; 30 (16): 1919-1925. 
Bretz F, Posch M, Glimm E, et al (2011). Graphical approaches for multiple comparison 
procedures using weighted Bonferroni, Simes or parametric tests. Biometrical Journal; 53, 894-
913.   
Bretz, F., Maurer, W., and Hommel, G. (2009) Test and power considerations for multiple 
endpoint analyses using sequentially rejective graphical procedures. Statistics in Medicine 30, 
1489-1501.  
  
Clopper, C.; Pearson, E.S. (1934). "The use of confidence or fiducial limits illustrated in the 
case of the binomial". Biometrika 26: 404–413 
National Cancer Institute (2010) Common Terminology Criteria for Adverse Events 
(CTCAE) v.4 data files and related documents:http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
De Buck SS, Jakab A, Boehm M, Bootle D, Juric D, Quadt C, Goggin TK (2014) Population 
pharmacokinetics and pharmacodynamics of BYL719, a phosphoinositide 3-kinase 
antagonist, in adult patients with advanced solid malignancies. Br J Clin Pharmacol; 
78(3):543-555 
Di Leo A, Jerusalem G, Petruzelka L, et al (2010) Results of the CONFIRM phase III trial 
comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with 
estrogen receptor-positive advanced breast cancer.J Clin Oncol. Oct 20;28(30):4594-600. 
Erratum in: J Clin Oncol.2011 Jun 1;29(16):2293. 
Di Leo A, Jerusalem G, Petruzelka L, Torres R, et al (2013) Final Overall Survival: 
Fulvestrant 500 mg vs 250 mg in the Randomized CONFIRM Trial. JNCI J Natl Cancer Inst 
106(1). 
Dodd E L, Korn L E, Freidlin B, Gray R, Bhattacharya S. An audit strategy for progression-
free survival. Biometrics, Vol 67, Issue 3; 1092-99, 2011 
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47 
Fayers PM, Aaronson NK, Bjordal K, et al, on behalf of the EORTC Quality of Life Group 
(2001) The EORTC QLQ-C30 Scoring Manual (3rd Edition). Published by: European 
Organisation for Research and Treatment of Cancer, Brussels 2001 
Fleming TR, Harrington DP, O’Brien PC (1984). Designs for group sequential tests. 
Controlled Clinical Trials 5: 348-361. 


Novartis 
Confidential 
Page 101 
SAP 
 
BYL719C/CBYL719C2301 
 
Fleming TR, Rothmann MD, Lu HL (2009). Issues in Using Progression-Free Survival When 
Evaluating Oncology Products. Journal of Clinical Oncology 27, 2874-2880 
Glimm, E., Maurer, W., and Bretz, F. (2010) Hierarchical testing of multiple endpoints in 
group-sequential trials. Statistics in Medicine 29, 219-228 
Haybittle JL (1971). Repeated assessments of results in clinical trials of cancer treatment". 
British. Journal of  Radiology 44 (526),: 793–797 
Hernan M., Brumback B., Robins J. Marginal structural models to estimate the causal effect of 
zidovudine on the survival of HIV-positive men. Epidemiology, 11(5), 561-570 (2000). 
Howell A, Robertson JF, Abram P, et al (2004) Comparison of fulvestrant versus tamoxifen 
for the treatment of advanced breast cancer in postmenopausal women previously untreated 
with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol.; 
22(9):1605- 1613. 
Hung HM, Wang SJ and O’Neil R (2007) Statistical considerations for testing multiple 
endpoints in group sequential or adaptive clinical trials. Journal of Biopharmaceutical Statistics 
17: 1201-1210.   
Hwang, I.K. Shih, W.J. and DeCani, J.S. (1990). Group sequential designs using a family of 
type I error probability spending functions. Statistics in Medicine 9, 1439-1445 
Jennison C, Turnbull B (2000) Group sequential methods with applications to clinical trials. 
Boca Raton, Chapman & Hall/CRC 
Johnston SR, Kilburn LS, Ellis P, et al (2013) SoFEA investigators. Fulvestrant plus 
anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase 
inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or 
metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet 
Oncol.;14(10):989-998. 
Lan, K. K. G. & Demets, D. L. (1983). Discrete sequential boundaries for clinical trials. 
Biometrika 70, 659-63 
Maurer W and Bretz F (2013) Memory and other properties of multiple test procedures 
generated by entangled graphs. Statist. Med. 2013, 32 1739–1753. 
Mouridsen H, Gershanovich M, Sun Y, et al (2003) Phase III study of letrozole versus 
tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis 
of survival and update of efficacy from the International Letrozole Breast Cancer Group. J 
Clin Oncol; 21 (11): 2101-09. 
O'Brien PC, Fleming TR (1979). A multiple testing procedure for clinical trials, Biometrics. 
35(3):549-56. 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity 
and activity impairment instrument. Pharmacoeconomics. 1993 Nov;4(5):353-65 
Robertson J, Lindemann J, Sally Garnett S, et al (2014). A Good Drug Made Better: The 
Fulvestrant Dose-Response Story Clin Breast Cancer, Vol. 14, No. 6, 381-9. 


Novartis 
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Page 102 
SAP 
 
BYL719C/CBYL719C2301 
 
Schoenfeld D (1981). The asymptotic properties of nonparametric tests for comparing 
survival distributions. Biometrika 68, 316-319.