Conditions: Breast Cancer
Keywords: advanced breast cancer PIK3CA CDK 4/6 inhibitor fulvestrant letrozole HR+ HER2-negative post menopausal pre-menopausal aromatase inhibitor endocrine treatment AI ET
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 383
Healthy volunteers: no

Brief summary:
The purpose of this study was to assess the efficacy and safety of treatment with alpelisib plus endocrine therapy (either fulvestrant or letrozole) in patients with hormone receptor (HR) positive, HER2-negative advanced breast cancer (aBC), harboring PIK3CA mutations, whose disease had progressed on or after prior treatments.

Detailed description:
The study comprised two phases:

1. Core Phase: included a treatment phase for all subjects from first subject first treatment (FSFT) until disease progression, unacceptable toxicity, or death until 18 months post last subject first treatment (LSFT) + 1 month safety follow-up (total 19 months post LSFT), discontinuation from the study treatment for any other reason, or sponsor terminates the study. At the start of the Core Phase, subjects were assigned to Cohort A, Cohort B, or Cohort C based on previous therapy as follows:

   * Cohort A: alpelisib (300 mg oral QD) + fulvestrant (500 mg intramuscular (IM)) to subjects whose last prior treatment was a CDK4/6i plus any AI;
   * Cohort B: alpelisib (300 mg oral QD) + letrozole (2.5 mg oral QD) to subjects whose last prior treatment was a CDK4/6i plus fulvestrant;
   * Cohort C: alpelisib (300 mg oral QD)+ fulvestrant (500 mg IM) to subjects who failed prior AI based therapy and whose last prior treatment was systemic chemotherapy or endocrine therapy (as monotherapy or in combination with targeted treatment except CDK 4/6i + AI). Endocrine therapy included letrozole, fulvestrant and CDK 4/6 inhibitor plus fulvestrant.
2. Extension Phase: included a treatment phase starting at the end of the treatment Core Phase until last subject last visit(LSLV) (up to 36 months). Following the end of the Core Phase, subjects continuing to derive benefit from study treatment who were not eligible for Post-Study Drug Supply (PSDS) in their country based on local regulations were re-consented and transitioned to the Extension Phase. Subjects continued on their existing study treatment assigned in the Core Phase until disease progression/lack of clinical benefit or any other reason for which the subject may have been discontinued from study treatment. If PSDS became available for a subject, the subject was to be discontinued from the study and to access treatment via PSDS. When subjects discontinued treatment for any reason, the end of treatment visit was performed after discontinuation of the medication , followed by safety follow-up 30 days after last dose.

A total of 340 subjects were planned to be enrolled, with approximately 112 subjects in each cohort. In the Core Phase, 379 subjects were analyzed, with 127 subjects in Cohort A, 126 subjects in Cohort B, and 126 subjects in Cohort C. In the Extension Phase, 11 subjects were analyzed, with 1 subject in Cohort A and 10 subjects in Cohort C.

Arms:
arm 1: Participants who received any Cyclin-Dependent Kinases 4 and 6 inhibitor (CDK 4/6i) plus aromatase inhibitor (AI) as immediate prior treatment will receive alpelisib + fulvestrant arm 2: Patients who received any CDK 4/6i plus fulvestrant as immediate prior treatment will receive alpelisib + letrozole arm 3: Participants who received systemic chemotherapy or endocrine therapy (ET) (as monotherapy or in combination with targeted treatment except CDK 4/6i + AI) as immediate prior treatment will receive alpelisib + fulvestrant.

Interventions: intervention 1: Alpelisib intervention 2: Fulvestrant intervention 3: Letrozole intervention 4: Goserelin intervention 5: Leuprolide
Intervention descriptions: intervention 1: 300 mg of alpelisib film-coated tablets administered orally once daily intervention 2: 500 mg of fulvestrant via intramuscular injection administered on Days 1, 15 on Cycle 1 and Day 1 at each cycle thereafter. Cycle=28 days intervention 3: 2.5 mg of letrozole film-coated tablets administered orally once daily intervention 4: 3.6 mg of goserelin via injectable subcutaneous implant administered every 28 days. Only for men in Cohort B and premenopausal women. intervention 5: 7.5 mg of leuprolide via injectable intramuscular depot administered every 28 days. Only for men in cohort B and premenopausal women.

Protocol document:
Prot_000.pdf: 
Novartis Research and Development
BYL719, Alpelisib
Oncology Clinical Protocol CBYL719X2402 / NCT03056755
BYLieve: A phase II, multicenter, open-label, three-cohort, 
non-comparative study to assess the efficacy and safety of 
alpelisib plus fulvestrant or letrozole in patients with 
PIK3CA mutant, hormone receptor (HR) positive, HER2-
negative advanced breast cancer (aBC), who have 
progressed on or after prior treatments
Document type
Amended Protocol Version 
EUDRACT number
2016-004586-67
Version number
06 (Clean)
Clinical Trial phase
II
Release date
28-Mar-2023
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template version 22-Jul-2016


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................8
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................14
Amendment 6 (28-Mar-2023) ...........................................................................................16
Amendment 5 (14-Jan-2022).............................................................................................18
Amendment 4 (31-Oct- 2019) ...........................................................................................23
Amendment 3 (30-Jan-2019).............................................................................................28
Amendment 2 (02-May-2018)...........................................................................................32
Amendment 1 (30-Jan-2018).............................................................................................34
Protocol summary:.............................................................................................................39
1
Background........................................................................................................................44
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............44
1.1.1
Hormone receptor-positive breast cancer..............................................44
1.1.2
Treatment options for HR+, HER2- negative premenopausal aBC......45
1.1.3
PI3K pathway........................................................................................46
1.1.4
PI3K pathway in HR+ breast cancer.....................................................47
1.2
Introduction to investigational treatment(s) and other study treatment(s).............48
1.2.1
Overview of letrozole............................................................................48
1.2.2
Overview of fulvestrant.........................................................................49
1.2.3
Overview of LHRH agonists.................................................................50
1.2.4
Overview of alpelisib............................................................................51
1.2.5
Overview of the combination of alpelisib and endocrine treatments....57
1.2.6
Potential for drug interactions...............................................................58
2
Rationale............................................................................................................................59
2.1
Study rationale and purpose...................................................................................59
2.2
Rationale for the study design ...............................................................................60
2.3
Rationale for dose and regimen selection..............................................................61
2.4
Rationale for choice of combination drugs............................................................62
2.5
Rationale for choice of comparators drugs............................................................62
2.6
Risks and benefits..................................................................................................62
2.6.1
Potential benefit for participants...........................................................62
2.6.2
Potential risks to clinical trial participants............................................63


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Risk management strategies..................................................................63
2.6.4
Rationale for Public Health Emergency mitigation procedures............64
3
Objectives and endpoints...................................................................................................64
4
Study design ......................................................................................................................67
4.1
Description of study design ...................................................................................67
4.2
Timing of interim analyses and design adaptations...............................................70
4.3
Definition of end of study......................................................................................70
4.4
Early study termination..........................................................................................71
5
Population..........................................................................................................................71
5.1
Patient population..................................................................................................71
5.2
Inclusion criteria ....................................................................................................71
5.3
Exclusion criteria...................................................................................................74
6
Treatment...........................................................................................................................77
6.1
Study treatment......................................................................................................77
6.1.1
Dosing regimen.....................................................................................77
6.1.2
Ancillary treatments..............................................................................81
6.1.3
Rescue medication ................................................................................81
6.1.4
Guidelines for continuation of treatment ..............................................81
6.1.5
Treatment duration................................................................................81
6.2
Dose escalation guidelines.....................................................................................81
6.3
Dose modifications................................................................................................81
6.3.1
Dose modification and dose delay ........................................................81
6.3.2
Follow-up for toxicities.........................................................................92
6.3.3
Anticipated risks and safety concerns of the study drug.......................97
6.4
Concomitant medications ......................................................................................97
6.4.1
Permitted concomitant therapy .............................................................97
6.4.2
Permitted concomitant therapy requiring caution and/or action...........99
6.4.3
Use of bone modifying agents (BMA) ...............................................100
6.4.4
Prohibited concomitant therapy ..........................................................101
6.5
Patient numbering, treatment assignment............................................................101
6.5.1
Patient numbering ...............................................................................101
6.5.2
Treatment assignment .........................................................................101
6.5.3
Treatment blinding..............................................................................102
6.6
Study drug preparation and dispensation.............................................................102
6.6.1
Study treatment packaging and labeling .............................................103
6.6.2
Drug supply and storage......................................................................103


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Study drug compliance and accountability .........................................103
6.6.4
Disposal and destruction .....................................................................104
7
Visit schedule and assessments .......................................................................................105
7.1
Study flow and visit schedule..............................................................................105
7.1.1
Molecular pre-screening......................................................................114
7.1.2
Screening.............................................................................................114
7.1.3
Treatment period.................................................................................115
7.1.4
Extension Phase ..................................................................................116
7.1.5
Discontinuation of study treatment .....................................................116
7.1.6
Withdrawal of consent/ opposition to use data/biological samples ....118
7.1.7
Follow-up for safety evaluations.........................................................118
7.1.8
Efficacy follow-up ..............................................................................119
7.1.9
Survival follow-up ..............................................................................119
7.1.10
Lost to follow-up.................................................................................119
7.1.11
End of post-treatment follow-up.........................................................119
7.2
Assessment types.................................................................................................120
7.2.1
Efficacy assessments...........................................................................120
7.2.2
Safety and tolerability assessments.....................................................122
128
8
Safety monitoring and reporting......................................................................................131
8.1
Adverse events.....................................................................................................131
8.1.1
Definitions and reporting ....................................................................131
8.1.2
Laboratory test abnormalities..............................................................133
8.1.3
Adverse events of special interest.......................................................133
8.2
Serious adverse events.........................................................................................133
8.2.1
Definitions...........................................................................................133
8.2.2
Reporting.............................................................................................134
8.3
Emergency unblinding of treatment assignment .................................................135
8.4
Pregnancies..........................................................................................................135
8.5
Warnings and precautions....................................................................................135
8.6
Data Monitoring Committee................................................................................136
8.7
Steering Committee .............................................................................................136
9
Data collection and management.....................................................................................136
9.1
Data confidentiality .............................................................................................136
9.2
Site monitoring ....................................................................................................136
9.3
Data collection.....................................................................................................137


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Database management and quality control..........................................................137
10 Statistical methods and data analysis ..............................................................................138
10.1
Analysis sets ........................................................................................................138
10.1.1
Full analysis Set ..................................................................................138
10.1.2
Safety set .............................................................................................138
10.1.3
Per-protocol set ...................................................................................138
10.1.4
Dose-determining analysis set.............................................................139
10.1.5
Pharmacokinetic analysis set...............................................................139
10.1.6
Other analysis sets...............................................................................139
10.2
Patient demographics/other baseline characteristics ...........................................139
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................139
10.4
Primary objective.................................................................................................140
10.4.1
Variable...............................................................................................140
10.4.2
Statistical hypothesis, model, and method of analysis........................140
10.4.3
Handling of missing values/censoring/discontinuations.....................141
10.4.4
Supportive and Sensitivity analyses....................................................141
10.5
Secondary objectives ...........................................................................................141
10.5.1
Secondary efficacy objective(s)..........................................................141
10.5.2
Safety objectives .................................................................................143
10.5.3
Pharmacokinetics ................................................................................145
145
10.5.5
Resource utilization.............................................................................146
10.5.6
Patient-reported outcomes...................................................................146
10.6
Exploratory objectives.........................................................................................146
10.7
Interim analysis....................................................................................................146
10.8
Sample size calculation........................................................................................146
10.9
Power for analysis of key secondary variables....................................................147
11 Ethical considerations and administrative procedures ....................................................147
11.1
Regulatory and ethical compliance......................................................................147
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................147
11.3
Informed consent procedures...............................................................................148
11.4
Discontinuation of the study................................................................................149
11.5
Publication of study protocol and results.............................................................149
11.6
Study documentation, record keeping and retention of documents.....................150
11.7
Confidentiality of study documents and patient records .....................................151
11.8
Audits and inspections.........................................................................................151


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Financial disclosures............................................................................................151
12 Protocol adherence ..........................................................................................................152
12.1
Amendments to the protocol................................................................................152
13 References (available upon request)................................................................................153
14 Appendices ......................................................................................................................158
14.1
Appendix 1 - List of concomitant medications....................................................158
14.1.1
Permitted Medication to be used with caution....................................158
14.1.2
Prohibited Medication.........................................................................158
14.2
Appendix 2: Guidelines for the treatment of alpelisib induced diarrhea.............160
14.3
Appendix 3 Guidelines for the treatment of study drug induced stomatitis/oral 
mucositis..............................................................................................................164
14.4
Appendix 4 – Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.......................................................................................................165
14.5
Appendix 5 - Guidelines for response, duration of overall response, TTF, 
TTP, progression-free survival and overall survival (based on RECIST 1.1).....168
List of tables
Table 1-1
PI3K signaling pathway mutations and alterations in breast cancer.....48
Table 3-1
Objectives and related endpoints ..........................................................65
Table 6-1
Dose and treatment schedule.................................................................77
Table 6-2
Dose reduction sequential steps for alpelisib........................................82
Table 6-3
Criteria for interruption and re-initiation of alpelisib treatment ...........83
Table 6-4
Management of pneumonitis.................................................................92
Table 6-5
Alternative causes of liver disease ........................................................96
Table 6-6
Packaging and labeling .......................................................................103
Table 6-7
Supply and storage of study treatments ..............................................103
Table 7-1
Visit evaluation schedule – Core Phase ..............................................106
Table 7-2
Visit evaluation schedule – Extension Phase......................................113
Table 7-3
Imaging assessment collection guidance ............................................122
Table 7-4
ECOG performance status...................................................................123
Table 7-5
Central clinical laboratory parameters collection plan during Core 
Phase ...................................................................................................125
Table 7-6
Local ECG collection plan..................................................................128
129
Table 10-1
Exact 95% Confidence Interval ..........................................................140
Table 10-2
Operating Characteristics....................................................................147
Table 14-1
List of CYP450 substrates to be used with caution.............................158


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Table 14-2
List of prohibited strong inducers of CYP3A4 ...................................159
Table 14-3
List of prohibited BCRP inhibitors .....................................................159
Table 14-4
NCI CTCAE version 4.03 grading of diarrhea for patients without 
colostomy............................................................................................160
Table 14-5
Liver event and laboratory trigger definitions ....................................165
Table 14-6
Follow-up requirements for liver laboratory triggers with liver 
symptoms ............................................................................................165
Table 14-7
Follow-up requirements for liver laboratory triggers..........................166


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List of figures
Figure 1-1
Schematic representation of the PI3K pathway ....................................47
Figure 4-1
Pre-Screening to Screening...................................................................67
Figure 4-2
Study Design .........................................................................................69


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List of abbreviations
aBC
Advanced Breast Cancer
ADA
American Diabetes Association
ADL
Activities of Daily Living
AE
Adverse Event
AESI
Adverse Events of Special Interest
AI
Aromatase Inhibitor
Akt 
Protein Kinase B
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase/Glutamic Pyruvic Transaminase/GPT
ANA
Antinuclear Antibody
ANC
Absolute Neutrophil Count
aPTT
Activated partial thromboplastin time
ARA
Acid Reducing Agents 
ASCO
American Society of Clinical Oncology
ASMA
Anti-smooth Muscle Antibody
AST
Aspartate Aminotransferase/Glutamic Oxaloacetic Transaminase/GOT
ATM
Ataxia-telengiectasia mutation
AUC
Area Under the Curve 
bid
bis in diem (twice a day)
BAL
Broncho-Alveolar Lavage 
BC
Breast Cancer
BCRP
Breast Cancer Resistance Protein
BMA
Bone Modifying Agents
BMI
Body Mass Index
BOR 
Best overall response 
BSA
Body Surface Area
BSEP
Bile Salt Export Pump
BUN
Blood Urea Nitrogen
CAR
Constitutive Androstane Receptor
CBR
Clinical Benefit Rate 
CDK4/6
Cyclin-Dependent Kinases 4 and 6
CDKi
Cyclin-Dependent Kinase inhibitor 
CDS
Core Data Sheet
CFR
Code of Federal Regulations
CHF
Congestive Heart Failure
CI
Confidence Interval
CK
Creatine Kinase
CL
Clearance
CLIA
Clinical Laboratory Improvement Amendments
Cmin
Minimum Concentration
Cmax
Maximum Concentration
CMV
Cytomegalovirus


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CMO&PS
Chief Medical Office and Patient Safety 
CNS
Central Nervous System
CR
Complete Response
CRO
Contract Research Organization
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
Circulating Tumor Deoxyribonucleic Acid
CTP
Clinical Trial Protocol
CV
Coefficient of Variation
CYP
Cytochrome P
DDI
Drug-Drug Interaction
DILI
Drug-Induced Liver Injury
DKA
Diabetic Ketoacidosis
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic Acid
DoR
Duration of Overall Response
DTI
Direct Thrombin Inhibitors
EASD
European Association for the Study of Diabetes
EBV
Epstein-Barr virus
EC
Ethics Committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report/Record Form; the term CRF can be applied to either 
EDC or Paper
EDC
Electronic Data Capture
EGFR
Epidermal Growth Factor Receptor
EM
Erythema Multiforme
EMA
European Medicines Agency
EOT
End of Treatment
ER
Estrogen Receptor
ERCP
Endoscopic Retrograde Cholangio Pancreatography
ET
Endocrine Therapy 
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDG-PET
Fluorodeoxyglucose Positron Emission Tomography
FFPE
Formalin-fixed paraffin-embedded
Fg
Intestinal Availability
FG
Fasting Glucose
FISH
Fluorescence In Situ Hybridization
FPFT
First Patient First Treatment
FPG
Fasting Plasma Glucose


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FSH
Follicle-stimulating Hormone
G
Grade
GABA
Gamma-aminobutyric acid
GCS
Global Clinical Supply
GGT
Gamma-glutamyltranspeptidase
GI
Gastrointestinal
GLDH
Glutamate dehydrogenase
GnRH
Gonadotropin Releasing Hormone
HAV
Hepatitis A Virus
HbA1c
Glycosylated Hemoglobin
HbsAg
Hepatitis Surface Antigen
HDL
High Density Lipoprotein
HER2
Human Epidermal Growth Factor Receptor 2
HEV
Hepatitis E Virus
HHNKS
Hyperglycemic Hyperosmolar Non-Ketotic Syndrome
HIV
Human Immunodeficiency Virus
HR
Hormone Receptor
HR+
Hormone Receptor Positive
HSV
Herpes Simplex Virus
i.v.
intravenous(ly)
IA
Interim Analysis
IB
Investigator Brochure
IC
Inhibitor Concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IgA
Immunoglobulin A
IgE
Immunoglobulin E
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IHC
Immunohistochemistry
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response 
System 
IWRS
Interactive Web Response System
LDH
Lactate dehydrogenase
LDL
Low Density Lipoprotein
LFT
Liver Function Tests
LHRH
Luteinizing Hormone-Releasing Hormone
LLN
Lower limit of normal 
LPFT
Last Patient First Treatment


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LPLT
Last Patient Last Treatment
LPLV
Last Patient Last Visit
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
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
MRP2
Multidrug Resistance Protein 2
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
ONJ
Osteonecrosis of the Jaw
ORR
Overall Response Rate
OS
Overall Survival
PBPK
Physiologically based Pharmokinetics
p.o.
per os (by mouth/orally)
PD
Progressive Disease
PET/CT
Positron Emission Tomography/Computed Tomography
PFS
Progression-Free Survival
PFS2
Progression-Free Survival in next-line treatment
P-gp
P-glycoprotein
PgR
Progesterone Receptor
PHI
Protected Health Information
PI3K
Phosphatidylinositol-3-kinase
PIK3CA
Gene which encodes the p110alpha catalytic subunit of PI3K
PIKKs
Phosphoinositol 3-kinase-related- kinases
PK
Pharmacokinetics
PPS
Per-Protocol Set
PR
Partial Response
PROS
Patient Reported Outcomes
PSDS
Post-Study Drug Supply
PSL
Protocol Standard Language
PT
Prothrombin Time
PTEN
Phosphatase and Tensin Homolog
PTT
Partial Thromboplastin Time


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q.d.
Quaque Die (every day)
QTcF
Q-T interval in the ECG (corrected according to the formula of Fridericia)
R Value
ALT/ALP in x ULN
RANK
Receptor activator of nuclear factor - kB
RBC
Red Blood Cells
REB
RBG
Research Ethics Board
Random Blood Glucose 
RP2D
Recommended Phase Two Dose 
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Steering Committee
SD
Stable Disease
SERM
Selective Estrogen Receptor modulator
SGLT2
Sodium glucose cotransporter 2
SGLT2i
Sodium glucose transporter 2 inhibitor
SISH
Silver in situ Hybridization
SJS
Stevens-Johnson-Syndrome
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reaction
t.i.d.
Three times a day
TBIL
Total Bilirubin
Tc-99
Technetium-99
TdP
Torsade de Pointes
TEN
Toxic Epidermal Necrolysis
Tmax
Time to reach maximum plasma concentration
ULN
Upper Limit of Normal
USPI
United States Prescribing Information
Vps
Vacuolar protein sorting
WBC
White Blood Cell
WHO
World Health Organization
WoC
Withdrawal of Consent


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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 or study 
patient
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 treated at a specific dose and 
regimen (i.e. treatment group) at the same time
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 groups 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.
Personal Data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes 
subject identifier information, study information and biological 
samples
Random Blood Glucose
Blood glucose levels measured from a blood sample taken at a 
random time, regardless of when the subject last ate
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 
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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
Variable
Identifier used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified timepoints
Withdrawal of study consent 
(WoC)/Opposition to use of 
data/biological samples
Withdrawal of consent from the study occurs when the participant 
explicitly requests to  stop use of their data and biological samples 
(opposition to use data and biological samples) AND no longer 
wishes to receive study treatment AND does not  agree to further 
protocol required assessments. This request should be in writing 
(depending on local regulations) and recorded in the source 
documentation.
Opposition to use data/biological samples occurs in the countries 
where collection and processing of personal data is justified by a 
different legal reason than consent.


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Amended Protocol Version 06 (Clean)
Protocol No. CBYL719X2402
Amendment 6 (28-Mar-2023)
The first study patient was screened on 14-Aug-2017, and as of 14-Dec-2020, study enrollment 
is complete and a total of 380 patients have been enrolled in the study. As of 30-Jan-2022, 9 
patients remain on treatment.
The primary purpose of this amendment is to increase the duration of the Extension Phase from 
up to 12 months to up to 36 months) to allow treatment access for patients who are continuing 
to benefit from study treatment following the previous defined end of treatment (18 months post 
LPFT, per protocol amendments 4 and 5) and where Post-Study Drug Supply (PSDS) is not 
allowed per local regulations. The study will continue to consist of two phases: the Core Phase 
(initial treatment phase, FPFT until 18 months post LPFT) and the Extension Phase (treatment 
phase starting at the end of Core Phase until 36 months).  
Rationale for increasing the duration of the Extension Phase:
PSDS is not allowed per local regulations for some of the participating countries; the Study 
Extension Phase will be a mechanism to continue to provide study treatment. Patients who are 
benefiting from treatment and are eligible for PSDS or a rollover protocol becomes available, 
should be discontinued from the study and access treatment via PSDS or rollover trial 
(whichever occurs first).   For patients continuing in the Extension Phase, study treatment will 
be provided for the respective assigned Cohort treatment that the patients were receiving during 
the Core Phase. 
During the Extension Phase, patients will continue to be evaluated as per institution’s standard 
of care to determine clinical benefit and safety will continue to be monitored as per the protocol 
requirements. The only efficacy assessment to be collected will be the physician’s 
determination of whether or not the patient is continuing to clinically benefit from the study 
treatment. Since the purpose of the extension phase is to provide continued access to study 
treatment, study assessments (such as central labs, RECIST, etc.) collected during the Core 
Phase will no longer be required and are detailed in the protocol. 
In addition, the protocol is revised to align with the alpelisib protocol standard language based 
on other studies in the BYL719 development program and the following updated documents 
since the last protocol amendment: 

Investigator Brochure (IB) Edition 17 (11-Jul-2022)

Updated Core Data Sheet (CDS) version 2.3 (12Sep2022)

One Clinical Trial Protocol (CTP) Oncology template version 5.0 (14-Jan-2022)
The changes are outlined as follows in order of appearance:

Protocol Summary:

Study Design: Updated duration of the Extension Phase

Section 1.2.4.2 : Updated Clinical experience per IB

Section 2.2: Updated duration of the Extension Phase 

Section 4.1: Study Design – Updated duration of the Extension Phase


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Protocol No. CBYL719X2402

Figure 4-2: Updated Study Design schematic increasing the duration of the Extension 
Phase

Section 4.3: Updated the durations for the Extension Phase

Section 6.1.5: Updated Treatment duration regarding the duration of the Extension Phase

Table 6-3: Updated text regarding monitoring and management of hyperglycemia Grade 1, 
2 and 4. Added definitions and updated management details for diarrhea and colitis, for 
grades 1, 2 and 3. Added additional antihistamine guidance for treatment of grade 2, 3 and 
4 skin toxicity in addition to any grade of Stevens-Johnson-Syndrome.

Section 6.3.2.1.2: Updated text for the guidelines for the treatment of study drug induced 
skin toxicity as per IB/PSL

Section 6.3.2.1.3: Updated text for the guidelines for alpelisib induced hyperglycemia as 
per IB/PSL

Section 6.3.2.1.4: Updated text to remove ‘perform’ from sentence

Section 6.3.2.3: Updated text for the guidelines for hypersensitivity as per IB/PSL

Section 6.4.1.1: Updated Oral anti-diabetes text as per IB/PSL

Section 6.4.3: Updated text to ‘bone modifying agents’ as per CTP v5

Section 7.1.4: Updated consent information for the increased Extension Phase

Section 13.0 added Jabbour S., and Ziring B reference

Section 14.2: Updated text for the guidelines for alpelisib induced diarrhea as per IB/PSL
IRB/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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Amended Protocol Version 06 (Clean)
Protocol No. CBYL719X2402
Amendment 5 (14-Jan-2022)
The first study patient was screened on 14-Aug-2017, and as of 14-Dec-2020, study enrollment 
is complete and a total of 380 patients have been enrolled in the study. As of 04-Jan-2022, 21 
patients remain on treatment.
The primary purpose of this amendment is to add an extension phase (for up to 12 months) to 
provide treatment access to patients who are continuing to benefit from treatment following the 
previous defined end of treatment (18 months post LPFT, per protocol amendment 4) where 
Post-Study Drug Supply (PSDS) is not allowed per local regulations.The study will then consist 
of two phases: the Core Phase (initial treatment phase, FPFT until 18 months post LPFT) and 
the Extension Phase (treatment phase starting at the end of Core Phase until 12 months).  An 
interim analysis will be done to evaluate the data from the Core Phase.
In addition, the protocol is revised to align with the alpelisib protocol standard language based 
on other studies in the BYL719 development program and the following updated documents 
since the last protocol amendment: 

Investigator Brochure (IB) Edition 15 (20-Aug-2020) and Edition 16 (07-Jul-2021)

Updated Core Data Sheet (CDS) version 2.1 (10-May-2021)

One Clinical Trial Protocol (CTP) Oncology template version 4.0 (15-Feb-2021)
Rationale for addition of an extension phase:
PSDS is not allowed per local regulations for some of the participating countries; the Study 
Extension Phase will be a mechanism to continue to provide treatment. Patients who are 
benefiting from treatment and are eligible for PSDS will exit the trial at the end of the main 
study Core Phase.  For patients entering the Extension Phase, treatment will be provided for the 
respective assigned Cohort treatment that the patients were receiving during the Core Phase. 
During the Extension Phase, patients will be evaluated as per institution’s standard of care to 
determine clinical benefit and safety will continue to be monitored as per the protocol 
requirements. The only efficacy assessment to be collected will be the physician’s 
determination of whether or not the patient is continuing to clinically benefit from the study 
treatment. Since the purpose of the extension phase is to provide continued access to treatment, 
study assessments (such as central labs, RECIST, etc.) collected during the Core Phase will no 
longer be required and are detailed in the protocol.  As the Extension Phase will extend Last 
Patient Last Visit (LPLV) by up to 12 months, an interim analysis has been added to evaluate 
all data up to the end of the Core Phase.
Note: Efficacy assessments will continue to be collected as per protocol until approval of this 
amendment and participants have transitioned to the Extension Phase. 
Rationale for protocol standard language/IB updates:
The protocol amendment is aimed to align with the most current alpelisib protocol standard 
language and IB with regard to safety management (particularly hyperglycemia and rash), 
alpelisib dose modifications, and Drug-Drug Interactions (DDI).


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This amendment also addresses: 

Correction to the frequency of monitoring blood glucose for the management of 
hyperglycemia Grade 2 as it was inconsistent with the latest Core Data Sheet (CDS) 
version 2.1 (10-May-2021).

Minor editorial changes and additional clarifications as described in the list of changes 
below are included
The changes are outlined as follows in order of appearance:

Title Page: Removed list of authors per current One CTP template

Updated List of abbreviations

Updated Glossary of Terms for Withdrawal of Consent and added details for the 
opposition to the use of data/biological samples as per One CTP template

Protocol Summary:

Added Protocol Number

Study Design: Added details of the Core and Extension Phases

Efficacy assessments: Added clarified assessments during Core and Extension 
Phases

Safety assessments: Added detail of Safety assessments during the Extension 
Phase

Other assessments: Clarified biopsy samples to be collected at the end of the 
Core Phase

Data analysis: Added third interim analysis to evaluate all data up to the end of 
the Core phase

Section 1.2.4.1: Updated Non-clinical experience, Pharmacodynamics of alpelisib per IB

Section 1.2.4.2 : Updated Clinical experience per IB

Section 1.2.4.3: Updated Clinical pharmacokinetics and added Consideration of gender 
effect per IB 

Section 2.2: Added details of the Core and Extension Phases 

Section 2.6.2: Added “Trial” to the section title

Section 2.6.3: Updated risk management in relation to women of childbearing potential 
and sexually active males.

Section 2.6.4: Added new section per CTP template regarding public health emergency 
mitigation procedures

Table 3-1: Added Ext Phase objectives/endpoint for evaluating clinical benefit 

Section 4.1: Study Design – Added details of the Core and Extension Phases 

Figure 4-2: Updated Study Design schematic to include the Extension Phase


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
Section 4.2: Updated the timing of interim analysis to include Core Phase Interim 
Analysis 3 (IA3) 

Section 4.3: Updated the End of study in reference to Extension Phase and defined the 
durations for the Core and Extension Phases

Section 6.1.1: Updated Novartis Drug Supply group to the current name: Global Clinical 
Supply (GCS); also clarified Treatment Phases to include Core and Extension Phase

Section 6.1.1.1: Updated alpelisib dosing per IB/PSL

Section 6.1.1.1.1: Updated additional dosing guidelines per IB/PSL

Section 6.1.5: Updated Treatment duration in regards to the duration of the Core and 
Extension Phases

Section 6.3.1.4: Updated clarification of CTCAE version for alpelisib AEs as per IB/PSL 
and added text regarding withholding alpelisib dosing.

Table 6-3: Updated text regarding interruption and re-initiation of alpelisib treatment; 
corrected frequency of monitoring blood glucose for the management of hyperglycemia 
Grade 2, 3, and 4. Added description for the grading of diarrhea, updated dose 
modifications for diarrhea grade 2. Added additional antihistamine guidance for treatment 
of grade 3 skin toxicity.

Section 6.3.2: Updated text regarding the follow-up until resolution for treatment that is 
interrupted or permanently discontinued as per IB/PSL; clarified the post-treatment 
follow-up for toxicities are safety follow-ups.

Section 6.3.2.1.2: Updated text for the guidelines for the treatment of study drug induced 
skin toxicity as per IB/PSL

Section 6.3.2.1.3: Updated text for the guidelines for alpelisib induced hyperglycemia as 
per IB/PSL

Section 6.3.2.2: Added details for follow-up on potential drug-induced liver injury cases 
as per IB/PSL

Section 6.3.2.3: New Section added for guideline for hypersensitivity as per IB/PSL

Section 6.4.1: Updated text for permitted concomitant therapy as per IB/PSL as per CTP 
template; clarified Concomitant Medications or the Surgical and Medical Procedures 
eCRF completed during Core Phase only.

Section 6.4.1.1: Updated Oral anti-diabetes text as per IB/PSL

Section 6.4.1.4: Updated Palliative radiotherapy as per IB/PSL

Section 6.4.2: Updated permitted concomitant therapy requiring caution and/or action as 
per IB/PSL

Section 6.4.3: Updated Use of bisphosphonates as per IB/PSL

Section 6.4.4: Updated Prohibited concomitant therapy per IB/PSL

Section 6.5.2: Treatment assignment clarified it occurs at the start of the Core Phase

Section 6.6: Clarified text for study drug preparation and dispensation; added text for 
mitigations for delivery of IMP to patient’s home during a public health emergency as per 
CTP template


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
Section 6.6.1: Updated Novartis Drug Supply management group to the current name: 
Global Clinical Supply (GCS)

Section 6.6.4: Updated Disposal and destruction per CTP template

Section 7.1: Updated text in regards to the Core and Extension Phase for the study flow 
and visit schedule and added updated text for this section related to Public Health 
emergency as per CTP template

Table 7-1: Updated table to include Core Phase

Table 7-2: New VES for Extension Phase added; the subsequent tables of Section 7 are 
renumbered accordingly and their respective cross-references have also been updated

Section 7.1.3: Clarified Core and Extension Phase treatment periods

Section 7.1.4: Added new section for Extension Phase procedures

Section 7.1.5: Updated discontinuation of study treatment in regards to the Core and 
Extension phases 

Section 7.1.6: Updated Withdrawal of Consent text and added detail for Opposition to the 
use of data/biological samples as per CTP template

Section 7.1.7: Clarified follow-up for safety evaluations in the Core and Extension Phases

Section 7.1.8: Clarified text for efficacy followup for the Core Phase only

Section 7.1.9: Clarified text for survival followup for the Core Phase only

Section 7.1.11: Clarified text regarding end of study disposition phase eCRF for the Core 
and Extension Phases

Section 7.2.1.1: Clarified imaging tumor assessments are required in Core Phase only and 
no per protocol efficacy assessments other than physician’s determination as per standard 
of care of whether or not the patient is continuing to derive clinical benefit from the study 
treatment.

Section 7.2.2: Clarified Safety and tolerability assessments during the Core and Extension 
Phases

Section 7.2.2.1: Clarified physical examination during the Core Phase only

Section 7.2.2.3: Clarified Weight done during the Core Phase only

Section 7.2.2.4: Clarified ECOG performance status during the Core Phase only

Section 7.2.2.5 and Table 7-5: Clarified Laboratory evaluations are required during the 
Core Phase only and if needed during the Extension Phase per standard of care labs will 
go for local testing (instead of central lab)

Section 7.2.2.5.1: Clarified Hematology required during Core Phase only

Section 7.2.2.5.2: Clarified Clinical chemistry required during Core Phase only

Section 7.2.2.5.3: Clarified monitoring of RBG and fasting c-peptide, lipid panel, amylase, 
lipase and HbA1c during the Core Phase

Section 7.2.2.5.4: Clarified Coagulation assessment during the Core Phase

Section 7.2.2.5.5: Clarified Urinalysis during the Core Phase 

Section 7.2.2.5.6: Clarified Urine test required in the Core and Extension Phase

Section 7.2.2.6: Clarified Radiological examinations required in Core Phase


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
Section 7.2.2.7: Clarified Cardiac Assessments to be performed in the Core Phase

Table 7-6: Clarified Local ECG collection at EoT is during the Core Phase

Section 7.2.2.7.2: Clarified Cardiac imaging during the Core Phase
 

Section 8.2.2: updated SAE report requirement as required by BfArM (Federal Institute 
for Drugs and Medical Devices in Germany)

Section 8.4: Updated Pregnancy reporting and follow-up text per CTP template

Section 10.5.1.7: New section added for analysis of extension phase clinical benefit.

Section 10.7: Added details of the Core Phase interim analysis (IA3)

Section 10.8: Clarified the first two interim analysis under sample size calculation 

Section 11.3: Updated the text for Informed Consent procedures based on CTP template

Section 14.1.2: Updated date for list of CYP inducers per IB/PSL

Table 14-3: Updated Prohibited Medication per IB/PSL

Table 14-5: Updated Liver Event and laboratory trigger definitions per IB/PSL

Table 14-6: Updated Follow-up requirements for liver laboratory triggers with liver 
symptoms per IB/PSL

Table 14-7: Updated Follow-up requirements for liver laboratory triggers
IRB/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Protocol No. CBYL719X2402
Amendment 4 (31-Oct- 2019)
The first study patient was screened on 14-Aug-2017 and as of 08 Oct 2019, 254 patients have 
been enrolled in the study CBYL719X2402.
The primary purpose of this amendment is to revise protocol language, in order to allow 
analyses of the primary endpoint for each cohort independent of the other cohorts. The primary 
analysis for each cohort will be performed 6 months after the last patient enrolled in that specific 
cohort has started treatment.
The purpose of this amendment is also to provide a protocol update on the following based on 
the recently released IB Edition 13:
-
New clinical pharmacology data and Drug-Drug Interactions (DDI)
-
Update of the Inclusion /Exclusion criteria
-
Update on permitted concomitant medications to be used with caution, prohibited 
medications and the use of bisphosphonates/denosumab
-
Update on guidance of dose interruption/modifications, management of AEs associated 
with the use of alpelisib, and guidance for follow-up on toxicities.  
-
Other editorial changes, to align with BYL new protocols in other indications
Rationale
Re: Cohort Primary Analysis: Based on the difference in timing between cohorts in enrollment 
and completion of the minimum 6 months follow up required for the primary analyses, the 
protocol language is being revised to allow analyses of the primary endpoint for each cohort 
independent of the other cohorts. This will allow for earlier availability of the primary analyses 
by cohort
Re: IB update: On 24-May-2019, based on the results of the pivotal Phase III study 
CBYL719C2301, the United States Food and Drug Administration (FDA) granted approval of 
alpelisib in combination with fulvestrant for the treatment of postmenopausal women, and men, 
with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-
negative, PIK3CA-mutated, advanced or metastatic breast cancer as detected by an FDA-
approved test following progression on or after an endocrine-based regimen. Other global 
submissions are currently under review by other Health Authorities worldwide. The 
Investigator’s Brochure (IB) Edition 13, dated 15-Oct-2019, included comprehensive 
assessments of SOLAR-1 safety data (with cutoff date: 20 Oct 2018) and all other available 
safety data which led to further defining alpelisib safety profile and risks associated with 
alpelisib.  Additionally, the IB was updated with new DDI data which warrants an update of the 
concomitant medications to be used with caution and the prohibited medications.  Accordingly, 
this amendment covers these updates along with updates for the existing guidelines for the 
management of adverse events associated with the use of alpelisib and follow-up on toxicities.


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This amendment also addresses: 

Clarification on Cohort C patient population regarding prior endocrine therapy. Prior 
endocrine therapy can include monotherapy or in combination (except Cyclin-
Dependent Kinases 4 and 6 inhibitors (CDK 4/6i+ AI); combination with CDK4/6i plus 
fulvestrant may be included after enrollment completion of Cohort B. The purpose is to 
evaluate the clinical benefit of alpelisib + fulvestrant in patients who received CDK4/6i 
plus fulvestrant as immediate prior therapy; this will assess alpelisib activity in 
overcoming endocrine resistance while maintaining the same endocrine partner, 
fulvestrant.  Note: CDK 4/6i + AI is not included in Cohort C as this is studied under 
Cohort A.

Minor editorial changes and additional clarifications as described in the list of changes 
below are included
Changes to the protocol: 
The changes are outlined in order of appearance: 

Updated current authors

Updated List of abbreviations

Protocol Summary:
o
Investigational and reference therapy – clarified Cohort C prior therapy
o
Efficacy assessments – deleted 18 months after LPFV
o
Data Analysis – deleted at the final analysis

Section 1.2.4.2: Updated Clinical experience and approval information of Alpelisib 
(Piqray®)

Section 1.2.4.3: Added SOLAR1 pharmacokinetic analyses and data on food effect

Section 2.2: Clarified patient population in Cohort C: Includes patients who received 
prior ET as monotherapy or combination (excluding CDK 4/6i + AI); after completion 
of enrollment of Cohort B, patients who receive prior CDK4/6 inhibitors plus fulvestrant 
are eligible, This change was also updated in the protocol summary, Sections 4.1, 5.2, 
6.1.1 and 6.5.2

Section 4.1, Figure 4-2: corrected LPLV to LPFT and under Cohort C corrected and 
deleted “monotherapy”, which was a note to file from previous protocol amendment 
(PA3)

Section 4.3: 
o
Removed redundant text already stated in Section 10 regarding analysis timings  
o
Clarified and corrected end of study definition
Since end of study is defined in Section 4.3, revised redundant text throughout document when 
referring to “end of study” without repeating the 18 months follow up text, etc.

Section 5.2 Inclusion criteria:


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o
#7: clarified Cohort C prior therapy
o
#10: updated total serum bilirubin to <2 x ULN (from ≤ULN) and added any 
elevated bilirubin should be asymptomatic at enrollment

Section 5.3 Exclusion criteria:
o
#9 added [testing not mandatory unless required by local regulations or 
requirements]
o
#10 corrected CYP3A4 (from CYP3A) and added  inhibitors of BCRP
o
#13 added based on investigator discretion
o
#14 added interstitial lung disease 
o
#19 added Erythema Multiforme (EM) and Drug Reaction with Eosinophilia and 
Systemic Symptoms (DRESS)
o
#20 C is updated with text prior to initiating study treatment
o
#21 (new) ‘subjects with unresolved osteonecrosis of the jaw’ based on 
observations within SOLAR-1 data 

Section 6.1.1.1 Alpelisib dosing: Additional guidance on missed dose instructions 
indicating, if greater than 9 hours, skip the dose

Table 6-3: Updates to Criteria for interruption and re-initiation of alpelisib treatment 
made per IB: 
o
Updates made to Hyperglycemia, Diarrhea and Skin and subcutaneous tissue 
disorders 
o
Updated criteria for Isolated AST or ALT Elevation, Combined elevations of 
AST or ALT and total Bilirubin, and Cardiac investigations 
o
Updated criteria for skin and subcutaneous tissue disorders

Section 6.3.2.1.1: added Alpelisib association with pneumonitis/interstitial lung disease 
and to closely monitor subjects for signs and symptoms of pneumonitis

Section 6.3.2.1.2: Guidelines for the treatment of study drug induced skin toxicity: 
o
Clarification for Grade 3 events recommend photography and skin biopsies, for 
Grade 4 they must be taken 
o
Inclusion of anti-histamine administration prior to onset of rash may decrease 
the incidence and severity based on data from SOLAR-1 study

Section 6.3.2.1.3 updated with low processed food intake and with due to the short half-
life of alpelisib all glucose lowering medications should be discontinued when alpelisib 
is stopped

Section 6.3.2.2: Follow up on potential drug-induced liver injury (DILI) cases. 
Additional language included specifying other causes of abnormal liver tests should be 


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considered and clarified before diagnosis of DILI is confirmed. Table 6-4 (new) 
included highlighting alternative causes of liver disease 

Section 6.4.1.1 updated with hyperglycemia and CYP2C9

Section 6.4.1.2 updated with gastric protection agents

Section 6.4.2: Updated text for medications to be used with caution for CYP2C9, 
CYP2B6, CYP3A4 and Herbal Medication 

Section 6.4.3 (new): Additional information and guidance on the use of bisphosphonates 
based on SOLAR-1 study data and the incidence of osteonecrosis of the jaw with 
alpelisib in combination with fulvestrant. 

Section 6.4.4 (previously 6.4.3): Prohibited Concomitant Therapy 
o
Inclusion of strong CYP3A4 inducers based on additional data (as listed in Table 
14-2)
o
Inclusion of BCRP efflux transporters
o
Removed risk of Torsades de pointes  and drugs associated with QT 
prolongation and/or TdP

Table 7-1: VES – added Skin Photographs for skin toxicity/SJS/TEN

Table 7-6 updated with visit details for skin samples

Section 7.2.3.1.1 Clarified bone samples cannot be accepted for central confirmation 
mutation testing

Section 10: Revised text with respect to timing of primary analyses for each cohort (refer 
to protocol amendment purpose and rationale above for details).  Clarified final analysis 
will be at the end of the study as defined in Section 4.3 

Section 13.0 added Lee CA et al reference 

Section 14.1 Appendix 1:
o
Added Table 14-1 (new) List of CYP450 substrates to be used with caution and 
text under Section 14.1.1 (new) Permitted medication to be used with caution
o
Added Table 14-2 (new) List of prohibited strong inducers of CYP3A4 and 
added text under Section 14.1.2 (new) Strong inducers of CYP3A4
o
Deleted previous Table 14-1 List of CYP450 substrates to be used with caution 
,  Table 14-2 List of prohibited QT prolonging drugs, Table 14-3 List of QT 
prolonging drugs to be used with caution and Section 14.1.2 Drugs that prolong 
the QT interval and/or induce Torsades de Pointes
o
Section 14.1.3 BCRP inhibitors: Updated text and replaced Table 14-4 list of 
BCRP inhibitors to be used with caution with Table 14-3 (new) List of prohibited 
BCRP inhibitors


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
Section14.4 Appendix 4 Liver event and laboratory trigger definitions and follow-up 
requirements (new) : added text and Table 14-5 (new) Liver event and laboratory trigger 
definitions
IRB/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 3 (30-Jan-2019) 
Amendment rationale 
The first study patient was screened on 14-Aug-2017 and as of 22-Jan-2019, 127 patients have 
been enrolled in the study CBYL719X2402.
The purpose of this amendment is to:

Add a new cohort (C) to enroll patients who have failed prior aromatase inhibitor (AI) 
treatment (either in the adjuvant or metastatic setting) and received systemic 
chemotherapy or endocrine treatment (ET) as immediate prior treatment.

Increase the total number of patients to approximately 340 for this study; this includes 
increasing the sample size for the existent cohorts (A & B) from 80 patients to 112 
patients and the addition of the third cohort (C) consisting of 112 patients.

Revise assessments to include only those assessments that are clinically necessary to 
reduce patient inconvenience. Please refer to Table 7-1 for all revisions.

Allow monitoring of fasting or random blood glucose (RBG) levels instead of the current 
mandatory fasting glucose (FG) tests. Please refer to Section 7.2.2.5.3.

Add one additional interim analysis to be performed when approximately
patients 
(50% of enrolled patients) have been treated in the study (regardless of cohort) and have at 
least 6 months of follow up on study.
Rationale to add Cohort C
The primary analysis from the phase III [CBYL719C2301 (SOLAR-1)] study confirms 
statistically significant and clinically relevant benefit with alpelisib in combination with 
fulvestrant in PIK3CA mutant, HR+ HER2- advanced breast cancer patients who have 
progressed on AI treatment. The BYLieve study was originally designed to investigate the 
benefit risk ratio of PIK3CA inhibitor treatment following prior use of CDK4/6 inhibitor 
treatments but was restricted to patients who received CDK4/6 inhibitors as their last treatment 
prior to study entry. Since then, the approval of CDK4/6 inhibitors for use in first line metastatic 
breast cancer has led to increasing number of patients receiving the treatment in an earlier line,  
followed by systemic chemotherapy or ET. Based on these developments in the current 
treatment landscape for aBC and the results from SOLAR -1 study, the enrollment into BYLieve 
study is being extended to patients who may have received systemic chemotherapy or an ET as 
immediate prior treatment and have previously failed AI treatment (either in adjuvant or 
metastatic setting).
The sample size from cohorts A and B was revised to allow for a more robust assessment of 
benefits vs. risk in the investigated patient populations.
Rationale to allow assessment of random blood glucose levels (non- fasted):
The primary analysis of SOLAR-1 [CBYL719C2301] confirms previously established safety 
and tolerability for alpelisib from early phase studies. The class effect of hyperglycemia can be 
monitored through regular blood tests and upon occurrence, is readily manageable through 
existing guidelines recommended in the protocol. Based on this information, the study is being 
amended to allow for monitoring of either fasting or random blood glucose (RBG) levels (non-


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fasted). Patients who experience rise in fasting or RBG levels will be subjected to previous 
management guidelines: plasma glucose levels can be monitored via peripheral blood tests at 
the discretion of the investigator. 
Rationale to add the interim analysis
A second interim analysis will be performed when approximately 
patients (50% of enrolled 
patients) have been treated in the study (regardless of cohort) a
have at least 6 months of 
follow up. This interim analysis will be performed to report preliminary efficacy (ORR, CBR) 
as well as key safety data in a descriptive fashion to provide additional information in this 
patient population. 
Changes to the protocol
The changes are outlined as follows in order of appearance:

Title of protocol revised to include three cohorts and patients that have progressed on or 
after prior treatments

Updated current authors 

Revised protocol summary sections for title, brief title, purpose and rationale, primary 
objective, secondary objective, study design, population, key inclusion, investigational 
and reference therapy, efficacy assessments, safety assessment and data analysis

Section 2.1: Revised to include cohort C patient population and updated key purpose of 
the study

Section 2.2: Revised to include cohort C patient population 

Section 2.3: Revised to include cohort C patient population 

Section 2.5: Deleted reference to CDK4/6 inhibitors 

Section 2.6.1: Revised to include cohort C patient population

Table 3-1: Revised to update primary objective to include cohort C patient population,  
add secondary objective of overall survival 

Section 4.1: Revised to include cohort C patient population, approximate number of 
patients to prescreen and enroll and revision to allow tumor assessments to be collected 
every 12 weeks

Figures 4-1 and 4-2:  Revised to include cohort C patient population

Section 4.2: Add additional interim analysis 

Section 4.3: Revised to update primary and final analysis 

Section: 4.4: Revised to new template language for early termination reasons 

Section 5.1: Revised to include cohort C patient population

Section 5.2: Revised to include cohort C patient population

Section 6.1.1: Revised to include cohort C patient population

Section 6.1.1.2: Revised to remove no dose modification for letrozole

Section 6.1.1.3: Revised to remove no dose medication for fulvestrant

Section 6.3.1.1: Revised to remove no dose medication for fulvestrant

Section 6.3.1.2: Revised to remove no dose modification for letrozole


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
Section 6.3.1.4: Revised to remove no dose modification letrozole, fulvestrant, goserelin 
and leuprolide

Table 6-3: Revised dose modifications to allow for RBG testing, updated management of 
skin toxicity 

Section 6.3.2.1.2: Revised management of skin toxicity

Section 6.3.2.1.3: Revised dose modifications to allow RBG testing

Section 6.5.2: Revised to include cohort C patient population

Table 7-1: Revised to update molecular prescreening in source only, allow tumor 
assessments to be collected every 12 weeks, other assessments to be conducted as 
clinically indicated, adding FBG or RBG collection, capture local PIK3CA mutation in
database, add cohort C dosing

Section 7.1.2.2: Revised to remove capture of prescreening patients in database

Section 7.1.2.3: Revised demographics collected based on CRF availability

Section 7.1.4: Revised tumor assessments to be collected every 12 weeks

Section 7.1.7: Revised tumor assessments to be collected every 12 weeks and revised 
eCRF page 

Section 7.1.8: Paragraph was deleted since it was duplicated from section 7.2.1.2

Section 7.1.10: Revised eCRF page 

Section 7.2.1.1: Removed whole body scan and revised tumor assessments to be collected 
every 12 weeks

Table 7-2: Removed whole body scan and revised tumor assessments to be collected every 
12 weeks

Section 7.2.2.5: Added RBG testing

Table 7-4: Removed fasting criteria for partial chemistry labs

Section 7.2.2.5.3: Added random glucose testing

Section 7.2.3.1.3: Revised to add information regarding optional testing 

Table 7-5: Deleted ECG at every 3 cycles

Section 10: Clarified primary and final analyses

Section 10.4: Revised to include cohort C patient population

Section 10.4.2: Revised to include cohort C patient population

Table 10-1: Revised confidence intervals

Section 10.5: Revised secondary objectives confidence intervals

Section 10.5.1.6: Added overall survival 
 

Section 10.7: Revised to include additional interim analysis

Section 10.8: Revised confidence intervals and updated sample size

Table 10-2: Updated Operating Characteristics

Section 11.3: Revised fetotoxic potential

Section 13: Added reference for SOLAR-1


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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 2 (02-May-2018)
Amendment rationale
The first study patient was screened on 14-Aug-2017 and as of 02-May-2018, 30 patients have 
been enrolled in the study CBYL719X2402.
The current amendment is intended to clarify the use of goserelin or leuprolide (LHRH agonists) 
as study treatment for pre-menopausal women (as applicable) and men (cohort B).
Changes to the protocol
The changes are outlined as follows in order of appearance:

Updated glossary of terms due to EEA General Data Protection Regulation (GDPR)

Section 1.1.2: Revised LHRH agonist to goserelin and leuprolide

Section 1.2.3: Clarified that goserelin or leuprolide (LHRH agonists) allowed for use in 
this study

Section 2.3: Clarified the usage of goserelin or leuprolide in men and premenopausal 
women in this study

Section 2.6 and 2.6.3: Added goserelin or leuprolide

Table 3-1: Aligned the endpoint correctly with objective

Section 4.1: Clarified that goserelin or leuprolide will be used for gonadal suppression

Figure 4-1: Updated to include the end of study information

Section 4.3: Clarified paragraph to align with protocol

Section 5.2: Inclusion criterion #6: clarified the requirement for menopausal status of 
goserelin or leuprolide to be used concomitantly with alpelisib in combination with 
fulvestrant or letrozole

Section 5.2; Inclusion criterion #7: clarified lines of treatment

Section 5.3: Exclusion criterion #1: added goserelin or leuprolide to the known 
hypersensitivity

Section 5.3: Exclusion criterion #20b: added to women that highly effective contraception 
during dosing and for at least 8 months after stopping study medication. Provides 
consistency between both males and females.

Section 6.1: Defined the use of goserelin or leuprolide for men and premenopausal women 
as study treatment

Section 6.1.1.1: Deleted paragraph and moved to Section 6.1 for clarity

Table 6-1: Renamed table and added goserelin and leuprolide dose and treatment 
scheduled

Section 6.1.1.4 and Section 6.1.1.5: Added section for dosing for goserelin and 
leuporolide

Section 6.3.1.3: Added section for goserelin and leuprolide dose modifications


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
Section 6.3.1.4: Deleted sentence under Table 6-2 as it was a duplicate from above 
paragraph

Section 6.3.1.4: Deleted last sentence in paragraph and moved to Section 6.3.2

Section 6.3.2: Clarified patient follow up information

Section 6.4.1: Corrected name of eCRF page

Section 6.4.1.3: Deleted paragraph as it was a duplicate from Section 6.4.1

Section 6.4.3: Clarified the use of probiotics

Section 6.6: Added goserelin and leuprolide study drug preparation

Table 6-5 and Table 6-6: Added goserelin and leuprolide supply and storage treatments

Table 7-1: Added goserelin and leuprolide under study administration

Section 7.1.5: Updated due to EEA General Data Protection Regulation (GDPR)

Section: 7.1.6: Clarified patient follow up information and updated eCRF to be collected

Section 7.2.2.7.1: Deleted last paragraph as it was a duplicate from above paragraph

Table 14-1: Removed footnotes as not required
IRB/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.
Amendment 02 also includes minor editorial changes and additional clarifications to address 
investigators’ questions as described in the list of changes below.


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Amendment 1 (30-Jan-2018)
Amendment rationale
The first study patient was screened on 14 Aug 2017 and as of 23 January 2018, 9 patients have 
been enrolled in the study CBYL719X2402.
The purpose of this amendment is to:

Provide updated guidance on the management of skin and subcutaneous reactions

Allow for premenopausal women to be included in the study as long as they are receiving 
concomitant ovarian suppression with LHRH agonist (examples for use in this study 
include but are not limited to goserelin, leuprolide or locally available treatment) based on 
current treatment guidelines as standard of care in this population throughout the duration 
of the study (ASCO Guidelines 2016) as requested from Steering committee.

Plan an Interim Analysis (IA) after at least
patients receiving alpelisib plus fulvestrant 
(cohort A) have at least 6 months of follow up. At the time of the IA, preliminary efficacy 
(ORR, CBR) as well as key safety data will be analyzed descriptively

Revise section 8.1.1 regarding the length of time needed for the safety follow up visit. 
Patient will be monitored for safety for 30 days after study treatment (alpelisib) 
discontinuation (this is longer than 5 half-lives for alpelisib). Since fulvestrant and 
letrozole are marketed products, and locally approved labeling is being followed, the 
safety follow-up period for these agents will also be 30 days.

Update alpelisib information based on the data available on the current IB version (v10, 
release date: 12 July 2017; safety cut-off date: 13 May 2017)

Update additional background information regarding preclinical data for alpelisib in PI3K 
mutant patients post CDK inhibitors and information to include rapidly changing 
advanced breast cancer (aBC) landscape
Rational to update 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 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.


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Rationale to modify the inclusion of Premenopausal patients
Premenopausal patients (receiving concomitant ovarian suppression with LHRH agonists as 
standard of care) are assessed to be allowed in the study, based on current treatment guidelines 
suggesting similar treatment strategies in premenopausal patients with ovarian suppression as 
post-menopausal patients. Standard language around contraception was added to the 
inclusion/exclusion criteria as of result of this change. Additional clinical data from a smaller 
study was also included.
Note: throughout this document perimenopausal and premenopausal status is grouped together 
and referred to as “premenopausal’.
Rationale to add the interim analysis
Due to lack of data availability in this patient population of post CDK 4/6 combination therapy, 
an interim analysis will be performed to report preliminary efficacy (ORR, CBR) as well as key 
safety data in a descriptive fashion.
Changes to the protocol
The changes are outlined as follows in order of appearance:

Protocol “acronym” BYLieve added to this protocol

List of abbreviations updated

Summary section of the protocol has been updated to maintain consistency with the 
main body of the protocol

Throughout the document: Typographical and grammatical corrections

Section 1.1.1: Updated breast cancer information

Section 1.1.2: Updated section to include epidemiology to include pre-menopausal 
women-

Section 1.1.4; Updated information regarding mechanism of action with PI3K/mTOR 
pathway

Section 1.2.2.1: Updated fulvestrant pharmacokinetic data

Section 1.2.3: Added information regarding LHRH agonist for pre-menopausal 
patients

Section 1.2.4.1: Added pharmacodynamics information for alpelisib

Section 1.2.4.1.2: Updated nonclinical PK and metabolism information for alpelisib

Section 1.2.4.1.3: Updated safety pharmacology and toxicology information for 
alpelisib

Section 1.2.4.2: Updated clinical information based on alpelisib investigator brochure 
version 10

Section 1.2.5.1: Updated clinical experience with alpelisib and aromatase inhibitors

Section 1.2.5.2: Updated alpelisib and fulvestrant information

Section 1.2.6.3: Added section to include low potential for drug-drug interactions with 
letrozole to be consistent within the protocol


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
Section 2.1: Updated study rationale and purpose with phase Ib [CBYL719XIC01] 
information

Section 2.2: Updated information for rationale for the study design to include recent 
preclinical data

Section 2.3: Updated rationale for dose and regimen to include premenopausal women

Section 2.6.3: Added information for risk management strategies

Section 4.1: Added information in description of study design to include 
premenopausal women.

Figure 4-1: Revised figure to update molecular prescreening window (can occur by 
Day -21).

Figure 4-2: Revised figure to add cohort A and B in the schematic

Section 4.2: Added interim analysis

Section 4.3: Revised information regarding the definition of end of study

Section 5.2: Inclusion criteria have been numerically rearranged for clarity and flow of 
criteria. These changes have not been tracked since no content was modified (only the 
numerical order)

Section 5.2 Inclusion criteria #2 added for consistency in the metastatic breast cancer 
population

Section 5.2 Inclusion criteria # 5 – revised to remove minimum slides requirements 
from a biopsy. Please note this requirement has not changed; it was only removed 
from inclusion criteria. 

Section 5.2 Inclusion criteria # 5 – added blood for a known pathology report 
confirming PIK3CA status

Section 5.2 Inclusion criteria #6 added to include pre-menopausal women population

Section 5.2: Inclusion criteria #7, 9. 10, 11 and 13 were revised for clarity

Section 5.3 Exclusion criteria #1 added to exclude patients with known 
hypersensitivities to study treatment medications

Section 5.3: Exclusion criteria bilateral diffuse lymphangitic carcinomatosis was 
removed

Section 5.3 Exclusion criteria # 4 revised to clarify diabetes mellitus

Section 5.3: Exclusion criteria #8 now revised for HIV patients regarding local HA 
regulations

Section 5.3: Exclusion criteria 7, 9, 14 and 17 were revised for clarity

A section 5.3: Exclusion criterion 19 was deleted due to the patient population of 
advanced metastatic breast cancer. It would be unethical for patients to wait 30 days or 
5 half-lives (especially if coming from Fulvestrant trial) from a previous trial to start 
another therapy due to the advanced condition

Section 5.3: Exclusion criteria #21 added to exclude patients who may be at higher 
risk of skin and subcutaneous reactions

Section 5.3 Exclusion criteria # 22 revised to add language due to premenopausal 
patients and contraception requirements


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
Section 6.1.1.1.1: Added to include additional information for fasting guidelines

Section 6.3.1.3: Revised to clarify recommendations for dose reduction for alpelisib

Table 6-3: Table revised for consistency to standard language for alpelisib compound

Section 6.3.2 and 6.3.2.1: Revised for clarity and consistency to standard language for 
alpelisib compound

Section 6.3.2.1.2: Revised to include Stevens-Johnson Syndrome

Table 6-6: Revised to include both central supplies for fulvestrant

Section 7.1: Revised to clarify molecular pre-screening ICF can occur by Day -21

Table 7-1 Added serum and urine pregnancy to allow for premenopausal patients; 
added estradiol for screening in patients < 60 years of age; revised molecular 
prescreening window (by Day -21), added cohort assignment page, local PIK3CA 
mutation assessment page and End of study treatment window to within 21 days of last 
dose

Section 7.1.1: Revised to clarify molecular pre-screening consent to complete by Day -
21 and clarified certified laboratory requirements

Section 7.1.2: Revised to clarify certified laboratory requirements

Section 7.1.4: deleted as duplicate information to section 7.1.5

Section 7.2.3.1: Revised to clarify that decalcified samples are not acceptable for 
PIK3CA mutation analysis

Section 7.2.3.1: Revision to clarify optional tumor tissue requirements

Section 7.2.2.5.6: Added pregnancy and hormone levels

Table 7-4: Revised to include pregnancy serum and urine tests due to adding pre-
menopausal population and estradiol testing

Table 7-6: Removed restriction on the age of archival tissue

Section 8.1.1: Revised to clarify when adverse events are collected and removed 5 half 
lives

Section 8.4: Added additional information regarding patient population

Section 9.1: last paragraph deleted as subject initials and date of birth are not collected 
for the study

Section 10.7 and 10.8: Added interim analysis plan

Section 13: Added new references

Appendices: Tables revised to be consistent with alpelisib standard language


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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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Protocol summary:
Protocol Number
CBYL719X2402
Title
BYLieve: A phase II, multicenter, open-label, three-cohort, non-
comparative study to assess the efficacy and safety of alpelisib 
plus fulvestrant or letrozole in patients with PIK3CA mutant, 
hormone receptor (HR) positive, HER2-negative advanced breast 
cancer (aBC), who have progressed on or after prior treatments
Brief title
Study assessing the efficacy and safety of alpelisib plus fulvestrant 
or letrozole, based on prior endocrine therapy, in patients with 
PIK3CA mutation with advanced breast cancer who have 
progressed on or after prior treatments
Sponsor and Clinical Phase
Novartis
Phase II
Investigation type
Drug 
Study type
Interventional 
Purpose and rationale
The purpose of this study is to assess the efficacy and safety of 
treatment with alpelisib (BYL719) plus endocrine therapy (either 
fulvestrant or letrozole) in patients with HR+, HER2-negative aBC, 
harboring PIK3CA mutations, who have progressed on or after prior 
treatments.
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 or letrozole.
Promising clinical activity has been observed with single agent 
alpelisib, in heavily pre-treated Estrogen Receptor (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) 
The primary objective is to assess the proportion of patients who 
are alive without disease progression at 6 months based on local 
investigator assessment per RECIST v1.1 separately in Cohorts A 
and C (alpelisib in combination with fulvestrant) and Cohort B 
(alpelisib in combination with letrozole) among patients with HR+, 
HER2-negative aBC harboring a PIK3CA mutation whose disease 
had progressed on or after prior treatments. 
Secondary Objectives

To assess Progression-Free Survival (PFS) based on local 
investigator assessment for each cohort

To assess PFS on next-line treatment (PFS2) for each cohort

To assess overall response rate (ORR) and clinical benefit rate 
(CBR) based on local investigator assessment for each cohort

To assess duration of response (DOR) in patients with 
confirmed complete response (CR) or partial response (PR) for 
each cohort

To evaluate the safety and tolerability of the combination for 
each cohort

To assess Overall Survival (OS) for each cohort


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
To evaluate the safety and tolerability of the combination for 
each cohort

Evaluate clinical benefit as assessed by the Investigator during 
the Extension Phases
Study design
This is a phase II, multicenter, open-label, three-cohort, non-
comparative study of alpelisib plus endocrine therapy (either 
fulvestrant or letrozole) in patients with HR+, HER2-negative aBC 
harboring PIK3CA mutation(s) in the tumor whose disease has 
progressed on or after prior treatments. 
The study includes two phases:
Core Phase: Includes treatment phase for all patients from First 
Patient First Treatment (FPFT) until 18 months post Last Patient 
First Treatment (LPFT) + 1 month Safety follow-up (total 19 months 
post LPFT)
Extension Phase: includes treatment phase starting at the end of 
the treatment Core Phase until Last Patient Last Visit (LPLV) (up to 
36 months); The extension treatment phase is only for patients who 
are continuing to benefit from study treatment at the end of the 
Core Phase who are not eligible for PSDS (Post-Study Drug 
Supply) in their country based on local regulations. Patients will 
continue on their existing study treatment assigned in the Core 
Phase until discontinuation or Last Patient Last Treatment (LPLT) 
of the Extension Phase. Note: If PSDS becomes available for a 
patient or a rollover protocol becomes available, the patient should 
be discontinued from the study and access treatment via PSDS or 
rollover trial (whichever occurs first).
Patients who are benefiting from the study treatment and are 
eligible for PSDS will exit the trial at the end of the Core Phase.
Population
The study will include a total of approximately 340 men and women 
(pre- and post-menopausal) with HR+, HER2-negative aBC 
harboring a PIK3CA mutation in the tumor, who progressed on or 
after prior treatments. 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 an adult male or female ≥ 18 years old.

Patient has adequate tumor tissue for the analysis of PIK3CA 
mutational status by a Novartis designated laboratory. It is 
recommended to provide a tumor sample collected after the 
most recent progression or recurrence.

Advanced (locoregionally recurrent or metastatic) breast 
cancer not amenable to curative therapy

Patient has been confirmed as PIK3CA mutant as determined 
by a certified designated laboratory

Patient has histologically and/or cytologically confirmed ER+ 
and/ or PgR+ BC

Patient has confirmed, HER2-negative aBC. HER2-negative 
defined as a negative in situ hybridization test or an 
immunohistochemistry (IHC) status of 0, 1+ or 2+.

Patients must be diagnosed with aBC, with documented 
evidence of tumor progression on or after prior treatments. No 


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more than one prior regimen of chemotherapy for the treatment 
of metastatic disease is permitted. The maximum number of 
prior therapies for aBC or mBC is limited to two (maintenance 
therapies, where applicable, must be regarded as part of the 
main therapy). Patients must have recovered to grade 1 or 
better from any adverse events (except alopecia) related to 
previous therapy prior to study entry. 

Patient has either measurable disease, i.e. at least one 
measurable lesion as per RECIST v1.1 criteria or if no 
measurable disease is present than at least one predominantly 
lytic bone lesion must be present

Patient has ECOG performance status of ≤ 2

Patient has adequate bone marrow function
Key Exclusion criteria

Patient has received prior treatment with any PI3K inhibitors

Patients with an established diagnosis of diabetes mellitus type 
I or uncontrolled type II (based on FG and HbA1c in inclusion 
criterion 11)

Patient has a concurrent malignancy or malignancy within 3 
years of study screening period, with the exception of 
adequately treated basal or squamous cell carcinoma, non-
melanoma skin cancer or curatively resected cervical cancer

Patient has received radiotherapy ≤ 4 weeks or limited field 
radiation for palliation ≤ 2 weeks prior to enrollment, and who 
has not recovered to grade 1 or better from related side effects 
of such therapy (with the exception of alopecia)

Patients receiving systemic corticosteroids ≤ 2 weeks prior to 
treatment with alpelisib

History of acute pancreatitis within 1 year of screening or past 
medical history of pancreatitis

Patient has impaired GI function or GI disease that may affect 
the absorption of study drugs

Patient has documented pneumonitis

Patients being concurrently treated with drugs recognized as 
being strong inhibitors or inducers of the isoenzyme 
Cytochrome P (CYP)3A within the last 5 days prior to study 
entry
Investigational and 
reference therapy
Male and pre and postmenopausal female patients with HR+, 
HER2-negative aBC patients harboring PIK3CA mutation(s) in the 
tumor who progressed on or after prior treatments will receive 
alpelisib combination therapy:
Cohort A: Patients who received any CDK 4/6 inhibitor plus AI as 
immediate prior treatment will receive alpelisib + fulvestrant
Cohort B: Patients who received any CDK 4/6 inhibitor plus 
fulvestrant as immediate prior treatment will receive alpelisib + 
letrozole
Cohort C: Patients who have received systemic chemotherapy, or 
ET (including monotherapy or in combination except CDK 4/6i + AI) 
as immediate prior treatment,  will receive alpelisib + fulvestrant


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Study 
treatment
Pharmaceutical form 
and route of 
administration
Frequency and/or Regimen
Fulvestrant
Two 5 ml injections for 
IM administration 
Dosed every 28 days (Day 1) 
and Day 15 of Cycle 1 and 
Day 1 for all subsequent 
Cycles 
Alpelisib
Film coated tablet
for oral use
Once daily
Letrozole
Film coated tablet for 
oral use
Once daily 
Goserelin
Injectable 
subcutaneous implant 
Every 28 days (only for men in 
cohort B and premenopausal 
women) 
Leuprolide
Injectable 
intramuscular depot
Every 28 days (only for men in 
cohort B and premenopausal 
women)
Efficacy assessments

Computed Tomography (CT)/ Magnetic Resonance Imaging 
(MRI) every 12 weeks until disease progression, death, 
withdrawal of consent, loss to follow-up, subject/guardian 
decision, or until the end of the Core Phase 

Brain CT or MRI as clinically indicated if brain lesion at 
screening

Bone X-ray, CT or MRI (if bone lesion at screening) every 12 
weeks until end of the Core Phase

Skin color photography (if skin lesions at screening) every 12 
weeks until end of the Core Phase

CT/ MRI for any disease outside of the chest, abdomen, pelvis 
(if lesion identified at screening) every 12 weeks until end of 
the Core Phase

Survival status every 12 weeks (or earlier if required) 
regardless of treatment discontinuation reason (except if 
consent is withdrawn, death or patient is lost to follow-up) or 
until the end of the Core Phase

During the Extension Phase, clinical benefit assessments will 
follow the local standard of care per the physician’s 
determination if the patient is continuing to clinically benefit 
from the study treatment.
Safety assessments

Core Phase:
o
Physical examination
o
ECOG performance status
o
Height, weight, and vital signs
o
12 lead ECGs
o
ECHO, MUGA scan as clinically indicated 
o
Laboratory assessments including hematology, 
biochemistry,  fasting glucose (FG), random blood glucose 
(RBG), HbA1c, fasting lipase, fasting amylase, coagulation 
and urinalysis

In the Extension Phase, safety assessments will consist of 
monitoring and recording all Adverse Events (AEs), including 
Serious Adverse Events (SAEs).


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Data analysis
The primary efficacy endpoint is the proportion of patients who are 
alive without disease progression at 6 months based on local 
investigator assessment using RECIST v1.1 in each cohort.
A proportion of 
 of patients alive without progression after 6 
months is considered as a clinically meaningful threshold in all the 
cohorts for this study. 
Therefore, evidence of treatment effect in each cohort will be tested 
using the following hypothesis:
H0: p ≤0.30 vs. H1: p >0.30
Where p is the proportion of patients who are alive without 
progression at 6 months.
Three Interim Analyses (IA) are planned for this study. The first IA 
will be performed after at least
patients receiving alpelisib plus 
fulvestrant (cohort A) have at l
t 6 months of follow-up. 
A second IA will be performed when approximately
patients 
have been treated in the study (regardless of cohort) and have at 
least 6 months of follow-up on study. A third IA will be performed 
after the Core Phase has ended. 
The first two interim analyses will be performed to report 
preliminary efficacy (ORR, CBR) as well as key safety data in a 
descriptive fashion to provide additional information in this patient 
population. The third interim analysis will be performed to report all 
efficacy and safety data up to the end of the Core Phase.
The final analysis will be performed after LPLV of the study which 
include cumulative data (eg safety and clinical benefit) since the 
Core Phase analysis.
The primary efficacy analysis will be performed using modified full 
analysis set (mFAS). The modified Full Analysis Set (mFAS) 
comprises all patients of the FAS population who have PIK3CA 
mutation confirmed by a Novartis designated laboratory. The 
assessment of safety will be based mainly on the frequency of 
adverse events and laboratory values that fall outside of pre-
determined ranges.
Key words
HR+, Human Epidermal Growth Factor Receptor 2 (HER2)-
negative, advanced breast cancer, alpelisib, fulvestrant, letrozole, 
Phosphoinositol 3-kinase-related-kinases (PI3K), Gene encoding 
p110alpha catalytic subunit of PI3K (PIK3CA) mutant, Phase II, 
CDK 4/6 inhibitor, men, pre and postmenopausal, aromatase 
inhibitor, endocrine therapy


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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. It is estimated that more than 1.7 
million new cases of breast cancer occurred among women worldwide in 2012 (GLOBOCAN 
2012). It is estimated that worldwide over 508,000 women died in 2011 due to breast cancer 
(Global Health Estimates, WHO 2012). In 2014, an estimated 232,670 new cases were 
diagnosed in women in the United States; of those, 133,310 were in women < 65 years old. 
Fewer than 5% of breast cancers occur in women < 40 years old (American Cancer Society 
2014), but it is still the leading cause of cancer death among women 20 to 59 years old (Siegel 
2014). 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 2014, 
Agrawal 2007, Patten 2013, Giordano 2002). Subtypes of invasive 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 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)) including selective ER modulators (SERM; tamoxifen), ER 
antagonists (fulvestrant), selective nonsteroidal AIs (NSAI; anastrozole and letrozole) and 
steroidal aromatase inhibitors (AIs; exemestane). Blocking estrogen signaling with tamoxifen 
has been the main approach in treatment for ER+ breast cancer for over 35 years, especially in 
pre-menopausal women. 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 2009; NCCN 2017). In 
those patients that progress the combination of targeted agent and endocrine therapies have also 
been evaluated in the Bolero-2 trial: everolimus, a (Mammalian Target of Rapamycin (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 demonstrating progression survival improvement (Baselga 2012; Yardley 2014).
Recent data have noted that cell cycle related genes and proteins are frequently dysregulated in 
breast cancer. Cyclin D kinases inhibitors have been introduced with palbociclib, a Cyclin-
Dependent Kinase 4 and 6 inhibitor (CDK4/6i) now 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 a phase II Paloma-1 study (Finn 2015). Recently, palbociclib in combination with an AI was 
approved in EU in the similar population based on the phase 3 Paloma- 2 study (Finn 2016) in 
which the addition of palbociclib to letrozole resulted in a median PFS of 24.8 months vs 14.5 


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months in letrozole alone. Furthermore, a Phase III study of palbociclib in combination with 
fulvestrant in second line HR+ mBC patients (Paloma-3) demonstrated significant improvement 
in PFS versus fulvestrant alone (9.5 months vs 4.6 months) (Cristofanilli 2016). Ribociclib is 
another CDK 4/6 inhibitor, recently approved in both United States and Europe in HR+, HER2-
negative post-menopausal patients with advanced breast cancer. MONALEESA-2, a Phase III 
study of ribociclib in combination with letrozole in the first line aBC setting met its primary 
endpoint early at a pre-defined interim efficacy analysis, demonstrating a statistical and 
clinically meaningful benefit in PFS with the combination compared with letrozole alone 
(Hazard Ratio=0.556; 95% CI, 0.429, 0.720; p=0.00000329x 106) (Hortobagyi 2016). Recent 
updates demonstrated continued benefit for patients with combination with PFS at 25.3 months 
compared with 16.0 months in letrozole alone group (Hazard Ratio=0.568; 95% CI,0.457-0.704; 
p=9.63x10-8) (Hortobagyi 2017).
Another CDK4/6 inhibitor, abemaciclib, also demonstrated clinical efficacy in same population 
in MONARCH-3 study, results showed a statistical and clinical meaningful improvement in 
PFS with combination arm with anastrozole or letrozole compared with letrozole alone (Hazard 
Ratio= 0.54, 95% CI, 0.41-0.72, p=0.000021) (Goetz 2017). Abemaciclib with Monarch -2 
results also received FDA approval in post progression population on neoadjuvant/adjuvant or 
while post first line metastatic setting on endocrine therapy in combination on continuous daily 
dosing with fulvestrant 500 mg showing extended PFS benefit versus fulvestrant alone (median, 
16.4 vs. 9.3 months; Hazard Ratio 0. 553; 95% CI, 0.449 to 0.681; p <0.001) (Sledge 2017).
1.1.2
Treatment options for HR+, HER2- negative premenopausal aBC
In premenopausal patients without previous exposure to an antiestrogen, initial treatment of 
advanced/metastatic disease involves the use of a selective ER modulator alone or ovarian 
suppression/ablation plus endocrine therapy as for postmenopausal women. Tamoxifen is 
approved for the treatment of metastatic breast cancer in this population, which works by 
blocking the ER in the breast cancer cells, thereby preventing estrogen from binding. In women 
< 40 years of age with HR+ breast cancer, 5 years of adjuvant tamoxifen, with or without 
ovarian suppression, is considered the standard endocrine treatment and remains the first choice 
for endocrine therapy in the metastatic setting as well (Christinat 2013). Tamoxifen may be 
given either alone or in combination with an ovarian function suppression (OFS) agent, such as 
goserelin or leuprolide, as approved agents for the palliative treatment of pre- and 
perimenopausal advanced breast cancer [Zoladex® or Lupron® Prescribing Information]. These 
agents may function through different pathways (those of estrogen withdrawal and estrogen 
receptor blockade, respectively), which might target different cell populations and suppress the 
tamoxifen-induced stimulation of the pituitary-ovarian function and act in a similar way to an 
oophorectomy (Davidson 2000).
In premenopausal women who received a prior endocrine therapy within 12 months, the 
preferred therapy involves ovarian ablation or suppression + endocrine therapy - such as 
aromatase inhibitors (AIs) as for post-menopausal patients (NCCN 2017). Based on the clinical 
benefit shown in postmenopausal patients, AIs in combination with ovarian function 
suppression (OFS) have been investigated in premenopausal patients with breast cancer in 
neoadjuvant, adjuvant and advanced settings. Although data are limited (Montagna 2013), 
clinical benefit of the combination of AIs and OFS agents in premenopausal women with 


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advanced ER+ breast cancer has been shown in small phase II studies with letrozole and 
anastrozole. Clinical guidelines have been updated to include treatment of pre-menopausal 
women as in parallel or similar with postmenopausal women with AI in combination with OFS 
agents as standard of care.
1.1.3
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 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 2009). Resistance to a variety of 
therapeutic interventions, including chemotherapy, hormonal therapy and anti-HER2 therapies, 
can also be linked to constitutive activation of the PI3K pathway (McCubrey 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 2006; Cully 2006).
A schematic representation of these PI3K components is shown in Figure 1-1.


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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 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 2006). However, some mutations were also identified in other domains of PI3K, such
as the C2 domain (Bader 2005; Samuels 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 (Protein Kinase B) and phospho-
S6), to drive cellular transformation in vitro and in vivo, and to enhance cell survival (Zhao 
2008, Mankoo 2009). Mutations in the C2 domain were shown to induce or facilitate 
conformational changes leading to an increased activity of PI3Kα (Burke 2012, Hon 2012). 
Overall, the majority of gain-of function mutations identified in the PIK3CA 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 2009).
1.1.4
PI3K pathway in HR+ breast cancer
The 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).


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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)
Pre-clinical data suggest that the ER pathway interacts with the PI3K pathway with extensive 
crosstalk between ER and growth factor pathway (Miller 2011; 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 2004; Crespo 2002; Huang 
2004; Mita 2003; Wullschleger 2006). This mechanism is linked to de novo or acquired 
resistance to endocrine therapy (Campbell 2001), including AI resistance (Shoman 2005; 
Crowder 2009; Miller 2011). 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 2009).
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of letrozole
Letrozole (Femara®) is a nonsteroidal competitive inhibitor of the aromatase enzyme system 
with demonstrated efficacy in the treatment of postmenopausal patients with HR+ breast cancer. 
Letrozole acts by inhibiting in a highly selective fashion the conversion of adrenal androgens 
to estrogens, which is the primary source of estrogens in postmenopausal women. Letrozole is 
a highly selective inhibitor of aromatase that induces a 75% to 95% decrease of estrogen levels 
after two weeks of treatment using daily doses of 0.1 to 5 mg, with no significant clinical and 
laboratory toxicities nor changes in levels of other hormones of the endocrine system as shown 
in early phase I (Lipton 1995; Trunet 1996). Letrozole was compared with tamoxifen in a phase 
III trial in the first line setting in ER+/HER2+ breast cancer. Letrozole was superior to 
tamoxifen for time to progression (median, 9.4 vs 6.0 months) and median OS was longer for 
letrozole (median, 34 vs 30 months) but this difference was not statistically significant 
(Mouridsen 2001). Letrozole is indicated for the treatment of advanced HR+ breast cancer, both 
in the first -line setting as well as in patients who have disease progression following anti-
estrogen therapy. It is also indicated for the adjuvant treatment of women with HR+ early breast 
cancer as well as the extended adjuvant treatment of patients who have received 5 years of 
tamoxifen therapy.
The most frequently reported adverse events that were significantly different from placebo for 
letrozole in the adjuvant and extended adjuvant setting include hot flashes, arthralgia/arthritis 
and myalgia. In the first line setting, the most frequently reported adverse events include 
musculoskeletal pain (bone/back pain and arthralgia), hot flashes, nausea and dyspnea and 


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incidences of adverse events were similar for tamoxifen in this setting. In general, the observed 
adverse reactions are mild to moderate in nature [Femara® Prescribing Information, Novartis].
1.2.1.1
Clinical pharmacokinetics of letrozole
Letrozole is administered orally once daily at a dose of 2.5 mg and is rapidly and completely 
absorbed from the gastrointestinal tract. Concomitant intake of food has no effect on the extent 
of letrozole absorption and only a minor effect on the rate of absorption, which is considered to 
be of no clinical relevance. The terminal elimination half -life of letrozole is 2 days and steady-
state plasma concentration with daily dosing at the standard dose is reached in 2-3 weeks. 
Letrozole is metabolized via CYP3A4 to a pharmacologically-inactive carbinol metabolite 
(4,4’-methanol-bisbenzonitrile) and renal excretion of the glucuronide conjugate of this 
metabolite is the major pathway of letrozole clearance.
For further details, please refer to the latest [Femara® Prescribing Information, Novartis].
1.2.2
Overview of fulvestrant
Fulvestrant (Faslodex®) is the first-in-class unique ER down regulator with no known agonist 
effects (Addo 2002). In fact, the fulvestrant mechanism of action is distinct from other 
endocrine agents (Wakeling 2000); it binds, blocks and, unlike tamoxifen or other SERMs, 
degrades the ER and completely inhibits 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 2005).
Fulvestrant is approved for the treatment of HR+ mBC in postmenopausal women with disease 
progression following anti-estrogen therapy (USA, Europe). However, current clinical practice 
and treatment guidelines also include fulvestrant as treatment option for postmenopausal 
women without symptomatic visceral disease after recurrence or progression to an AI (NCCN 
2017).
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. For further details please refer to the latest [Faslodex®
Prescribing Information].
The phase III FALCON trial demonstrated superior median PFS for fulvestrant 500 mg q.d. 
compared to anastrozole 1 mg in the 1st line treatment of postmenopausal women with locally-
advanced or metastatic breast cancer, who have not had prior hormonal treatment for hormone 
receptor positive (HR+) breast cancer. The results show that the median PFS was 2.8 months 
longer with fulvestrant than anastrozole (Hazard ratio 0.797; 95% Confidence Interval (CI): 
0.637-0.999; p=0.0486). The median PFS was 16.6 months in the fulvestrant arm, compared 
with 13.8 months in the anastrozole arm. The most commonly reported adverse events in the 
fulvestrant and anastrozole arms were arthralgia (16.7% vs 10.3%), hot flashes (11.4% vs 


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10.3%), and nausea (10.5% vs 10.3%), respectively (Robertson 2016). Fulvestrant has since 
(2017) received approval for first line indication in the US and Europe.
1.2.2.1
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. 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. 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). For 
further details on clinical pharmacokinetics of fulvestrant, please refer to the latest [Faslodex®
Prescribing Information].
1.2.3
Overview of LHRH agonists
Luteinizing Hormone-Releasing Hormone (LHRH) or Gonadotropin Releasing Hormone 
(GnRH) agonists are synthetic analogues of gonadotropin-releasing hormone that by continuous 
stimulation of the GnRH receptor achieve desensitization of the pituitary gland to LHRH. 
LHRH agonists differ from the naturally-occurring LHRH by modification(-s) in the 
decapeptide structure (usually by amino acid substitution in position 6, but also in positions 9 
and 10) to decrease degradation of the molecule. LHRH agonists allowed for use in this study 
are goserelin or leuprolide. However, one-month depot formulation of LHRH agonists must be 
used to suppress ovarian function in premenopausal women throughout this study as the 3-
month depot formulations do not reliably suppress estrogen levels in all patients (Gradishar 
2016).
The most common AEs occurring in women treated with LHRH agonists included hot flashes, 
headache, sweating, acne, emotional lability, depression, decreased libido, vaginitis, breast 
atrophy, seborrhea and peripheral edema.
The most common AE occurring in men treated with LHRH agonists include a transitory 
elevation in testosterone levels can occur in men after the first few doses, followed by the 
expected decrease of these hormonal levels; as a result, the most commonly observed adverse 
reactions, which occurred in at least 1 out of 10 men (10%) who participated in clinical trials, 
are hot flashes, sexual dysfunction, decreased erections and lower urinary tract symptoms (for 
example, urinary urgency, cystitis, blood in your urine). Some patients may experience a 
temporary increase in bone pain.


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Refer to the most recent regional prescribing information and/or clinical guidelines for more 
information on [Zoladex® and Lupron® prescribing information]. 
1.2.4
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 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 2014). In vivo, alpelisib has demonstrated 
dose-dependent tumor growth inhibition in various subcutaneous tumor transplant models.
For further details on clinical and non-clinical experience, please refer to the latest version of 
[Alpelisib Investigators Brochure].
1.2.4.1
Non-clinical experience
1.2.4.1.1 Pharmacodynamics of alpelisib
Alpelisib shows significant preclinical antitumor activity. In biochemical assays, alpelisib 
inhibits p110α (inhibitor concentration causing half maximal inhibition [IC50]=4.6 nM) much 
more potently than the p110δ and γ isoforms and PIK4β and has weak or no activity against 
p110β, Vps34 and mTOR. Alpelisib is equipotent against the most common somatic mutations 
of p110α (H1047R, E545K) compared to wild type p110α, and is selective against a wide range 
of protein kinases with at least a 50-fold selectivity window compared to p110α. The potency 
and selectivity of alpelisib is confirmed at the cellular level in mechanistic and relevant tumor 
cell lines. Alpelisib potently inhibits p110α cellular activity (IC50=74 nM) and shows 
significant selectivity against the p110β and p110δ isoforms (above 15-fold). Alpelisib is not 
interfering with phosphoinositol 3-kinase-related- kinases (PIKKs) involved in DNA-damage 
repair processes (IC50> 30μM on S15P-p53 and IC50> 10μM on S1981P-ataxia-telangiectasia 
mutation [ATM]). In vitro, alpelisib inhibits the phosphorylation of PI3K downstream targets 
and the proliferation of various cancer cell lines, and showed increased activity in cell lines 
harboring gene alterations in PIK3CA. Gain-of-function mutations in the gene encoding the 
catalytic α-subunit of PI3K (PIK3CA) lead to activation of PI3Kα and Akt-signaling, cellular 
transformation and the generation of tumors in in vitro and in vivo models.
In multiple cancer indications, including breast cancer, alpelisib inhibited the phosphorylation 
of PI3K downstream targets, including Akt and showed activity in cell lines harboring a 
PIK3CA mutation. In vivo, alpelisib inhibited the PI3K/Akt signaling pathway and reduced 
tumor growth in xenograft models, including models of multiple cancer indications, including 
breast cancer. More detailed information on the pharmacology of alpelisib, single and multiple 
dose pharmacokinetic (PK) studies conducted in multiple species and nonclinical safety 
evaluations, is provided in the [Alpelisib (BYL719) Investigator’s Brochure].


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1.2.4.1.2 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.
Alpelisib was found to be a time-dependent inhibitor of CYP3A4 (Ki 5.6 µM, Kinact 0.011 
min-1). Reversible inhibition of CYP2C8 (Ki 32 µM = 14 µg/ml), CYP2C9 (Ki 22 µM = ~10 
µg/ml) and CYP2C19 (IC50 75 µM) was also observed. Alpelisib may inhibit metabolic 
clearance of co-medications metabolized by CYP3A4, CYP2C8, CYP2C9 and CYP2C19, if 
sufficiently high concentrations are achieved in vivo. A risk assessment based on the 
mechanistic static model (or a “net effect model”) (Fahmi 2008), assuming a very sensitive 
substrate (fm =1) and no gut metabolism (Fg = 1), predicted an AUCR to be <1.1 with the 
lowest measured Ki for CYP2C9 at the calculated unbound hepatic inlet concentration (1.2 µM) 
at MTD level dose. Hence it is unlikely that inhibition of CYP2C9 or other CYP2C-family 
enzymes, which showed an even less inhibitory potential, translates into a clinical relevant 
interaction.
While clinically significant pregnant X receptor-(PXR)-mediated induction of CYP3A4 or 
aromatic hydrocarbon receptor-mediated induction of CYP1A2 by alpelisib has not been 
expected based on the negative result from in vitro nuclear activation assays, there has been 
recent growing evidence from a hepatocyte induction assay that alpelisib can induce CYP3A4 
(EC50 = 1.7 μM, Emax = 0.83 relative to RIF control), likely via activation and crosstalk with 
the constitutive androstane receptor (CAR) receptor. Based on preliminary clinical data from 
the study investigating the combination of alpelisib with the CYP3A4 sensitive substrate 
everolimus [CBYL719Z2102] which showed no increase of everolimus exposure after 


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concomitant administration with alpelisib at steady state, as well as physiologically-based 
pharmacokinetic (PBPK) modelling of alpelisib using SimCyp, time-dependent inhibition and 
induction of CYP3A4 by alpelisib seem to result in a neutral net effect in vivo at clinically 
relevant exposures.
Alpelisib is a substrate of Breast Cancer Resistance protein (BCRP) and has low affinity for P-
glycoprotein (P-gp/MDR1). Alpelisib does not inhibit BCRP or Multi-drug resistance protein-
2 (MRP2), but showed very weak inhibition of P-gp (IC50 = 97 µM). As the maximal inhibition 
of P-gp was only about 32% with respect to positive control, the overall interaction potential is 
expected to be low. Uptake of alpelisib in human hepatocytes was not influenced by inhibitors 
of the transporter families organic cation transporter (OCT), organic anion transporter (OAT), 
organic anion-transporting polypeptide (OATP) and sodium taurocholate co-transporting 
polypeptide (NTCP). Assessment of the hepatobiliary disposition mechanisms of alpelisib in 
sandwich cultured rat and human hepatocytes showed that it is actively transported into bile 
pockets.
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 
(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.
For further details on nonclinical PK and metabolism experience, please refer to the latest 
version of [Alpelisib Investigators Brochure].
1.2.4.1.3 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 the 4- and 13-week studies, reversibility of toxicity findings was assessed for a 4-


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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.
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.
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.
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 
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.
For further details on safety pharmacology and toxicology experience, please refer to the latest 
version of [Alpelisib Investigators Brochure].
1.2.4.1.4 Genotoxicity status of alpelisib and metabolites
There is no evidence of a potential to induce reverse gene mutations or numerical or structural 
chromosome aberrations was seen for alpelisib.
For further details on genotoxicity data, please refer to the latest version of [Alpelisib 
Investigators Brochure].
1.2.4.2
Clinical experience
As of the cut-off date of 23-May-2022, a total of 2566 patients (including cancer patients, 
hepatic impaired subjects, healthy volunteers, and Patient Reported Outcomes (PROS)) had 
been exposed to alpelisib across 42 Novartis sponsored studies with alpelisib as a single agent 
or in combination (everolimus, everolimus + exemestane, MEK162, LGX818, LJM716, 
ribociclib, imatinib, trastuzumab emtansine (T-DM1), pertuzumab, olaparib), endocrine 


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therapy (e.g. fulvestrant, letrozole) or chemotherapy (e.g. sb-paclitaxel, nab-paclitaxel, 
AUY922, AMG479, cetuximab, INC280, LDK378, LSZ102, BGJ398, tamoxifen-goserelin ).
Alpelisib (Piqray®) was first approved on 24-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. On 27-Jul-2020, the European Medicines Agency (EMA) approved alpelisib in 
combination with fulvestrant for the treatment of postmenopausal women, and men, with 
hormone receptor (HR)positive, human epidermal growth factor receptor 2 (HER2)negative, 
locally advanced or metastatic breast cancer with a PIK3CA mutation after disease progression 
following endocrine therapy as monotherapy.
These approvals were based on the primary efficacy results of CBYL719C2301 (SOLAR-1) a 
Phase III, randomized, multicenter, double-blind, placebo-controlled, study that met its primary 
endpoint in patients with HR-positive, HER2-negative advanced breast cancer with a PIK3CA 
mutation with a statistically significant and clinically meaningful improvement in PFS in favor 
of the alpelisib plus fulvestrant arm (Hazard Ratio=0.65, 95% CI: 0.50, 0.85, p=0.00065, one-
sided) (cut-off date of 12-Jun-2018). Median PFS was prolonged by 5.3 months, from 5.7 
months (95% CI: 3.7, 7.4) in the placebo plus fulvestrant arm to 11.0 months (95% CI: 7.5, 
14.5) in the alpelisib plus fulvestrant arm. No clinically meaningful PFS benefit was observed 
in patients whose tumors did not have a PIK3CA tissue mutation (Hazard Ratio = 0.85; 95% 
CI: 0.58, 1.25).
The OS analysis for SOLAR-1 study was conducted, with cut-off date of 23-Apr-2020, based 
on 181 deaths. While the OS results did not cross the prespecified efficacy boundary, there was 
a clinically relevant improvement in OS of 7.9 months for patients with a PIK3CA mutation 
taking alpelisib plus fulvestrant compared to placebo plus fulvestrant (median OS 39.3 months 
vs. 31.4 months; this result did not reach the pre-specified threshold of statistical significance 
(one-sided p≤0.0161); Hazard Ratio=0.86; 95% CI: 0.64-1.15; p=0.15). 
With a median follow-up of 42.4 months, the safety profile remains consistent with that 
previously reported based on the latest safety analysis for SOLAR-1 study (cut-off date of 23-
Apr-2020). All grade AEs were reported in ≥ 20% of participants in the alpelisib plus fulvestrant 
treatment arm were hyperglycemia (65.8%), diarrhea (59.5%), nausea (46.8%), decreased 
appetite (36.3%), rash (51.8%), vomiting (28.5%), weight decreased (27.8%), fatigue (43.7%) 
(also includes asthenia), stomatitis (30.3%), and alopecia (20.4%). Grade ≥ 3 AEs in≥5% of 
patients were hyperglycemia (37%), rash (9.9%), maculo-papular (8.8%), diarrhea (7%), and 
weight decreased (5.3%). No Grade 4 diarrhea or rash was reported in the study. Less commonly 
reported, but clinically important, adverse reactions were pneumonitis, severe hypersensitivity 
and severe cutaneous reactions. More detailed information regarding alpelisib is available in 
the [Alpelisib (BYL719) Investigator's Brochure], Piqray® USPI and SmPC.


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Alpelisib has been investigated both as a single agent and as combination therapy in 42 Novartis 
sponsored clinical studies and as of 23-May-2022; 25 studies have been completed and 17 
studies are ongoing. The safety profile of alpelisib is well characterized and manageable with 
generally reversible AEs. More detailed preclinical and clinical information is provided in the 
[Alpelisib (BYL719) Investigator’s Brochure].
1.2.4.3
Clinical pharmacokinetics
The pharmacokinetics of alpelisib has been studied in healthy volunteers 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 
fold and steady-state plasma concentrations are reached within 3 days following daily dosage. 
In adult subjects 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 
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.
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.
Alpelisib inhibits CYP3A4 in a time-dependent manner and induces CYP2B6, CYP2C9 and 
CYP3A4 in vitro. Alpelisib is an inhibitor of P-gp. No clinically significant differences in 
pharmacokinetics of everolimus (a substrate of CYP3A4 and P-gp), however, were observed 
when coadministered with alpelisib. Alpelisib has a low potential to inhibit BCRP (Breast 
Cancer Resistance Protein), MRP2, BSEP, OATP1B1, OATP1B3, OCT1, OAT1, OAT3, 
OCT2, MATE1, and MATE2K at clinically relevant concentrations.
For further details on clinical pharmacokinetics, please refer to the latest version of [Alpelisib 
Investigators Brochure].


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Consideration of gender effect
The impact of gender on the pharmacokinetics of alpelisib was evaluated with a population PK 
approach. Due to the SOLAR-1 study enrolling primarily females (one male was randomized), 
this assessment was based on the Phase I population PK model. The analysis included 52 
(21.2%) males and 193 (78.8%) females from Phase I studies CBYL719X1101 (in patients from 
Japan with advanced solid tumors) and CBYL719X2101 (as a first-in-human dose escalation 
and expansion study) single agent and fulvestrant combination data. In the final model, males 
had a 35% higher clearance (CL) compared to females, leading to a reduction in AUC by ~25% 
compared to a female with the same covariates. While exposure-response analysis in PIK3CA-
mutant, ER-positive, HER2-negative metastatic breast cancer indicated relationships between 
exposure (PK exposure and dose intensity) and safety (hyperglycemia, rash) and efficacy (PFS), 
the clinical impact of the difference in males is difficult to assess at present, given the magnitude 
of the change and the observed intra-subject (intra-CV% ~30%) and inter-subject variability 
(~20%) in cancer patients as well as limited data in the male population. 
1.2.5
Overview of the combination of alpelisib and endocrine treatments
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 2014) in line with the concept of synthetic 
lethality seen previously when PI3K was inhibited in an estrogen deprived cell line (Crowder 
2009). For further details on preclinical experience, please refer to the latest version of 
[Alpelisib Investigators Brochure].
1.2.5.1
Clinical experience with alpelisib and aromatase inhibitors in mBC
A completed investigator initiated trial (IIT), phase Ib (n=26) assessed the combination of 
alpelisib + letrozole in previously treated HR+ HER2-negative metastatic breast cancer patients. 
All the patients were pretreated with AI, 18 patients received endocrine therapy and 8 of them 
received chemotherapy in the metastatic setting, respectively. The RP2D of alpelisib in 
combination with letrozole was established as 300 mg/d q.d. Most common Grade 3 AEs at this 
dose were hyperglycemia, diarrhea (12% each), and transaminitis (6%). Overall, 5 PRs (19%) 
were reported, with SD in 12 (46%) patients. Six out 9 patients on treatment for ≥ 6 months had 
a PIK3CA mutant breast cancer, though clinical activity was not restricted to patients with 
PIK3CA mutant tumors alone (Mayer 2016).
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. Maximum Tolerated Dose (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) (Shah 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 


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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 2014).
1.2.5.2
Experience with alpelisib and fulvestrant in mBC
The combination of alpelisib with fulvestrant was investigated as part of study 
[CBYL719X2101] in 87 patients with heavily pre-treated HR+ mBC in two groups: patients 
with mutated PIK3CA (52 patients, 59.8%) and patients with wild-type PIK3CA (33 patients, 
37.9%). For two patients (2.3%), PIK3CA mutational status was unknown. The MTD was 
declared at alpelisib 400 mg QD and fulvestrant 500mg q28 days, with DLTs in 4 patients 
(diarrhea, vomiting, decreased appetite, abdominal, distension and fatigue). Also alpelisib doses 
of 350 mg and 300 mg QD were investigated and mainly 300 mg QD emerged as the best 
tolerated dose in this combination. Overall, the most frequent AEs (>20%), regardless of grade, 
causality and alpelisib dose, suspected of being drug related were diarrhea (56.3%), nausea 
(42.5%), hyperglycemia (48.3%), decreased appetite (37.9%), fatigue (29.9%), vomiting 
(25.3%), stomatitis (27.6%) and fatigue (29.9%). Preliminary clinical efficacy of alpelisib + 
fulvestrant was demonstrated across all dose levels. Best overall response (BOR) achieved was 
confirmed PR for 13 (26.5%) patients and SD for 26 (53.1%) patients with PIK3CA mutant 
tumors versus PR for 0 (0%) patient and SD for 15 (46.9%) patients with PIK3CA non-mutant 
tumors. Disease control rate was 79.6% (95% CI: 65.7–89.8) and 46.9% (95% CI: 29.1–65.3) 
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 (9.1 months vs 4.7 
months). Overall, 7 patients are still on treatment in this study (2 on alpelisib as single agent, 5 
receiving alpelisib with fulvestrant (Juric 2016). This data led to a design of 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 [SOLAR-1, 
[CBYL719C2301].
For further details on clinical experience, please refer to the latest version of [Alpelisib 
Investigators Brochure].
1.2.6
Potential for drug interactions
1.2.6.1
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 Investigators 
Brochure].


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1.2.6.2
Low Potential for drug-drug interactions with fulvestrant
The potential for a DDI between fulvestrant and co-administered drugs is considered to be 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 
ketoconazole (strong 
CYP3A4 inhibitor) demonstrated no effect on fulvestrant 
pharmacokinetics. Therefore, a DDI involving fulvestrant and alpelisib are unlikely to occur 
[Faslodex® Prescribing Information].
1.2.6.3
Low Potential for drug-drug interactions with letrozole
The potential for a drug-drug interaction between letrozole and co-administered drugs is 
considered low. There are no known drug interactions with letrozole.
2
Rationale
2.1
Study rationale and purpose
The purpose of this study is to assess the efficacy and safety of treatment with alpelisib plus 
endocrine therapy (either fulvestrant or letrozole) in patients with HR+, HER2-negative aBC, 
harboring PIK3CA mutations, whose disease has progressed on or after prior treatments.
As described above, 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 
endocrine therapy, in particular fulvestrant (O’Brien 2014). Clinical activity has been observed 
when single agent alpelisib was given in heavily pre-treated ER+ (mBC) patients and also when 
alpelisib was given in combination with fulvestrant or AI to HR+, HER2-negative mBC patients 
(Janku 2014; Mayer 2016).
In HR+ BC, alpelisib has shown synergistic antitumor effects when used with endocrine therapy 
(e.g. letrozole). Clinical activity was observed independently of PIK3CA mutation status 
although clinical benefit was seen in a higher proportion of patients with PIK3CA mutated 
tumors. Therefore, the results from this phase Ib investigator initiated trial (IIT), investigating 
the combination of alpelisib + letrozole in previously treated HR+, HER2-negative metastatic 
breast cancer (mBC) patients study provides evidence that alpelisib plus letrozole is safe, 
tolerable and active in post-menopausal patients with ER+/HER2-negative metastatic breast 
cancer refractory to endocrine therapy (Mayer 2016).
Additionally in the phase Ib B-YOND study [CBYL791XIC01], premenopausal women with 
advanced HR+ breast cancer were treated with alpelisib and buparlisib. Interim data from the 
study, in a small group of 16 patients alpelisib in combination with tamoxifen and goserelin 
achieved 44% clinical benefit rate with 7 (44%) achieving partial response per RECIST v1.1, 
as best overall response, and a generally manageable safety profile. This led to conclusion that 
these pathways should also be further explored in this pre-menopausal population (Lu 2017).


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Rationale for enrolling PIK3CA mutant patients
Up to 45% of HR+ BC 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 2014), sensitivity to alpelisib in combination with 
fulvestrant was observed in PIK3CA mutant patients (see Figure 1-1, Section 1.2.4.1). Indeed, 
HR+ BC 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 BC tumors as well (Fritsch 2014).
Clinical data confirms 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) (Mayer 2014; Shah 2014; Janku 2014; Andre 2018). 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.
The key purpose of this study is to evaluate the efficacy and safety of alpelisib in combination 
with an endocrine partner for patients with tumors harboring PIK3CA mutations, who have 
progressed on or after prior treatments. 
Preclinical breast cancer cell lines with acquired resistance to palbociclib data indicate that 
acquired resistance to CDK4/6 inhibition occurs through a loss of independence to Rb signaling; 
therefore targeting PI3K/mTOR as an alternative pathway might be a viable strategy requiring 
further clinical investigation (O’Brien 2017).Therefore, this study will include assessment of  
the efficacy and safety of alpelisib combination in PIK3CA mutant HR+, HER2-negative aBC 
patients following progression on CDKi based regimen. The choice of hormonal combination 
partner with alpelisib (fulvestrant or letrozole) will be determined based on the CDKi 
combination partner drug used prior to study entry in these patients.
2.2
Rationale for the study design
This is a phase II, multicenter, open-label, three-cohort, non-comparative study of alpelisib plus 
endocrine therapy (either fulvestrant or letrozole) in patients with HR+, HER2-negative aBC 
harboring PIK3CA mutation(s) in the tumor who have progressed on or after prior treatments.  
Patients will be assigned to cohort A, B or C based on the most recent prior therapy; patients 
whose prior treatment is CDK 4/6 inhibitor plus fulvestrant will be enrolled in Cohort B until 
Cohort B enrollment is closed and then enrolled into Cohort C until it is closed for enrollment.  
Eligible patients include male and female (pre and post-menopausal) patients with HR+, HER2-
negative aBC harboring PIK3CA mutation(s) whose disease has progressed on or after prior 
treatments. 
PIK3CA mutations will be identified by analyzing the PIK3CA gene for hotspots known to 
impact the PI3K function in exons 7, 9 and 20 (see Section 7.2.3.1.1). These hotspots are 
anticipated to include the majority of the PIK3CA mutations identified in HR+ breast cancer 
patients so far and have shown sensitivity to alpelisib in vitro (Novartis Internal Data).Based 
on Novartis Internal Data obtained on a similar population, frequency of PIK3CA mutation 
status in HR+ breast cancer is anticipated to be approximately 40% based on data from Novartis 


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sponsored trials [CBKM120F2302 and CBKM120F2303]. Patients will be assigned to each 
cohort as follows:
Cohort A: Patients who received any CDK 4/6 inhibitor plus any AI as immediate prior 
treatment, will receive alpelisib + fulvestrant
Cohort B: Patients who received any CDK 4/6 inhibitor plus fulvestrant as immediate prior 
treatment, will receive alpelisib + letrozole
Cohort C: Patients who received systemic chemotherapy or ET (as monotherapy or in 
combination with targeted treatment except CDK 4/6i + AI) as immediate prior treatment will 
receive alpelisib + fulvestrant
Note: In Cohort C, ET includes letrozole, fulvestrant and CDK 4/6 inhibitor plus fulvestrant. It 
is hypothesized that patients with tumors harboring a PIK3CA mutation could derive clinically 
relevant benefits with a PI3K inhibitor containing treatment. This study will provide 
preliminary evidence of efficacy for the combination of alpelisib with letrozole or fulvestrant 
in this patient population of advanced HR+ breast cancer.
The study includes two phases:
Core Phase: Includes treatment phase for all patients from FPFT until 18 months post LPFT + 
1 month Safety follow-up (total 19 months post LPFT)
Extension Phase: includes treatment phase starting at the end of the treatment Core Phase until 
LPLV (up to 36 months); The extension treatment phase is only for patients who are continuing 
to benefit from study treatment at the end of the Core Phase who are not eligible for PSDS in 
their country based on local regulations. Patients will continue on their existing study treatment 
assigned in the Core Phase until discontinuation (refer to Section 7.1.5) or LPLT of the 
Extension Phase. Note: If PSDS becomes available for a patient or a rollover protocol becomes 
available, the patient should be discontinued from the study and access treatment via PSDS or 
rollover trial (whichever occurs first).
Patients who are benefiting from treatment and are eligible for PSDS will exit the trial at the 
end of the Core Phase.
2.3
Rationale for dose and regimen selection
As described in Section 1.2.4.3, the recommended dose for alpelisib in combination with 
fulvestrant was 300 mg q.d. Alpelisib 300 mg q.d. has also emerged to be the best tolerated 
dose in combination with AIs (Mayer 2014; Shah 2014; Munster 2014; [CBYL719A2201]
study) (see Section 1.2.4.2 and Section 1.2.4.3).
Therefore, in this clinical trial alpelisib will be given at the dose of 300 mg q.d. together with 
fulvestrant (in cohorts A and C) administered as per the product labeling (Faslodex® EU 
Summary of Product Characteristics (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 cohort B 
alpelisib will be given at the same dose of 300 mg q.d. together with letrozole administered per 
the product labeling (Femara® Prescribing Information, Novartis): 2.5 mg q.d., orally. In this 
study, a cycle is defined as 28 ± 3 days.


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Premenopausal women, in addition to the study medications, will also receive goserelin or 
leuprolide (as necessary) to achieve adequate hormonal suppression.
Men in cohorts A and C (alpelisib in combination with fulvestrant) are not required to receive 
LHRH agonist. For men in cohort B (alpelisib in combination with letrozole) goserelin or 
leuprolide will be added for hormonal suppression.
The standard dose of goserelin (3.6 mg subcutaneously every 28 days) and leuprolide (7.5 mg 
i.m. every 28 days) will be used in this study. Goserelin or leuprolide are not expected to affect 
the metabolism of nor be affected by co-administration of other drugs. Refer to the most recent 
regional prescribing information and/or clinical guidelines for more information on LHRH 
agonists.
2.4
Rationale for choice of combination drugs
The rationale to combine alpelisib with fulvestrant is discussed in Section 1.2.5.2.
The rationale to combine alpelisib with letrozole is discussed in Section 1.2.5.1.
2.5
Rationale for choice of comparators drugs
There are no comparator drugs due to the fact there is no data to suggest how prior treatment 
may impact the outcome of any subsequent treatment with AI or fulvestrant and/or PI3K 
inhibitors. This is a non-comparative study which will provide early data for both combinations.
2.6
Risks and benefits
Appropriate eligibility criteria as well as specific dose modification and stopping rules, are 
included in this protocol as guidance for the investigators. Recommended guidelines for 
prophylactic or supportive management of study-drug induced adverse events are provided in 
Section 6. The risk to subjects in this trial may be minimized by compliance with the eligibility 
criteria and study procedures, as well as, close clinical monitoring pre-identifying risk factors 
and outlining dose stopping rules. There may be unforeseen risks with alpelisib, fulvestrant, 
letrozole or their combination which could be serious.
The addition of goserelin or leuprolide to premenopausal women and male patients is not 
expected to affect the metabolism of nor be affected by co-administration of the other drugs 
(alpelisib in combination with fulvestrant or letrozole), so no additional safety risks are expected 
with this combination.
For further details on clinical safety, please refer to the latest version of [Alpelisib Investigators 
Brochure], [Faslodex® prescribing information], [Femara® Prescribing Information, Novartis], 
[Zoladex® prescribing information] and [Lupron® prescribing information].
2.6.1
Potential benefit for participants
Treatment with alpelisib in combination with fulvestrant or letrozole may result in an improved 
clinical benefit in men and women (pre and post-menopausal) with HR+, HER2-negative aBC, 
who progressed on or after prior treatments and harbor the PIK3CA mutation. All patients 
enrolled in this trial will receive an active endocrine therapy in combination with alpelisib for 
their disease (see Section 2.5). Based on preclinical and preliminary clinical data (see Section 


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1.2.4), treatment with alpelisib in combination with fulvestrant or letrozole is expected to have 
an acceptable safety profile and it is hypothesized that it will result in delayed disease 
progression.
For further details on clinical safety, please refer to Section 1.2.2 and the latest version of 
[Alpelisib Investigators Brochure].
2.6.2
Potential risks to clinical trial participants
See Section 2.6.3.
2.6.3
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 or interruptions or discontinuations 
as outlined in Section 6.3. There may be unforeseen risks with alpelisib in combination with 
fulvestrant or letrozole.
Patients in this study will be carefully monitored for key toxicities that have been observed with 
alpelisib (see Section 1.2.4) with combination of fulvestrant or letrozole (see Section 1.2.1) 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 6.4.4), close safety monitoring (see 
Section 8.1) and dose adjustment guidelines (see Section 6.3) for alpelisib and fulvestrant 
[Faslodex® prescribing information], letrozole prescribing information [Femara® Prescribing 
Information, Novartis] goserelin and leuprolide [Zoladex® prescribing information] and 
[Lupron® prescribing information].
A Steering Committee (SC) (see Section 8.7) will be established comprising 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 safety data across the alpelisib program for early detection of 
potential safety signal assessment in a timely manner.
Women of childbearing potential and sexually active males must be informed that taking this 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study and up to the period required after the last dose of study treatment. Based on findings in 
animals and its mechanism of action, alpelisib can cause fetal harm when administered to a 
pregnant woman. In animal reproduction studies, oral administration of alpelisib to pregnant 
rats and rabbits during organogenesis caused adverse developmental outcomes, including 
embryo-fetal mortality (postimplantation loss), reduced fetal weights, and increased incidences 
of fetal malformations at maternal exposures based on area under the curve (AUC) that were 
≥0.8 times the exposure in humans at the recommended dose of 300 mg/day. Advise pregnant 
women and females of reproductive potential of the potential risk to a fetus.


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Patients must therefore agree to adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the participant will not reliably comply, they 
should not be entered or continue in the study.
Study related risks include, but are not limited to, collection of fresh tumor samples, blood 
collections, the different imaging methods including Echocardiogram (ECHO) or multiple 
gated acquisition (MUGA) scan, bone scans and electrocardiograms (ECGs). Please refer to the 
Consent Form for more information.
Based on key anticipated benefits and potential risks, the benefit-risk balance is anticipated to 
be positive for the target population of this trial.
2.6.4
Rationale for Public Health Emergency mitigation procedures
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic,
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity
are listed in relevant sections. Notification of the Public health emergency should be discussed
with Novartis prior to implementation of mitigation procedures, and permitted/approved by
Local or Regional Health Authorities and Ethics Committees as appropriate.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
To assess the proportion of patients who are alive without 
disease progression at 6 months based on local investigator 
assessment per RECIST v1.1 separately in cohorts A and C 
(alpelisib in combination with fulvestrant) and cohort B 
(alpelisib in combination with letrozole) among patients with 
HR+, HER2-negative aBC harboring a PIK3CA mutation 
who have progressed on or after prior treatments.
The primary endpoint of this study is the proportion of patients 
who are alive without disease progression at 6 months based 
on local investigator assessment using RECIST v1.1 in each 
cohort
Secondary
Refer to Section 10.5
To assess PFS based on local investigator assessment for 
each cohort.
PFS based on local investigator assessment using RECIST 
v1.1 in each cohort
To assess PFS on next-line treatment (PFS2) for each 
cohort.
PFS2 based on local investigator assessment in each cohort
To assess overall response rate (ORR) and clinical benefit 
rate (CBR) based on local investigator assessment for each 
cohort.
ORR based on local investigator’s assessment according to 
RECIST v1.1 in each cohort
Clinical Benefit Rate (CBR) based on local investigator’s 
assessment according to RECIST v1.1 in each cohort
To assess duration of response (DOR) in patients with 
confirmed complete response (CR) or PR for each cohort.
Duration of Response is the time from the date of first 
documented response (confirmed CR or PR) to the date of 
first documented progression or death
To assess Overall Survival (OS) for each cohort
Overall Survival is defined as the time of start of treatment to 
date of death or lost to follow-up.
To evaluate the safety and tolerability of the combination for 
each cohort.
Type, frequency and severity of adverse events per CTCAE 
v4.03
Type, frequency and severity of laboratory toxicities per 
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Objective
Endpoint
Analysis
Evaluate clinical benefit as assessed by the Investigator 
during the Extension Phase
Proportion of patients with clinical benefit as assessed by the 
Investigator at scheduled visits


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4
Study design
4.1
Description of study design
This is a phase II, multicenter, open-label, three-cohort, non-comparative study of alpelisib plus
endocrine therapy (either fulvestrant or letrozole) in patients (pre and post-menopausal women 
and men) with HR+, HER2-negative aBC harboring PIK3CA mutation(s) in the tumor, whose 
disease has progressed on or after prior treatments. Gonadal suppression must be achieved with 
either goserelin or leuprolide in men and premenopausal women patients.
Patients must have the PIK3CA mutation to be eligible for the trial as detailed in inclusion 
criteria. Patients will be required to sign a molecular pre-screening consent to have their 
mutational status either analyzed by providing adequate tumor tissue or if PIK3CA status is 
known, providing tumor tissue to confirm PIK3CA mutational status using a Novartis 
designated central laboratory. This will be conducted during a pre-screening phase prior to 
enrolling into the trial by Day -21. Approximately 1300 patients are expected to be pre-screened 
to identify PIK3CA mutational status. Those patients that harbor the PIK3CA mutation are 
eligible for the study and will then have the opportunity to sign the main ICF to begin screening 
procedures to determine eligibility.
Figure 4-1
Pre-Screening to Screening
Approximately 340 patients (approximately 112 in each cohort), with HR+, HER2-negative 
Sign molecular pre-screening ICF 
( no later than day -21)
Register in IRT
Sign main ICF and 
perform screening 
procedures 
(Day -21 to -1) 
Patient cohort assignment in IRT based on prior treatment with 
AI or fulvestrant to either: 
(alpelisib + (A and C) fulvestrant or B) letrozole
PIK3CA mutation status
for study eligibility 
Local pathology report confirming status and 
tumor sample (archival or newly obtained)
OR
Archival or Newly obtained tumor biopsy 
sample 
Yes
No
Eligibility checklist in IRT
Pre-
Screen 
Failure


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aBC harboring a PIK3CA mutation in tumor tissue, that have progressed on or after prior 
treatments are expected to be enrolled. Patients will be assigned to Cohort A, B or C based on 
the most recent prior therapy; patients whose prior treatment is CDK 4/6 inhibitor plus 
fulvestrant will be enrolled in Cohort B until Cohort B enrollment is closed and then in Cohort 
C until it is closed for enrollment.
At the start of the Core Phase, patients will be assigned to a cohort based on previous therapy 
(AI or fulvestrant) as indicated below:
Cohort A: Patients who received any CDK 4/6 inhibitor plus any AI as immediate prior 
treatment will receive alpelisib + fulvestrant
Cohort B: Patients who received any CDK 4/6 inhibitor plus fulvestrant as immediate prior 
treatment will receive alpelisib + letrozole
Cohort C: Patients who received systemic chemotherapy or ET (as monotherapy or in 
combination with targeted treatment except CDK 4/6i + AI) as immediate prior treatment will 
receive alpelisib + fulvestrant. 
Note: In Cohort C, ET includes letrozole, fulvestrant and CDK 4/6 inhibitor plus fulvestrant.
The study includes two phases:
Core Phase: includes treatment phase for all patients from FPFT until 18 months post LPFT + 
1 month Safety follow-up (total 19 months post LPFT)
Extension Phase: includes treatment phase starting at the end of the treatment Core Phase until 
LPLV (up to 36 months). The extension treatment phase is only for patients who are continuing 
to benefit from study treatment at the end of the Core Phase who are not eligible for PSDS in 
their country based on local regulations. Patients will continue on their existing study treatment 
assigned in the Core Phase until discontinuation (refer to Section 7.1.5) or LPLT of the 
Extension Phase. Note: If PSDS becomes available for a patient or a rollover protocol becomes 
available, the patient should be discontinued from the study and access treatment via PSDS or 
rollover trial (whichever occurs first).
Patients who are benefiting from the study treatment and are eligible for PSDS will exit the trial 
at the end of the Core Phase.


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Figure 4-2
Study Design
A Steering Committee (SC) will be established comprising investigators and Novartis 
representatives 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.
Treatment crossover between cohorts will not be permitted in this study.
This study will use an Interactive Response Technology (IRT) system for patient molecular 
screening, screening, enrollment, discontinuation, and study medication management.
Safety data collected will include (S)AE reporting, grade 3/4 AEs, events of special interest, 
AEs leading to discontinuation and deaths, vital signs, physical examination, variation of the 
ECOG performance status, and hematology and clinical chemistry laboratory parameters at 
study visits while the patient remains on study and for 30 days after discontinuation.
After discontinuation of study treatment, all patients will be followed for safety for at least 30 
days except in case of death, loss to follow-up or withdrawal of consent. For details please refer 
to Section 7.1.5.
All patients will be assessed for efficacy by the investigator; progression free survival (PFS) 
and best overall tumor response, using the Response Evaluation Criteria in Solid Tumor 
(RECIST v1.1), based on investigator assessment will be collected during the Core Phase. 


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Tumor assessments should be performed according to the current standard of care (every 12 
weeks, until disease progression regardless of treatment discontinuation reason (except if 
consent is withdrawn, death or patient is lost to follow-up) until the end of the Core Phase. It is 
strongly recommended that a tumor assessment is performed before patient is switched to a new 
antineoplastic therapy and collected to determine PFS2.
4.2
Timing of interim analyses and design adaptations
Three Interim Analyses (IA), descriptive in nature, are planned for this study. The first IA will
be performed after at least
patients receiving alpelisib plus fulvestrant (cohort A) have at 
least 6 months of follow-up on study. The second IA after at least
patients have been treated 
(regardless of cohort) and have at least 6 months of follow-up on study. The third IA will be 
performed after the Core Phase ends.
The primary endpoint will not be analyzed and no statistical hypothesis will be tested during 
any of the IAs and therefore multiplicity adjustments are not required.
4.3
Definition of end of study
Core Phase: The end of the Core Phase is defined as 19 months after last patient first treatment 
(LPFT); which includes 18 month follow-up plus 1 month safety follow-up.
Extension Phase: The extension starts after the last treatment for the Core Phase (LPLT of Core 
Phase) and will continue until the end of study; the end of study is defined as 37 months from 
extension start, which includes 36 months treatment extension plus 1 month safety follow-up.
The start of the Extension Phase will overlap with the safety follow-up phase of the Core Phase.
Note: if all patients in the study discontinue treatment prior to the of the Core Phase or 
Extension Phases end, the end of study will be sooner. 
In the Core Phase, patients will receive treatment until disease progression, unacceptable 
toxicity, death, until 18 months after LPFT or discontinuation from the study treatment for any 
other reason. Following discontinuation of study treatment for any reason other than disease 
progression, withdrawal of consent, lost to follow-up or death, patients will continue to be 
followed for efficacy (only for Core Phase). Patients will be followed for disease progression 
and survival regardless of treatment discontinuation reason (except if consent is withdrawn, 
death or patient is lost to follow-up) until the end of the Core Phase. 
If alpelisib is not commercially available and reimbursed in a participating country by the time 
the Core Phase is completed, patients continuing to derive clinical benefit from study treatment 
will be able to continue receiving trial therapy through alternative sources within local 
regulations (e.g. Managed Access Program (MAP)). If no local alternative program is available, 
patients continuing to benefit at the end of treatment will be able to continue treatment on the 
Extension Phase.


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4.4
Early study termination
The study can be terminated by Novartis at any time.  Reasons for early termination:

Unexpected, significant or unacceptable safety risk to patients enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data

Discontinuation of study drug development 
Should this be necessary, the patient should be seen as soon as possible and the same 
assessments should be performed as described in Section 7 for a discontinued or withdrawn 
patient. 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 Institutional Review Boards (IRBs) and/or Ethics 
Committees (ECs) of the early termination of the trial.
5
Population
5.1
Patient population
This study will include men and women (pre and post-menopausal) with HR+, HER2-negative 
aBC harboring a PIK3CA mutation in tumor tissue and have progressed on or after prior 
treatments.
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.
Rescreening will be allowed for patients to repeat safety procedures and all eligibility must be 
reconfirmed prior to start of study treatment. Patients can only be rescreened once and will 
retain the same screening number.
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 male or female ≥ 18 years old at the time of consent and has signed 
informed consent (ICF) before any trial related activities and according to local guidelines.
2. Males or females with advanced (locoregionally recurrent or metastatic) breast cancer not 
amenable to curative therapy.
3. Patient has a histologically and/or cytologically confirmed diagnosis of ER+ and/or PgR+ 
breast cancer by local laboratory.
4. Patient has a confirmed, HER2-negative aBC. HER2-negative defined as a negative in situ 
hybridization test or an immunohistochemistry (IHC) status of 0, 1+ or 2+. If IHC is 2+, a 


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negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory 
testing.
5. Patient has PIK3CA mutation confirmed by a Novartis designated laboratory, in which 
adequate formalin-fixed paraffin-embedded tissue sections with >10% tumor tissue must 
be provided. It is recommended to provide a tumor sample collected after the most recent 
progression or recurrence,
Or
Patient has a pathology report confirming PIK3CA mutant status by a certified laboratory 
using a validated PIK3CA mutation assay (either from tissue or blood). It is also 
mandatory to provide a tumor sample (either archival or newly obtained) for PIK3CA 
mutation confirmation by a Novartis designated laboratory. It is recommended the tumor 
sample is collected after the most recent progression or recurrence.
6. In case of women, both premenopausal and postmenopausal patients are allowed to be 
included in this study; menopausal status is relevant for the requirement of goserelin or 
leuprolide to be used concomitantly with alpelisib in combination with fulvestrant or 
letrozole.
a. Patient is postmenopausal woman defined as either:
1. Prior bilateral oophorectomy or
2. Age ≥60 or
3. Age <60 and amenorrhea for 12 or more months (in the absence of 
chemotherapy, tamoxifen, toremifene, or ovarian suppression) and FSH and/or 
estradiol in the postmenopausal range per local normal range.
If patient is taking tamoxifen or toremifene and age <60, then FSH and plasma 
estradiol levels should be in post-menopausal range per local normal range.
Note: For women using therapy-induced amenorrhea other than ovarian 
radiation, goserelin or leuprolide, serial measurements (per local guidelines) of 
FSH and/or estradiol are needed to ensure menopausal status.
b. Patient is premenopausal defined as either:

Patient had last menstrual period within the last 12 months OR

If on tamoxifen or toremifene with in the past 14 days, plasma estradiol and FSH 
must be in the premenopausal range per local normal range, OR

In case of therapy induced amenorrhea, plasma estradiol and/or FSH must be in 
the premenopausal range per local normal range
Note: Throughout this document, peri-menopausal and pre-menopausal status is 
grouped together and referred as “Premenopausal”
7. Patients must have documented evidence of tumor progression on or after

CDK 4/6 inhibitor treatment as last treatment regimen in cohorts A and B

AI treatment (either in adjuvant or metastatic setting) and received systemic 
chemotherapy or ET (monotherapy or combination except CDK 4/6i + AI) as last 
treatment regimen in cohort C: Note, upon completion of enrollment of Cohort B,  


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patients whose receive CDK4/6i+ Fulvestrant as immediate prior therapy are eligible 
for Cohort C .

No more than two (2) prior anti-cancer therapies for aBC. Each unique regimen or 
‘line’ is defined as a single or combination of medications given for a new relapse/ 
recurrence. Maintenance therapies, where applicable, must be regarded as part of the 
main treatment.  

Received no more than one prior regimen of chemotherapy for the treatment of 
advanced/metastatic disease is permitted,
Note: Patients who received chemotherapy in (neo) adjuvant therapy for breast cancer 
are eligible. 
Recovered to grade 1 or better from any adverse events (except alopecia or other 
toxicities not considered a safety risk for the patient at investigator’s discretion) 
related to previous anti-cancer therapy prior to study entry,
8. Patients must have either: 
Measurable disease, i.e. at least one measurable lesion as per RECIST v1.1 criteria. 
(Tumor lesions previously irradiated or subjected to other locoregional therapy will only 
be considered measurable if disease progression at the treated site after completion of 
therapy is clearly documented),
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 adequate bone marrow and coagulation function as shown by the following 
laboratory values:

Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L

Platelets ≥ 100 x 109/L (For patients with lesions involving the bone marrow, platelet 
count ≥ 75 x 109/L may be acceptable)

Hemoglobin ≥ 9.0 g/dL

INR ≤ 1.5 (INR ≤ 2.0 will be allowed for those patients treated with vitamin K 
antagonist)
10. Patient has adequate liver function as shown by:

In absence of liver metastases, serum aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤ 2.5 x ULN or ≤ 5 x upper limit of normal (ULN) if hepatic 
metastases are present,

Total serum bilirubin <2 x  ULN (any elevated bilirubin should be asymptomatic at 
enrollment) 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
11. Patient has adequate renal function:

Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 35 ml/min using Cockcroft-
Fault formula


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12. Patient has fasting plasma glucose (FPG) ≤140 mg/dL (7.7 mmol/L) and glycosylated 
hemoglobin (HbA1c) ≤ 6.4% (both criteria have to be met)
*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.
13. Patient has potassium, magnesium and calcium (corrected for albumin), within normal 
limits (either by central or local lab), or ≤ Grade 1 severity according to NCI-CTCAE 
v4.03 if judged clinically not significant by the investigator, or correctable with 
supplements before entry of study; re-screen is allowed.
14. Fasting serum amylase ≤ 2 × ULN.
15. Fasting serum lipase ≤ ULN.
16. Patient has ECOG (Eastern Cooperative Oncology Group) Performance Status ≤ 2.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patient has a known hypersensitivity to alpelisib, fulvestrant, letrozole, goserelin or 
leuprolide or to any of the excipients of alpelisib, fulvestrant, letrozole, goserelin or 
leuprolide.
2. Patient has received prior treatment with any PI3K inhibitors.
3. Patients with central nervous system (CNS) involvement unless they meet ALL of the 
following criteria:

At least 4 weeks from prior therapy completion (including radiation and/or surgery) to 
starting the study treatment.

Clinically stable CNS tumor at the time of screening untreated or without evidence of 
progressions for at least 4 weeks after treatment as determined by clinical 
examination and brain imaging (MRI or CT) during screening period and stable low 
dose of steroids for 2 weeks prior to initiating study treatment.
4. Patients with an established diagnosis of diabetes mellitus type I or uncontrolled type II 
(based on FPG and HbA1c, see inclusion criterion 12).
5. Patient has a concurrent malignancy or malignancy within 3 years of study screening 
period, with the exception of adequately treated, basal or squamous cell carcinoma, non-
melanoma skin cancer or curatively resected cervical cancer.
6. Patient has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 
weeks prior to enrollment, and who has not recovered to grade 1 or better from related 
side effects of such therapy (with the exception of alopecia).
7. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to 
starting treatment with alpelisib or has not fully recovered from side effects of such 
treatment. Note: The following uses of corticosteroids are permitted: single doses, topical 


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applications (e.g., for rash), inhaled sprays (e.g. for obstructive airways diseases), eye 
drops or local injections (e.g., intra-articular), stable CNS tumor on consistent low dose 
of steroids.
8. Patients with a known history of HIV seropositivity. Screening for HIV infection at 
baseline is not mandatory (unless required by local HA regulations).
9. Any concurrent severe and/ or uncontrolled medical conditions that would, in the 
investigator’s judgment, contraindicate patient participation in the clinical study (e.g. 
chronic active hepatitis [testing not mandatory unless required by local regulations or 
requirements], severe hepatic impairment, etc.).
10. Patients being concurrently treated with drugs recognized as being strong inhibitors or 
inducers of the isoenzyme CYP3A4 or inhibitors of BCRP; switching to different 
medications prior to entry of treatment phase is allowed within the last 5 days prior to 
study treatment (see Appendix 1 for complete list).
11. Patient has a history of noncompliance to medical regimens.
12. Patient with severe liver impairment (Child Pugh score B/C).
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) based on 
investigator discretion.
14. Patient has documented pneumonitis / interstitial lung disease which is active and 
requiring treatment (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).
15. Patient is concurrently using other anti-cancer therapy. All anti-cancer therapy must be 
discontinued prior to day one of study treatment. Drugs with overlapping toxicities must 
be discontinued within 7 days and AE resolved to NCI CTCAE v4.03 Grade ≤1 prior to 
study treatment. Exception to this criterion: patients with any grade of alopecia are 
allowed to enter the study.
16. Patient has had major surgery within 14 days prior to starting treatment with alpelisib or 
has not recovered from major side effects.
17. Patient has any of the following cardiac abnormalities:

Symptomatic congestive heart failure
i.
History of documented congestive heart failure (New York Heart Association 
functional classification III-IV), documented cardiomyopathy
ii.
Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple 
Gated acquisition (MUGA) scan or echocardiogram (ECHO)

Myocardial infarction ≤ 6 months prior to enrollment

Unstable angina pectoris

Serious uncontrolled cardiac arrhythmia

Symptomatic pericarditis


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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.
18. History of acute pancreatitis within 1 year of screening or past medical history of chronic 
pancreatitis.
19. Patient has a history of severe cutaneous reactions like Stevens-Johnson-Syndrome (SJS), 
Erythema Multiforme (EM), Toxic Epidermal Necrolysis (TEN) or Drug Reaction with 
Eosinophilia and Systemic Symptoms (DRESS).
20. Patient who does not apply highly effective contraception during the treatment with 
alpelisib and through the duration as defined below after the final dose of alpelisib
a. Sexually active males 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 plus fulvestrant, letrozole, goserelin or leuprolide 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.
b. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for at least 1 year after stopping the study medication.
Highly effective contraception methods include:

Total abstinence when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow-up hormone level assessment.

Male partner sterilization (at least 6 months prior to screening). For female 
patients on the study the vasectomized male partner should be the sole partner for 
that patient.

Placement of an intrauterine device (IUD).
Note: Use of oral (estrogen and progesterone), transdermal, injected or implanted 
hormonal methods of contraception as well as hormonal replacement therapy is 
not allowed in this study; barrier method is not considered an effective method.
c. Patient is pregnant or lactating, where pregnancy is defined as state of a female after 
conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotrophin (hCG) lab test prior to initiating study treatment.
21. Subjects with unresolved osteonecrosis of the jaw. 


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6
Treatment
6.1
Study treatment
For this study, the term “investigational drug” refers to Novartis study drug alpelisib. Study 
treatment in this protocol refers to the combination of drugs and includes investigational drug 
(alpelisib) as well as fulvestrant or letrozole and for men and premenopausal women goserelin 
or leuprolide as applicable. The storage conditions for alpelisib are described on the medication 
label. Novartis Global Clinical Supply (GCS) or its designee will provide alpelisib 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 either centrally or locally according to local practice and 
regulations, 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.
Letrozole, goserelin and leuprolide will be procured locally according to local practice and 
regulations, 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 electronic Case Report Form (eCRF).
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.
6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule
Study drugs
Pharmaceutical form and 
route of administration
Dose2
Frequency and/or Regimen
Alpelisib
Film coated tablet for oral 
use
300 mg
(e.g. 2 x 50 mg 
tablets+1x200 mg 
tablet) 1
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
Letrozole
Film coated tablet for oral 
use
2.5 mg 
Daily (continuous) starting 
C1D1
Goserelin
Injectable Subcutaneous 
implant
3.6 mg
Every 28 days (only for men 
in cohort B and 
premenopausal women)


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Study drugs
Pharmaceutical form and 
route of administration
Dose2
Frequency and/or Regimen
Leuprolide
Injectable Intramuscular 
Depot
7.5 mg
Every 28 days (only for men 
in cohort B and 
premenopausal women)
1.
In case of patient supply difficulties, any combination of alpelisib (according to patient assignment) may be
taken to consume the total dose.
2.
Dose reduction levels for alpelisib will be administered accordingly. For example, alpelisib 250mg should 
preferentially be administered as 1 X 50 mg tablets + 1 x 200 mg tablet.
All eligible patients will be assigned to their respective cohorts based on prior treatment; 
patients whose prior treatment is CDK 4/6 inhibitor plus fulvestrant will be enrolled in Cohort 
B until Cohort B enrollment is closed and then in Cohort C until it is closed for enrollment.:

Cohort A - PIK3CA mutant pre-treated with CDK 4/6i plus AI will receive:

Alpelisib 300 mg p.o. + fulvestrant 500 mg i.m.

Cohort B - PIK3CA mutant pre-treated with CDK 4/6i plus fulvestrant will receive:

Alpelisib 300 mg p.o. + letrozole 2.5 mg p.o

Cohort C - PIK3CA mutant pre-treated with systemic chemotherapy or ET will receive:

Alpelisib 300 mg p.o. + fulvestrant 500 mg i.m.
During treatment phases (during Core and Extension), alpelisib 300 mg 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 for Cohorts A and C. Similarly, alpelisib 300 mg will be 
administered orally once daily on a continuous dosing schedule starting on Cycle 1 Day 1 in 
combination with letrozole 2.5 mg starting on Cycle 1 Day 1 of every cycle thereafter (+/- 3 
days) in a 28 days cycle for Cohort B. Treatment crossovers between Cohorts will not be 
permitted in this study. A complete cycle of treatment is defined as 28 days of once daily 
continuous treatment of alpelisib in combination with fulvestrant or letrozole.
For men and premenopausal women, either goserelin will be given as an injectable 
subcutaneous implant or leuprolide will be given as an intramuscular injection. Either goserelin 
or leuprolide is recommended to be administered on day 1 starting at Cycle 1 and then every 28 
days. Goserelin or leuprolide must be given as the monthly injection dosage form, as data has 
shown the 3-month depot dosage forms do not reliably suppress hormonal levels in all patients 
(NCCN 2017). If a patient is already receiving goserelin or leuprolide before C1D1, a 28 days 
schedule should be maintained based on the pre-existing dosing schedule. Please refer to the 
local approved prescribing information.
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.


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6.1.1.1
Alpelisib dosing
Alpelisib at a dose of 300 mg 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), or 
letrozole (2.5 mg).
The investigator or responsible site personnel should instruct the participant to take the study 
drugs as per protocol (promote compliance). Drug accountability must be performed on a 
regular basis. Participants will be instructed to return unused alpelisib tablets to the site at the 
end of each cycle or at the time of discontinuation of study treatment. The site personnel will 
ensure that the appropriate dose of each study drug is administered at each visit and will provide 
the participant with the correct amount of drugs for subsequent dosing.
Alpelisib is dosed on a flat scale of mg/day and not by weight or body surface area. There will 
be no breaks between dosing cycles.
The following general guidelines should be followed for alpelisib administration:

Patients should be instructed to take the dose of alpelisib once daily at approximately the 
same time each day after food (preferably in the morning), 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 must be taken within 1 hour after a meal or snack. If, for any reason, a breakfast 
(or other meal) was not consumed, then the patient should take study treatment with a glass 
of water within 1 hour after a snack at any later point in time. If a dose of alpelisib is missed, 
it can be taken immediately after food and within 9 hours after the time it is usually 
administered. After more than 9 hours, the dose should be skipped for that day. On the next 
day, alpelisib should be taken at the usual time. 

Alpelisib should be taken with a glass of water. Tablets should be swallowed whole (tablets 
should not be chewed, crushed or split prior to swallowing). Tablets that are broken, cracked, 
or otherwise not intact should not be ingested.

If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose. The occurrence and frequency of any vomiting during a 
treatment cycle must be noted in the adverse events section of the eCRF

Should any participant enrolled on the study miss a scheduled dose of alpelisib, the 
participant will be allowed to take immediately the missed scheduled dose up to a 
maximum of 9 hours after that scheduled dose time. If greater than 9 hours after the 
scheduled dose time, the missed dose should not be taken, and the participant should take 
their allotted dose at the next scheduled time.
6.1.1.1.1 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:


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The patient must be fasting overnight for 8-12 hours prior to the blood collection, but can freely 
drink water and coffee/tea (unsweetened and without milk). After this blood sample, the patient 
should have a light breakfast. Alpelisib must be taken within 1 hour after the meal in the clinic.
6.1.1.2
Letrozole dosing
Letrozole at a dose of 2.5 mg will be administered orally once daily on a continuous dosing 
cycle starting at cycle 1 day 1.
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.
6.1.1.3
Fulvestrant dosing
Fulvestrant 500 mg will be given at cycle 1 day 1 and 15 after cohort assignment and then at 
Day 1 of each subsequent cycle during the treatment phase. Fulvestrant is administered 
intramuscularly into the buttocks slowly as two 5mL injections, one in each buttock.
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.
6.1.1.4
Goserelin dosing
For men in cohort B and premenopausal women goserelin will be given as an injectable 
subcutaneous implant in a dose of 3.6 mg starting at Cycle 1 Day 1 and then every 28 days. 
Goserelin must be given as the monthly injection dosage form, as the 3-month depot dosage 
forms do no reliably suppress hormonal levels in all patients. If a patient is already receiving 
goserelin before C1D1, a 28 days schedule should be maintained based on the pre-existing 
dosing schedule.
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.
6.1.1.5
Leuprolide dosing
For men in cohort B and premenopausal women leuprolide will be given as an injectable 
intramuscular injection in a dose of 7.5 mg starting at Cycle 1 Day 1 and then every 28 days. 
Leuprolide must be given as the monthly injection dosage form, as the 3-month depot dosage 
forms do not reliably suppress hormonal levels in all patients. If a patient is already receiving 
leuprolide before C1D1, a 28 day schedule should be maintained based on the pre-existing 
dosing schedule.
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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6.1.2
Ancillary treatments
Not applicable.
6.1.3
Rescue medication
Not applicable.
6.1.4
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 investigator’s 
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.
6.1.5
Treatment duration
Patients will be treated until disease progression (radiologically documented according to 
RECIST v1.1) or until discontinuation of study treatment due to any other reason. In the Core 
Phase, patients will receive treatment until disease progression, unacceptable toxicity, death, 
until 18 months after LPFT or discontinuation from the study treatment for any other reason 
and in the Extension Phase, patients will receive study treatment until discontinuation per 
Section 7.1.5 until 36 months. 
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 interruptions 
and/or reductions are either recommended or mandated in order to allow patients to continue 
the study treatment.
These dose modifications are summarized in Table 6-2. Deviations from mandatory dose 
interruptions and/or reductions are not allowed. Permanent treatment discontinuation is 
mandatory for specific events indicated as such in Table 6-2 or listed in Section 7.1.5.
These dose changes must be recorded on the Dosage Administration Record eCRF.


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6.3.1.1
Fulvestrant
The established clinical dose of fulvestrant (500 mg) will be used in cohorts A and C in this 
study. For information on fulvestrant and management of related AEs refer to the [Faslodex®
SmPC or local Prescribing Information].
6.3.1.2
Letrozole
The established clinical dose of letrozole (2.5 mg) will be used in cohort B in this study. For 
information on letrozole and management of related AEs refer to the latest [Femara ®
Prescribing Information, Novartis].
6.3.1.3
Goserelin and leuprolide
The established clinical dose of goserelin or leuprolide will be used in men and premenopausal 
women patients and no dose modification is planned in this study. Patients receiving LHRH 
agonists will be monitored regularly per local institutional clinical guidelines to confirm a post-
menopausal status, according to local laboratory ranges of FSH and estradiol levels.
Refer to the most recent regional prescribing information and/or clinical guidelines for more 
information on LHRH agonists.
6.3.1.4
Alpelisib
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. All dose modifications 
must be based on the worst preceding toxicity as graded by the NCI Common Terminology 
Criteria [NCI-CTCAE v4.03]. If the administration of alpelisib is interrupted for reasons other 
than toxicity, then treatment with alpelisib may be resumed at the same dose.
A maximum of 2 dose reductions of alpelisib from the recommended starting dose may be 
allowed before considering discontinuation of alpelisib treatment.
Please refer to Table 6-2 and Table 6-3 for guidance.
Table 6-2
Dose reduction sequential steps for alpelisib
Alpelisib 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 in the management of 
adverse reactions are summarized in Table 6-3. Adverse events for alpelisib are graded 
according to (Common Terminology Criteria for Adverse Events (CTCAE) v4.03 since this 
version is more objective with regards to hyperglycemia grading since it is based on laboratory 
values. 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.


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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 dose has been reduced, no re-escalation will occur, even upon 
resolution of AE.
If a participant requires a withholding of alpelisib dose, the participant should continue 
combination drug, per investigator discretion. All scheduled assessments will continue to be 
performed as per protocol. 
If administration of alpelisib dosing is held for more than 28 days, then alpelisib must be 
permanently discontinued. Grade 4 adverse events will lead to permanent discontinuation, 
irrespective of recovery time, unless otherwise specified. Patients requiring more than 2 dose 
reductions for alpelisib should be permanently discontinued.
Table 6-3
Criteria for interruption and re-initiation of alpelisib treatment
Dose Modifications for alpelisib as specified below. Fulvestrant and letrozole may be continued while 
alpelisib 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
Investigations (Fasting Glucose or Random blood glucose)
Hyperglycemia (see also Section 6.3.2.1.3)
Consultation with a diabetologist or healthcare provider experienced in the management of hyperglycemia is 
highly recommended for better assessment and management of alpelisib-induced hyperglycemia. Always 
recommend/reinforce on lifestyle changes as per American Diabetes Association (ADA) and/or European 
Association for the study of Diabetes (EASD), i.e. exercise and dietary advice (e.g. controlled carbohydrate 
intake, high fiber, low process food intake.  Three macronutrient balanced meals and 2 optional small snacks 
rather than one large meal).
Note: this table provides dose management recommendations. Local standard clinical practice may be followed 
for monitoring and managing hyperglycemia.  However dose reduction should only be based on FPG. As 
metformin is widely available, it is an appropriate choice as initial therapy for alpelisib-induced hyperglycemia. 
However, SGLT2 inhibitors as per local regulations, are acceptable as well and may be administered alone or 
in combination with metformin. The use of metformin XR can be considered as a suitable alternative to 
metformin IR, alone or in combination with an SGLT2 inhibitor, particularly for participants with at least one risk 
factor for the development of severe hyperglycemia, at the discretion of the Investigator and as per local 
regulations.  (Jabbour and Ziring, 2011).
Refer to Section 6.3.2.1.3 (“Guidelines for the treatment of alpelisib induced hyperglycemia”) for additional 
details regarding the use of metformin XR and/or SGLT2 inhibitors. In case of intolerance to or unavailability of 
metformin, investigator’s judgment should be exercised and as per local regulations, other oral anti-diabetic 
agents such as thiazolidinediones or dipeptidyl peptidase-4 inhibitors can be used.
SGLT2 inhibitor may increase the risk of euglycemic diabetic ketoacidosis and therefore, monitoring with serum 
/ urine ketones and consultation with a healthcare expert experienced in hyperglycemia management or a 
diabetologist should be considered.
Grade 1
FG > ULN - 160 mg/dL [> ULN - 8.9 mmol/L]
Maintain dose level and remind participant on 
lifestyle changes*.
Start/intensify metformin as per guidance below or 
in cooperation with a healthcare expert 


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Worst toxicity – CTCAE Grade (value)
Dose Modifications for alpelisib
For participants with baseline values between >ULN –
140 mg/dL (ULN – 7.7 mmol/L) this applies only for 
values > 140 mg/dL (7.7 mmol/L)
experienced in hyperglycemia management or a 
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. Alternatively, metformin XR once daily 
dosing may be considered instead of metformin 
immediate release.
Titrate to the MTD over a period of 3 weeks.
Alternatively, consider starting an SGLT2 inhibitor 
alone or in combination with metformin, especially 
in participants at risk for developing severe 
hyperglycemia (See Section 6.3.2.1.3 “Guidelines 
for the treatment of alpelisib induced 
hyperglycemia”). Starting dose and titration should 
be in accordance with the local prescribing 
information and consistent with local practice.
Monitor blood glucose as clinically indicated and 
at least weekly for 8 weeks, then continue 
checking at least every two weeks until blood 
glucose levels are within baseline values.
Grade 2
FG > 160 - 250 mg/dL [> 8.9 - 13.9 mmol/L]
Maintain dose level and remind patient of lifestyle 
changes*, exclude confounding factors like e.g. 
urinary tract infection, consider consultation with a 
healthcare expert experienced in hyperglycemia 
management or a diabetologist. 
Start/intensify oral anti-diabetic treatment with 
metformin or alternatively start an SGLT2 inhibitor 
alone or in combination with metformin.
Additional oral anti-diabetic agents may be 
initiated, if needed. If fasting glucose levels are 
still rising on maximum tolerated dose of
metformin or persistently > 160mg/dl (8.9 mmol/L), 
add an SGLT2 inhibitor if not already started, e.g. 
empagliflozin up to 25 mg (max. dose). 
Alternatively, an insulin-sensitizer, e.g. 
pioglitazone 30 mg (max. dose) can be added.
Monitor blood glucose as clinically indicated and 
at least twice weekly until FG resolves to ≤ Grade 
1.
If FPG does not resolve to ≤ Grade 1 within 21 
days after institution of appropriate anti-diabetic 
treatment, reduce alpelisib by 1 dose level
Continue with anti-diabetic treatment and check 
fasting glucose levels at least weekly for 8 weeks, 
then continue checking at least every 2 weeks, 


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Worst toxicity – CTCAE Grade (value)
Dose Modifications for alpelisib
alert treating physician if FG > 250 mg/dL (8.9 
mmol/L) .
Grade 3
FG > 250 - 500 mg/dL [> 13.9 - 27.8 mmol/L]
Omit alpelisib and confirm fasting status of the 
assessment. If non-fasting, re-check within 24 hours.
Regardless of fasting status, consider IV fluids if 
symptoms of hyperglycemia or signs of volume 
depletion.
Exclude confounding factors like e.g. urinary tract 
infection and consider consultation with a 
diabetologist.
Administer intravenous hydration and intervention for 
electrolyte/ketoacidosis/hyperosmolar disturbances as 
clinically appropriate. Insulin may be used for 1-2 
days until hyperglycemia resolves, however this may 
not be necessary in the majority of alpelisib-induced 
hyperglycemia given the short half-life of alpelisib. 
Start or further intensify oral anti-diabetic treatment 
and titrate as outlined for Grade 2.
Monitor blood glucose as clinically indicated and at 
least twice weekly until blood glucose levels resolve to 
≤ Grade 1.
If FG resolves to ≤ 160 mg/dL (8.9 mmol/L) within 
3-5 days, while off study treatment and on 
metformin, re-start alpelisib and reduce 1 dose 
level, continue with anti-diabetic treatment. A 
second or third anti-diabetic agent maybe initiated 
concomitantly, if needed, in consultation with a 
diabetologist. Check blood glucose at least weekly 
for 8 weeks, then continue checking at least every 
2 weeks, alert treating physician if FG>250mg/dl 
(13.9 mmol/L).
If FG does not resolve to ≤ 160 mg/dl (8.9 mmol/L) 
within 3-5 days while off study treatment and on 
metformin, consult a diabetologist for 
management of diabetes is strongly 
recommended. 
If FG does not resolve to ≤ 160 mg/dL(8.9 mmol/L)  
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 treatment.
Grade 4
FG > 500 mg/dL [> 27.8 mmol/L]
Omit alpelisib, confirm fasting status of the 
assessment. If non-fasting, re-check within 24 
hours.
Regardless of fasting status, consider IV fluids


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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 FG is confirmed as > 500 mg/dl (27.8 mmol/L) 
and confounding factors could be excluded, 
permanently discontinue patient from alpelisib.
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. .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
In cases where there is rapidly increasing serum glucose suspicious of severe clinical presentation and/or 
diabetic ketoacidosis) without obvious confounding factors and potentially need close observation and 
monitoring, a diabetologist should be consulted with consideration of potential hospitalization and close 
monitoring.
*specific recommendations please see Section 6.3.2.1.3.
Investigations (Hematologic)
Neutropenia (ANC)
Grade 1 (ANC < LLN - 1.5 x 109/L)
Grade 2 (ANC < 1.5 - 1.0 x 109/L)
Maintain dose level
Grade 3 (ANC < 1.0 - 0.5 x 109/L)
Grade 4 (ANC < 0.5 x 109/L)
Omit dose until resolved to ≤ Grade 1, then:
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then ↓1 dose level
Febrile neutropenia
(ANC < 1.0 x 109/L, with a single temperature of ≥ 
38.3 °C or a sustained temperature of ≥ 38 °C for 
more than one hour )
Omit dose until resolved, then ↓  1 dose level
Thrombocytopenia
Grade 1 (PLT < LLN - 75 x 109/L)
Grade 2 (PLT < 75 - 50 x 109/L)
Maintain dose level
Grade 3 (PLT < 50-25 x 109/L)
Omit dose until resolved to ≤ Grade 1, then:
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then ↓ 1 dose level
Grade 4 (PLT < 25 x 109/L)
Omit dose until resolved to ≤ Grade 1, then ↓ dose 
level
Investigations (Renal)
Serum creatinine
< 2 x ULN
Maintain dose level
2 – 3 x ULN
Omit dose until resolved to ≤ grade 1, then:


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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
Grade 4 ( > 6.0 x ULN)
Permanently discontinue patient from alpelisib
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)
Interrupt dose until recovery to Grade ≤ 1 and 
resume at the same dose if resolved in ≤ 14 days 
or resume at the next lower dose level if resolved 
in > 14 days.
Grade 3 (> 3.0 - 10.0 x ULN)
Interrupt dose until recovery to Grade ≤ 1, then 
resume at the next lower dose level.
Grade 4 (> 10.0 x ULN)
Permanently discontinue.
Isolated AST or ALT Elevation
Grade 1 (> ULN – 3.0 x ULN)
Grade 2 (> 3.0 - 5.0 x ULN)
No dose adjustment is required. Initiate appropriate 
medical therapy and monitor as clinically indicated.
Grade 3 (> 5.0 - 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
Combined elevations of AST or ALT and total Bilirubin
Please see specific instructions in Section 6.3.2.2
Investigations (Gastrointestinal)
Diarrhea is defined as: A disorder characterized by frequent and watery bowel movements.
Colitis is defined as a disorder characterized by inflammation of the colon. (see also Appendix 2)
Grade 1 (Increase of < 4 stools per day over baseline; 
mild increase in ostomy output compared to baseline)
OR
Asymptomatic colitis; clinical or diagnostic 
observations only; intervention not indicated
Maintain dose level but initiate appropriate medical 
therapy and monitor as clinically indicated
Grade 2 (Increase of 4 - 6 stools per day over 
baseline; moderate increase in ostomy output 
compared to baseline)
limiting instrumental Activities of Daily Living (ADL)
OR
Abdominal pain; mucus or blood in stool
Omit dose until resolved to ≤ Grade 1, initiate 
appropriate medical therapy then restart at same 
dose. 
If diarrhea returns as ≥ Grade 2, then omit dose until 
resolved ≤grade1, then decrease 1 dose level
Initiate or intensify appropriate medical therapy and 
monitor as clinically indicated.
For Grade 2 colitis consider additional treatment, such 
as steroids.
Grade 3 (Increase of ≥7 stools per day over baseline; 
hospitalization indicated; severe increase in ostomy 
output compared to baseline; limiting self-care ADL)
OR
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 


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Severe abdominal pain; peritoneal signs
medicinal products and / or fluid replacement and 
electrolyte supplements as clinically indicated. 
For Grade 3 colitis consider additional treatment, such 
as steroids.
Grade 4 (Life-threatening consequences; urgent 
intervention indicated)
Discontinue subject 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
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
Permanently discontinue patient from alpelisib
Grade 4
Permanently discontinue patient from alpelisib
Stomatitis/Oral mucositis (see also Appendix 3)
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
Skin and subcutaneous tissue disorders
Oral antihistamine administration may be considered prophylactically, at the time of initiation of treatment with 
alpelisib. Consultation with a dermatologist is highly recommended for better assessment and management of 
alpelisib-induced skin toxicity. (see also Section 6.3.2.1.2). Dermatologist consult is mandated for serious 
cutaneous reactions (i.e. fulfilling seriousness criteria for AE Reporting) and for severe cutaneous reactions like 
Stevens-Johnson-Syndrome, Toxic Epidermal Necrolysis, Erythema Multiforme, Drug Reaction with 
Eosinophilia and Systemic Symptoms (DRESS).
Rash


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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
Add oral anti-histamine (sedative or non-sedative)
If active rash is not resolved within 28 days of 
appropriate treatment, add a  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 a non-sedating anti-histamine such as 
cetirizine once daily during daytime and a sedating 
anti-histamine such as diphenhydramine once daily at 
night.
Grade 2 (10-30% BSA with active skin toxicity*)
Maintain dose level
Initiate or intensify high potency topical 
corticosteroids 3-4x daily, preferred compounds to 
use are Triamcinolone or Betamethasone as long 
as skin toxicity is active, during max. 28 days
Add systemic corticosteroids 20-40mg/d.
Add oral anti-histamine (sedative or non-sedative)
If rash resolves to ≤ G1 within 10 days systemic 
corticosteroid may be discontinued
For patients with symptoms like burning and/or 
pruritus add a non-sedating anti-histamine such as 
cetirizine once daily during daytime and a sedating 
anti-histamine such as diphenhydramine once daily at 
night.
Grade 3 (>30% BSA with active skin toxicity*)
Omit alpelisib dose until rash /skin toxicity is 
improved to Grade 1 or resolved, 
Strongly recommend documentation by 
photography and performing a skin biopsy. 
Initiate high potency topical corticosteroids 3-4x 
daily, preferred compounds to use are 
Triamcinolone or Betamethasone for at least 28 
days
Add systemic corticosteroids 20-40mg/d
Add oral anti-histamine (sedative or non-sedative)
If rash resolves to ≤ G1 within 10 days systemic 
corticosteroid may be discontinued.
Re-start alpelisib dose once rash /skin toxicity is 
fading but is no longer active (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 


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corticosteroid for at least 48 hours upon re-
challenge with alpelisib; if rash and/or pruritus do 
not reoccur within 48 hours after re-challenge with 
alpelisib, systemic corticosteroid may be 
discontinued
For patients with symptoms like burning 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.
Grade 4
(any % BSA associated with extensive superinfection, 
with IV antibiotics indicated; life-threatening 
consequences)
Permanently discontinue patient from alpelisib
Consult a dermatologist, strongly recommend 
documentation by photography and performing a 
skin biopsy if clinically indicated 
Treatment may follow guidelines for Grade 3 
above with the exception of rechallenge. 
Additional measures may be taken as per local 
treatment guidance
Any Grade of Stevens-Johnson-Syndrome/Toxic 
Epidermal Necrolysis/Drug Reaction with 
Eosinophilia and Systemic Symptoms (DRESS) or 
other SJS/TEN/DRESS-like severe skin reactions
Permanently discontinue patient from alpelisib 
treatment
Consult dermatologist, strongly recommend 
documentation by photography and performing a 
skin biopsy if clinically indicated. Follow local 
treatment guidelines for SJS/TEN/DRESS
*“Active” skin toxicities: If there are no new lesions or new areas of involvement developing, and if lesion 
appearance is changing color from red to pale or light brown, it is likely the skin toxicity has begun to fade and 
is not to be considered “active” any longer. Treatment reduction can be considered for these areas. The 
appearance of skin toxicity may fade slowly, over 10 days or more but not requiring ongoing therapy.
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 


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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
Omit dose for ≥ Grade 3 vomiting or Grade 3 nausea 
only if the vomiting or nausea cannot be controlled 
with optimal antiemetic (as per local practice)
For additional details on the safety profile of alpelisib, please refer to the alpelisib Investigator 
Brochure. 


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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. Patients should have weekly follow-up for 30 
days after discontinuation of study treatment or resolution of the AE to ≤ grade 1, whichever 
occurs first. Post treatment follow-up (for safety) includes all study assessments appropriate to 
monitor the event.
Participants whose treatment is interrupted or permanently discontinued due to an adverse event 
or a clinically significant laboratory value must be followed until resolution or stabilization of 
the event, whichever comes first. Further guidelines and recommendations for the management 
of specific study treatment combination-induced toxicities are provided below.
6.3.2.1
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 subjects 
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 interrupt alpelisib 
immediately (but may continue fulvestrant or letrozole 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. 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   and promptly initiate appropriate treatment 
and supportive measures. 
Table 6-4
Management of pneumonitis
Pneumonitis 
(any grade)
Immediately interrupt alpelisib for any case of suspected pneumonitis. Fulvestrant 
or letrozole may be continued, if clinically indicated. Obtain appropriate imaging 
(high resolution CT scan) and consider BAL and biopsy if appropriate based on 
clinical judgment. See Section 6.3.2.1.1 for details of management of pneumonitis. 
Treatment for pneumonitis should be initiated based on institution guidelines and 
generally includes high dose corticosteroids; antibiotic therapy should be 
administered concurrently if infectious causes are suspected. Alpelisib should be 
permanently discontinued in all patients with confirmed pneumonitis
6.3.2.1.2 Guidelines for the treatment of study drug induced skin toxicity
Skin toxicity is an adverse drug reaction observed with PI3Ki agents.


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Close monitoring of potential skin reactions will be performed at each planned visit and will be 
reported as an 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 co-
medication and treatment interruption if needed. Skin reactions may improve over several 
weeks.    If there are no new lesions or new areas of involvement developing, and if the 
appearance is changing color from red to pale or light brown, it is likely the eruption has begun 
to fade, and not considered active any longer. 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 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. 
In case of a Grade 3/4 skin toxicity, Novartis strongly recommends that photographs are taken 
and a skin biopsy is performed and stored at the site for source documentation. Antihistamines 
administered prior to rash onset may decrease incidence and severity of rash based on SOLAR-
1 Study; therefore, at the Investigator’s discretion, non-sedating antihistamines (e.g. cetirizine 
(Zyrtec©) fexofenadine (Allegra), loratadine (Claritin)) ) may be used as prophylactic treatment 
starting at Cycle 1 Day 1 to reduce severity of rash in all participants and especially for 
participants with a history of atopy such as allergic rhinitis, asthma, atopic dermatitis, or drug 
allergies. Antihistamine regimen should be continued for a minimum of 28 days after re-
challenge with alpelisib.
Recommended therapies for skin toxicity events of all grades and as clinically indicated include:

Consultation with a dermatologist should always be considered.

Mid to high potency topical steroids: triamcinolone 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 300 mg every 8 hours, 
Pregabalin 50-75 mg every 8 hours (to adjust of renal impairment). Depending on 
participant’s clinical condition, be aware of potential and common side effects 
observed with GABA agonists such as: somnolence, dizziness (both drugs) and 
peripheral edema (Gabapentin) among others adverse events.
For grade 4 skin events or any grade of severe cutaneous reactions (including SJS, TEN, EM, 
DRESS), alpelisib treatment must be permanently discontinued without any re-challenge. 
If dry skin has been reported, it is recommended that patients with dry skin use mild and 
fragrance free soaps and detergents. According to the severity and BSA extension patients may 
apply mild moisturizers, e.g. ammonium lactate cream 12%.


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Although preclinical experiments demonstrated that alpelisib has no potential phototoxic effect, 
patients should avoid sun exposure during treatment with alpelisib, especially when they 
already have experienced rash or other skin toxicities as the increased blood flow of the skin 
may worsen skin symptoms. 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.
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. FG 100 – 125 mg/dl; 5.6 - 6.9 mmol/L) and those with an established diagnosis of type 2 
diabetes mellitus should be monitored carefully, thus allowing an early detection and prompt 
management of increases in fasting glucose while on alpelisib treatment. However all patients, 
even those with fasting glucose within normal limits at screening, may develop alpelisib 
induced hyperglycemia which is an on-target effect seen with PI3K inhibitors. Patients should 
always be instructed to follow dietary guidelines provided by the American Diabetes 
Association and/or the European Association for the study of Diabetes, e.g. exercise and dietary 
advice (e.g. controlled carbohydrate intake, high fiber, low process food intake.  Three 
macronutrient balanced meals and 2 optional small snacks rather than one large meal)’.
Hyperglycemic hyperosmolar non-ketotic syndrome (HHNKS) and diabetic ketoacidosis (DKA) 
are two of the most serious metabolic complications associated with hyperglycemia. DKA is 
characterized by ketoacidosis and a comparatively lower hyperglycemic level (blood glucose 
250 mg/dL-600 mg/dL), while HHNKS is characterized by more severe hyperglycemia (blood 
glucose > 600 mg/dL) together with hyperosmolarity and dehydration without significant 
ketoacidosis. HHNKS is also known as non-ketotic hyperosmolar syndrome, hyperosmolar 
hyperglycemic state or hyperglycemic hyperosmolar non-ketotic coma. Most patients with 
HHNKS have a known history of diabetes mellitus Type 2. HHNKS usually develops over a 
course of many days to weeks, unlike DKA which can develop over the course of a few hours 
or days.
Detailed guidelines for management of alpelisib induced hyperglycemia is provided in Table 6-
3. This includes early administration of metformin or a sodium-glucose cotransporter 2 (SGLT2) 
inhibitor (alone or in combination with metformin). For more details on metformin XR, please 
refer to Table 6-3.
Local standard clinical practice may be followed for monitoring and managing hyperglycemia. 
Fasting glucose will be performed locally for rapid availability for safety evaluation and 
management guidance. However, it is strongly recommended that dose reduction be based on 
FPG only.


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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.
If metformin or an anti-diabetic agent is interrupted for radiologic assessments or another reason, 
then alternative hyperglycemia management should be considered for those days to ensure 
optimal hyperglycemia management.
Consultation with a diabetologist 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.
6.3.2.2
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. These events should be considered as clinically important and 
assessed appropriately to establish the diagnosis. The required clinical information, as detailed 
below, should be sought to obtain the medical diagnosis of the most likely cause of the observed 
laboratory abnormalities.
In general, any increase of serum aminotransferases to >3 x ULN should be followed by repeat 
testing within 48 to 72 hours. 
If total bilirubin is elevated >2 x ULN, fractionation into direct and indirect bilirubin is required. 
The threshold for potential DILI may depend on the 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


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
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]
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed as the cause of liver injury.
A detailed history, including relevant information such as Medical review needs to ensure that 
liver test elevations of ethanol consumption, concomitant medications, herbal remedies, 
supplement consumption, history of any pre-existing liver conditions or risk factors, should be 
collected.
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, 
Gamma-glutamyltranspeptidase (GGT), Glutamate dehydrogenase (GLDH), prothrombin time 
(PT)/International Normalized Ratio (INR), alkaline phosphatase, albumin, and creatine kinase.
Evaluate status of liver metastasis (new or exacerbation) or vascular occlusion - e.g. using CT,
MRI, or duplex sonography.
Perform relevant examinations (ultrasound or MRI, Endoscopic Retrograde Cholangio 
Pancreatography (ERCP)) as appropriate, to rule out an extrahepatic cause of cholestasis. 
Cholestasis is defined as an Alkaline Phosphatase (ALP) elevation > 2.0 x ULN with R value 
< 2 in participants without bone metastasis, or elevation of the-specific ALP isoenzyme in 
participants with bone metastasis.
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. In clinical 
situations where it is suspected that ALP elevations are from an extrahepatic source, the GGT 
can be used if available. GGT may be less specific than ALP as a marker of cholestatic injury, 
since GGT can also be elevated by enzyme induction or by ethanol consumption. It is more 
sensitive than ALP for detecting bile duct injury (livertox.nih.gov/rucam.html).
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 6-5 “Alternative causes of liver disease” provides guidance on specific clinical and 
diagnostic assessments which can be performed to rule out possible alternative causes of 
observed Liver Function Tests (LFT) abnormalities.
Table 6-5
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


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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.  
6.3.2.3
Guidelines for hypersensitivity
Alpelisib and combination drug are associated with hypersensitivity reactions, including 
anaphylaxis and angioedema. These are manifested by symptoms including, but not limited to, 
dyspnea, flushing, rash, fever, hypotension, dizziness, tachycardiaand facial or laryngeal 
oedema. Alpelisib and/or combination drug should be permanently discontinued and should not 
be re-introduced in participants 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).
6.4
Concomitant medications
6.4.1
Permitted concomitant therapy
Medications required to treat adverse events, manage cancer symptoms, concurrent diseases 
and supportive care agents, such as pain medications, anti-emetics and anti-diarrheal are 
allowed, except if specifically prohibited (see Section 14, Appendix 1).
All medications (other than study drug) and significant non-drug therapies (including vitamins, 
physical therapy, and blood transfusions) administered within 30 days prior to the start of study 
treatment and up to 30 days after the last dose of study treatment must be recorded on the 
Concomitant Medications or the Surgical and Medical Procedures eCRF (Core Phase only).
The investigator should instruct the participant to notify the study site about any new 
medications and/or non-drug therapies/procedures he/she takes after signing the informed 
consent. Each concomitant drug must be individually assessed against all exclusion 
criteria/prohibited medication. If in doubt, the investigator should contact the Novartis medical 
monitor before randomizing a participant or allowing a new medication to be started. If the 


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participant is already enrolled, contact Novartis to determine if the participant should continue 
participation in the study.
6.4.1.1
Oral anti-diabetics
Patients who develop hyperglycemia during the study should be treated according to the ADA 
(American Diabetes Association) guidance and/or European Association for the study of 
Diabetes (EASD). 
Consultation with a diabetologist or healthcare provider experienced in the management of 
hyperglycemia is highly recommended for better assessment and management of alpelisib-
induced hyperglycemia. It is recommended to start treatment with metformin, however sodium-
glucose cotransporter 2 (SGLT2) inhibitors as per standard practices/standard of care, may be 
a suitable alternative or add-on therapy to metformin. SGLT2 inhibitors are a class of diabetic 
medications that improve hyperglycemia primarily by promoting urinary glucose excretion. 
In the SOLAR-1 study, among the 284 participants who were randomized to receive alpelisib 
plus fulvestrant, 190 participants (67%) developed hyperglycemia, with 18 patients (6%) 
discontinuing alpelisib treatment due to hyperglycemia, as of 30-Sep-2019. 
Among those with hyperglycemia, 166 participants received concomitant anti-diabetic 
medications, primarily consisting of metformin (87%). However, in addition to metformin, 6 
participants also received an SGLT2 inhibitor, consisting of empagliflozin, ipragliflozin, or 
dapagliflozin. All 6 participants had ≥ 1 risk factor at baseline for developing hyperglycemia, 
defined as prediabetes (n = 4; 1 of whom had documented history of type 2 diabetes), diabetes 
(n = 2), and obesity (n = 2). The most severe hyperglycemia in these participants was grade (G) 
3 (n = 5). After initiating an SGLT2 inhibitor, all subsequent hyperglycemia events were G 1/2, 
except one G 3 event with steroids as a confounding factor. The duration of alpelisib ranged 
from 9.5 to 27.7 months in these 4 participants who discontinued alpelisib; and notably, 2 
participants were continuing to receive alpelisib after 37.0 and 40.0 months, respectively. None 
of the 6 participants discontinued alpelisib due to hyperglycemia.
Participants with at least one risk factor for the development of severe hyperglycemia, defined
as prediabetes/diabetes, and/or obesity (BMI ≥ 30), and/or age ≥ 75 years, may benefit from the 
initiation of an SGLT2 inhibitor with metformin, which is available as a single oral combination 
pill or as two separate medications. The decision to initiate an SGLT2 inhibitor alone in 
combination with metformin is at the discretion of the investigator. For more details on 
metformin XR, please refer to Table 6-3.
.
6.4.1.2
Gastric protection agents
Alpelisib is characterized by a pH-dependent solubility but can be co-administered with acid 
reducing agents (ARAs, e.g. proton-pump inhibitors, H2-antagonists and antacids), as long as 
it is taken after food. In a joint food effect and acid reducing DDI study food exhibited a more 
pronounced effect on the solubility of alpelisib than the effect of gastric pH value leading to a 
net decrease in AUC of on average by 21% when administered after a meal. 


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6.4.1.3
Corticosteroids
Chronic dosing of high levels of corticosteroids such as dexamethasone and prednisone may 
prolong or aggravate hyperglycemia (steroid-induced diabetes). Hyperglycemia is a common 
adverse event for PI3K inhibitors like alpelisib and should therefore be used with caution and 
patients closely monitored.
6.4.1.4
Palliative radiotherapy
Local radiotherapy for analgesic purposes or for lytic lesions at risk of fracture may be carried 
out if required. Participants requiring initiation of palliative radiotherapy during the course of 
the study should be assessed by appropriate image modalities to exclude disease progression 
per RECIST 1.1and the reason for its use must be clearly documented. If disease progression is 
documented, the participant should discontinue study treatment. No dose modification of study 
treatment is needed during radiotherapy.
6.4.2
Permitted concomitant therapy requiring caution and/or action
Medications to be used with caution during combined alpelisib, fulvestrant, or letrozole 
treatment in this study are listed below (see Table 14-1) in Appendix 1, this list is not 
comprehensive and is only meant to be used as a guide. The investigator may contact Novartis 
for any questions regarding the use of permitted concomitant therapy requiring caution and/or 
action.
These medications should be excluded from participant use if possible. If they must be given, 
based on the investigator’s judgment, then use with caution and consider an alpelisib and/or 
combination drug interruption, as appropriate, if the concomitant medication is only needed for 
a short time.
Medications to be used with caution:

Sensitive substrates for CYP3A4, CYP2B6, CYP2C9 and/or which have a narrow 
therapeutic index (Table 14-1) 

CYP2C9 substrates with narrow therapeutic index (NTI) (e.g. anticoagulants): In vitro 
evaluations indicated that pharmacological activity may be reduced by the CYP2C9 
induction effects of alpelisib. In the absence of clinical data, caution is recommended with 
therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative 
anticoagulants as alpelisib may reduce the clinical activity of such drugs (Table 14-1) “List 
of CYP450 substrates to be used with caution”). Alternatively, therapeutic anticoagulation 
may be accomplished using low- molecular weight heparin or Direct Thrombin inhibitors 
(DTIs) and Factor Xa inhibitors.

CYP2B6 sensitive substrates or CYP2B6 substrates with NTI: Based on a static 
mechanistic assessment with sensitive CYP2B6 substrates such as bupropion, a reduction 
of exposure by up to 3-fold can be expected when co-administered with alpelisib. In absence 
of clinical data, sensitive CYP2B6 substrates (e.g. bupropion, evafirenz) or CYP2B6 
substrates with a narrow therapeutic window should be used with caution in combination 
with alpelisib, as alpelisib may reduce the clinical activity of such drugs. (Table 14-1) “List 
of CYP450 substrates to be used with caution”)


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
Selected CYP3A4 substrates: Alpelisib can be co-administered with sensitive CYP3A4 
substrates (e.g. everolimus, midazolam) and CYP3A4 substrates with narrow therapeutic 
window (e.g. fentanyl). Caution is recommended when alpelisib is used in combination with 
CYP3A4 substrates that also possess an additional time dependent inhibition and induction 
potential on CYP3A4 that affects their own metabolism (e.g. ribociclib, encorafenib, refer 
to Table 14-2). Systemic exposures of such CYP3A4 auto inhibitors and auto inducers may 
be either decreased or increased depending on the drug and nature of auto-perpetrator 
potential, respectively, when alpelisib is co administered, based on PBPK simulations.

Herbal Medications: The use of herbal preparations/medications and dietary supplements 
are permitted with caution unless explicitly prohibited (see Section 6.4.4) for being strong 
inducers of CYP3A such as St. John’s Wort (Hypericum perforatum) and Avasimibe (see 
Table 14-2) or BCRP inhibitors such as Curcumin (see Table 14-3). Medications such as 
Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone, yohimbe, saw 
palmetto, black cohosh and ginseng should be avoided if possible due to their potential for 
complex interactions. Since cannabinoids have been shown to inhibit BCRP in vitro, 
medical cannabis should be used with caution. The use/frequency of use should be 
documented as a concomitant medication. Subjects closely monitored for increased 
adverse reactions (as the relevance of this interaction in vivo is currently unknown). In 
case of unexpected toxicities, subjects should stop using all herbal medications. Use of all 
such medications (including frequency of administration) should be documented.

Anticoagulants: Therapeutic doses of warfarin sodium (Coumadin®) or any other 
coumarin-derivative anticoagulants should be used with caution and fully avoided 
whenever possible because of its known interaction with many commonly used 
medications and certain foods. Alternatively, therapeutic anticoagulation may be 
accomplished using low-molecular weight heparin or Direct Thrombin inhibitors (DTIs) 
and Factor Xa inhibitors.
Please refer to the investigator brochure for more information. 
6.4.3
Use of bone modifying agents (BMA) 
The use of bone modifying agents (BMA, e.g. bisphosphonates/denosumab regardless of 
indication is allowed provided subjects have been on stable doses for at least 2 weeks prior to 
randomization. Stable dose should be maintained during the treatment period.
BMA may be given according to the local prescribing information and routine clinical practice, 
at the investigator’s discretion.
Participants taking BMA prior to entering the study should continue with the same 
bisphosphonate treatment, given as per local medical practice.
Participants requiring initiation of BMA treatment during the course of the study should be 
assessed by appropriate image modalities to exclude disease progression; if disease progression 
is documented, the subject should discontinue study treatment. If BMA is to be started after the 
first dose of study treatment, the reason for its use must be clearly documented.
Osteonecrosis of the jaw (ONJ) is a known adverse reaction for BMA. In the phase III Study 
C2301, ONJ was reported in 4.2% subjects (12/284) in the alpelisib plus fulvestrant arm 
compared to 1.4% subjects (4/287) in the placebo plus fulvestrant arm. All subjects 


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experiencing ONJ were also exposed to prior or concomitant bisphosphonates (e.g. zoledronic 
acid). Therefore, in subjects receiving alpelisib and bisphosphonates, an increased risk of 
development of ONJ cannot be excluded. For prevention and clinical management of ONJ, 
prescribing information of bisphosphonates / receptor activator of nuclear factor kappa-B 
(RANK)-ligand inhibitors (e.g. denosumab) should be followed.
6.4.4
Prohibited concomitant therapy
The following medications are prohibited during treatment in this study (see Table 14-2 and
Table 14-3 in Appendix 1), this list is not comprehensive and is only meant to be used as a 
guide. Please contact the medical monitor with any questions:

Strong inducers of CYP3A4: Avoid co-administration of alpelisib with a strong 
CYP3A4 inducers as it could potentially reduce the effectiveness of alpelisib (see 
Table 14-2). 

Inhibitors of Breast Cancer Resistance Protein (BCRP) efflux transporter: Avoid the 
use of BCRP inhibitors in subjects treated with alpelisib (see Table 14-3). If unable to 
use alternative drugs, closely monitor for increased adverse reactions.

Other investigational and antineoplastic therapies
.
Agents required for managing adverse events, cancer symptoms, and supportive care agents, 
such as anti-emetics, anti-diarrheal and probiotics are allowed unless listed above and/or in 
Appendix 1.
6.5
Patient numbering, treatment assignment
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 molecular pre-screening and is retained as the primary identifier 
for the patient throughout his/her entire participation in the trial. The subject number is a 7 digit 
number that consists of a 4 digit center number (assigned by Novartis) followed by a sequential 
3 digit subject numbers. Upon signing the molecular pre-screening 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 continue to the next phase or start 
treatment for any reason, the reason will be entered into the Screening Disposition page.
IRT must be notified within 10 days if the patient does not start treatment.
6.5.2
Treatment assignment
The assignment of a patient to a particular cohort will be coordinated by Novartis.


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At the start of the Core Phase, patients will be assigned to a cohort based on previous therapy 
(AI,  fulvestrant or systemic chemotherapy as indicated below); patients whose prior treatment 
is CDK 4/6 inhibitor plus fulvestrant will be enrolled in Cohort B until Cohort B enrollment is 
closed and then in Cohort C until it is closed for enrollment,:
Cohort A: Patients who received any CDK 4/6 inhibitor plus any AI as immediate prior 
treatment will receive alpelisib + fulvestrant
Cohort B: Patients who received any CDK 4/6 inhibitor plus fulvestrant as immediate prior 
treatment will receive alpelisib + letrozole
Cohort C: Patients who received systemic chemotherapy or ET (as monotherapy or in 
combination except for CDK 4/6i + AI) as immediate prior treatment will receive alpelisib + 
fulvestrant. 
6.5.3
Treatment blinding
This is an open label study.
6.6
Study drug preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section (for more details, please refer Section 6.1 “Study treatment”). 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 on an outpatient basis.
Fulvestrant or letrozole with or without LHRH agonists (goserelin or leuprolide (if applicable)) 
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 eCRF.
As per Section 2.6.4, during a Public Health emergency as declared by Local or Regional
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
delivery of IMP directly to a participant's home may be permitted (if allowed by Local or 
Regional Health Authorities and Ethics Committees as appropriate) in the event the Investigator 
has decided that an on-site visit by the participant is no longer appropriate or possible, and that 
it is in the interest of the participant's health to administer the study treatment even without 
performing an on-site visit. The dispatch of IMP from the site to the participant’s home remains 
under the accountability of the Investigator. Each shipment/provisioning will be for a maximum 
of 1-month supply. In this case, regular phone calls or virtual contacts (every 3 weeks or more 
frequently if needed) will occur between the site and the participant for instructional purposes, 
safety monitoring, investigation of any adverse events, ensuring participants continue to benefit 
from treatment, and discussion of the participant's health status until the participants can resume 
visits at the study site.


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6.6.1
Study treatment packaging and labeling
Study treatment, alpelisib, will be provided as global clinical open label supply and will be 
packed and labeled under the responsibility of Novartis, GCS.
Study treatment labels will comply with the legal requirements of each country and will include 
storage conditions, a unique medication number (corresponding to study treatment and strength). 
Responsible site personnel will identify the study treatment package(s) to dispense by the 
medication number(s) assigned by IRT to the patient. Site personnel will add the patient number 
on the label. If the label has 2-parts (base plus tear-off label), immediately before dispensing 
the package to the patient, site personnel will detach the outer part of the label from the package 
and affix it to the patient’s source document.
Table 6-6
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
Alpelisib 
Tablets in bottles
50 mg
200 mg
Labeled as BYL719 50mg and BYL719 
200mg
Once daily dosing
Fulvestrant
Refer to local product information
Refer to local product information
Letrozole
Refer to local product information 
Refer to local product information 
Goserelin
Refer to local product information
Refer to local product information.
Leuprolide
Refer to local product information
Refer to local product information.
Fulvestrant, letrozole or LHRH agonist (goserelin or leuprolide) packaging and labeling will be 
according to locally available supplies 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, alpelisib should be stored according to the instructions 
specified on the drug labels and in the Investigator’s Brochure.
Study treatments will be procured locally according to local practice and regulation, or supplied 
by Novartis (or its designee).
Table 6-7
Supply and storage of study treatments
Study treatments
Supply
Storage
Alpelisib 
Centrally supplied by Novartis
Refer to study drug label
Fulvestrant
Supplied locally or centrally 
based on local regulations
Refer to local product information
Letrozole
Supplied locally
Refer to local product information 
Goserelin
Locally
Refer to local product information
Leuprolide
Locally
Refer to local product information
6.6.3
Study drug compliance and accountability


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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.
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 site may destroy and document destruction of unused study treatment, drug labels and 
packaging as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, the investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to the Novartis 
monitor or to the Novartis address provided in the investigator folder at each site. If study 
treatment is administered at home e.g. oral medication, participants will be asked to return all 
unused study treatment and packaging at the end of the study or at the time of discontinuation 
of study treatment.


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7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 and Table 7-2 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 “S” in the table denotes the assessments that are only in the patient’s 
source documentation and do not need to be recorded in the clinical database. No eCRF’s will 
be used as a source document. The “D” in the table denotes the assessments to be recorded in 
the clinical database or received electronically from a vendor.
Participants who discontinue from study treatment are to return for 
reason the end of treatment visit as soon as possible, and attend the follow-up visits as indicated
in the Assessment Schedule.
Participants who discontinue from study or withdraw their consent/oppose the use of their
data/biological samples should be scheduled for a final evaluation visit if they agree, as soon as
possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and the adverse event and
concomitant medications not previously reported must be recorded on the CRF.
As per Section 2.6.4, during a Public Health emergency as declared by Local or Regional
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits,
alternative methods of providing continuing care may be implemented by the investigator as
the situation dictates. If allowable by a local Health Authority and depending on operational
capabilities, phone calls, virtual contacts (e.g. tele consult) or visits by site staff/ home nursing
staff to the participant´s home, can replace on-site study visits, for the duration of the disruption
until it is safe for the participant to visit the site again.
Allowed visit windows are specified as follows:

Molecular pre-screening must occur by Day -21 before the start of treatment.

Screening assessments, apart from those listed below, must occur before 21 days of the 
start of treatment as per Table 7-1.

For visits, a general ±7 day window is allowed except for C1D1 radiological assessments 
must be performed as outlined in Table 7-1 and Table 7-2.
Every effort should be made to follow the schedule outlined in Table 7-1 and Table 7-2.


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Table 7-1
Visit evaluation schedule – Core Phase
Category
Reference 
to 
Protocol 
Section
Screening Phase
Treatment Phase
End of 
study 
treatment 
(EoT) -
Core 
Phase
Post treatment and survival 
follow-up phase
Visit Name
Molecular 
Pre-
screening 
(by Day -
21) 
Screening
C1D1
C1D8
C1D15
C2D1
C2D15
Subsequent
cycles
(Day 1)
Within 21 
days of 
last dose
30 
days 
after 
last 
dose 
for 
safety
Every 12 
weeks
for efficacy 
applicable
Survival 
(Every 12 
weeks)
-21 
to -1
-14 
to -1
Obtain molecular 
Pre- screening 
informed consent
D
7.1.1
X
Obtain main 
informed consent 
D
7.1.2
X
IWRS/IRT 
Registration
S
7.1.2.1
X
Patient History
Demography
D
7.1.2.3
X
Inclusion/exclusio
n criteria
D
5.2 / 5.3
X
Eligibility checklist 
(within IRT) 
S
6.5
X
Medical history
D
7.1.2.3
X
Diagnosis and 
extent of cancer
D
7.1.2.3
X
Prior 
antineoplastic 
therapy 
D
7.1.2.3
X


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Category
Reference 
to 
Protocol 
Section
Screening Phase
Treatment Phase
End of 
study 
treatment 
(EoT) -
Core 
Phase
Post treatment and survival 
follow-up phase
Visit Name
Molecular 
Pre-
screening 
(by Day -
21) 
Screening
C1D1
C1D8
C1D15
C2D1
C2D15
Subsequent
cycles
(Day 1)
Within 21 
days of 
last dose
30 
days 
after 
last 
dose 
for 
safety
Every 12 
weeks
for efficacy 
applicable
Survival 
(Every 12 
weeks)
-21 
to -1
-14 
to -1
Prior/concomitant 
medications
D
6.4 / 
7.1.2.3
X
Continuous up to 30 days after last dose of study treatment
Surgical and 
medical 
procedures
D
7.1.2.3
X
Continuous up to 30 days after last dose of study treatment
Antineoplastic 
therapies
since 
discontinuation of 
study treatment
D
7.2.1.2
X
X
X
X
IWRS/IRT cohort 
assignment 
D
6.5.2
X
End of phase 
disposition
D
7.1
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


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Category
Reference 
to 
Protocol 
Section
Screening Phase
Treatment Phase
End of 
study 
treatment 
(EoT) -
Core 
Phase
Post treatment and survival 
follow-up phase
Visit Name
Molecular 
Pre-
screening 
(by Day -
21) 
Screening
C1D1
C1D8
C1D15
C2D1
C2D15
Subsequent
cycles
(Day 1)
Within 21 
days of 
last dose
30 
days 
after 
last 
dose 
for 
safety
Every 12 
weeks
for efficacy 
applicable
Survival 
(Every 12 
weeks)
-21 
to -1
-14 
to -1
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X
X
Physical 
examination
S
7.2.2.1
X
X
X
X
X
As clinically 
indicated 
X
Laboratory Assessments
Hematology 
D
7.2.2.5.1
X
X
X
X
X
Chemistry (Full)
D
7.2.2.5.2
X
X
X
Chemistry 
(Partial) 
D
7.2.2.5.2
X
X
Fasting plasma 
glucose
D
7.2.2.5.3
X
Fasting or random 
blood glucose
D
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
Fasting lipase, 
Fasting amylase
D
7.2.2.5.3
X
C3D1 and 
then as 
clinically 
indicated
X
Coagulation
D
7.2.2.5.4
X
FSH and/or 
estradiol
D
7.2.2.5.6
X


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Category
Reference 
to 
Protocol 
Section
Screening Phase
Treatment Phase
End of 
study 
treatment 
(EoT) -
Core 
Phase
Post treatment and survival 
follow-up phase
Visit Name
Molecular 
Pre-
screening 
(by Day -
21) 
Screening
C1D1
C1D8
C1D15
C2D1
C2D15
Subsequent
cycles
(Day 1)
Within 21 
days of 
last dose
30 
days 
after 
last 
dose 
for 
safety
Every 12 
weeks
for efficacy 
applicable
Survival 
(Every 12 
weeks)
-21 
to -1
-14 
to -1
Urinalysis 
(macroscopic)
D
7.2.2.5.5
X
As clinically indicated
X
Serum Pregnancy 
test (only 
premenopausal 
women)
D
7.2.2.5.6
X
X
Urine Pregnancy 
test (only 
premenopausal 
women) 
D
7.2.2.5.6
X every cycle
HIV testing (only if 
required by local 
regulations 
S
5.2
X
Imaging/Other Assessments
Tumor 
assessment and 
response by 
RECIST v1.1 
criteria
D
7.2.1.1
/14.5
X
Every 12 weeks 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 
for patients that did not have progression. 
12-Lead ECG
D
7.2.2.7.1
X
X
As clinically 
indicated 
X


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Category
Reference 
to 
Protocol 
Section
Screening Phase
Treatment Phase
End of 
study 
treatment 
(EoT) -
Core 
Phase
Post treatment and survival 
follow-up phase
Visit Name
Molecular 
Pre-
screening 
(by Day -
21) 
Screening
C1D1
C1D8
C1D15
C2D1
C2D15
Subsequent
cycles
(Day 1)
Within 21 
days of 
last dose
30 
days 
after 
last 
dose 
for 
safety
Every 12 
weeks
for efficacy 
applicable
Survival 
(Every 12 
weeks)
-21 
to -1
-14 
to -1
Cardiac imaging 
(MUGA or ECHO)
D
7.2.2.7.2
X
As clinically 
indicated
X
Safety
Adverse events
D
8.1
X
X
Continuous, up to 30 days after the last dose of study treatment


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Category
Reference 
to 
Protocol 
Section
Screening Phase
Treatment Phase
End of 
study 
treatment 
(EoT) -
Core 
Phase
Post treatment and survival 
follow-up phase
Visit Name
Molecular 
Pre-
screening 
(by Day -
21) 
Screening
C1D1
C1D8
C1D15
C2D1
C2D15
Subsequent
cycles
(Day 1)
Within 21 
days of 
last dose
30 
days 
after 
last 
dose 
for 
safety
Every 12 
weeks
for efficacy 
applicable
Survival 
(Every 12 
weeks)
-21 
to -1
-14 
to -1
Study Drug Administration
Alpelisib-oral
D
6.1.1
Daily
Fulvestrant-
injection (Cohort A 
& C)
D
6.1.1
X
X
X
X
Letrozole-oral 
(Cohort B)
D
6.1.1
Daily 
Goserelin (men/
premenopausal 
only)
D
6.1.1
X
X
X
Leuprolide (men/
premenopausal 
only)
D
6.1.1
X
X
X


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Category
Reference 
to 
Protocol 
Section
Screening Phase
Treatment Phase
End of 
study 
treatment 
(EoT) -
Core 
Phase
Post treatment and survival 
follow-up phase
Visit Name
Molecular 
Pre-
screening 
(by Day -
21) 
Screening
C1D1
C1D8
C1D15
C2D1
C2D15
Subsequent
cycles
(Day 1)
Within 21 
days of 
last dose
30 
days 
after 
last 
dose 
for 
safety
Every 12 
weeks
for efficacy 
applicable
Survival 
(Every 12 
weeks)
-21 
to -1
-14 
to -1
Survival Follow-up
D
7.1.9
X


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Table 7-2
Visit evaluation schedule – Extension Phase
Category
Reference to 
Protocol 
Section
Treatment Phase 
End of study 
treatment 
(EoT) 
Extension 
Phase
Post 
treatment 
extension 
phase
Visit Name
EXT 
C1D1
EXT 
C2D1
EXT C3D1
EXT 
C4D1
EXT C5D1
Subsequent
cycles
(EXT CXD1)
Within 21 
days of last 
dose
30 days 
after last 
dose for 
safety
Antineoplastic therapies
since discontinuation of 
study treatment
D
7.2.1.2
X
X
End of phase disposition
D
7.1
X
X
Confirmation of clinical 
benefit
D
7.1.4
Every 3 months ±7 days
Urine Pregnancy test 
(only premenopausal 
women)
S
7.2.2.5.6
X every cycle
Adverse events
D
8.1
Continuous, up to 30 days after the last dose of study treatment
Alpelisib-oral
D
6.1.1
Daily
Fulvestrant-injection 
(Cohort A & C)
D
6.1.1
X
X
X
X
X
X
Letrozole-oral (Cohort B)
D
6.1.1
Daily 
Goserelin (men/
premenopausal only)
D
6.1.1
X
X
X
X
X
X
Leuprolide (men/
premenopausal only)
D
6.1.1
X
X
X
X
X
X


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7.1.1
Molecular pre-screening
After signing the molecular pre-screening consent, tumor tissue (archival or newly obtained) 
will be sent to a Novartis-designated central laboratory to either analyze or confirm PIK3CA 
mutational status. This will be conducted during a pre-screening phase prior to study screening 
and enrolling into the trial (all pre-screening activities must be completed by Day -21).
Patients with a pathology report indicating PIK3CA mutant status, by a certified laboratory 
using a validated PIK3CA mutation assay (either from tissue or blood); must still provide a 
tumor sample (either archival or newly obtained) to confirm PIK3CA status by a Novartis 
designated central laboratory.
It is recommended to provide a tumor sample collected after the most recent progression or 
recurrence. Tumor tissue requirements, along with shipping requirements, will be detailed in 
the laboratory manual provided by the central laboratory.
7.1.2
Screening
Once PIK3CA mutation has been confirmed (either by Novartis designated central laboratory 
or certified laboratory using validated PIK3CA mutation assay (see Section 7.1.1) pathology 
report (either from tissue or blood)) and after signing the study ICF, the screening assessment 
will be done within 1 to 21 days prior to start of study treatment (see Table 7-1). Any screening 
assessment that is done outside the screening window (day -21 to day -1) must be repeated prior 
to C1D1.
Re-screening of patients is only allowed once per patient. In this case, the subject number 
assigned to the patient initially will be used and the patient will be identified with this number 
throughout his/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.
Any imaging assessments already completed during the regular work-up of the patient within 
45 days prior to study treatment, including before signing the main study ICF can be considered 
as the baseline images for this study.
7.1.2.1
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 in the IRT system by the investigator 
or designee prior to study treatment assignment. Please refer and comply with detailed 
guidelines in the [IRT Manual].


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7.1.2.2
Information to be collected on screening failures
Subjects who signed an ICF but failed to be started on treatment for any reason will be 
considered a screen failure. 
The screening failures will be entered on the Screening Phase Disposition Page.  Pre-screening 
failure information will only be entered into the IRT system.
The demographic information, informed consent, and Inclusion/Exclusion pages must also be 
completed for Screen Failure subjects. No other data will be entered into the clinical database 
for subjects who are screen failures, unless the subject experienced a Serious Adverse Event 
during the Screening Phase (see Section 8 for SAE reporting details). For molecular pre-
screening failures, only SAEs possibly related to a study procedure will be reported.
7.1.2.3
Patient demographics and other baseline characteristics
The data that will be collected on patient characteristics at the 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 eCRF 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 eCRF page and updated on a continual basis if there are 
any new changes to the medications.
Furthermore the following assessments will be performed:

Vital signs

Height, weight

Physical examination

Performance status (ECOG)

Laboratory evaluations (e.g., hematology, coagulation, biochemistry, fasting plasma 
glucose/c-peptide/serum lipid profile/HbA1c/lipase/amylase, FSH, pregnancy, urinalysis)

ECG

ECHO/MUGA

Radiological assessments (e.g. CT Scan)
7.1.3
Treatment period


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Patients will be treated with fulvestrant or letrozole plus alpelisib until disease progression, 
unacceptable toxicity, withdrawal of consent by the patient, patient is lost to follow-up, death, 
18 months after LPFT (Core Phase) and until 36 months of the Extension Phase, 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 and Table 7-2.
7.1.4
Extension Phase
Following the end of the Core Phase, patients continuing to derive benefit from study treatment 
who are not eligible for PSDS in their country based on local regulations will be transitioned to 
the Extension Phase until disease progression or any other reason for which the patient may be 
discontinued from study treatment (refer to Section 7.1.5). Patients will be re-consented for this 
amendment prior to continuing in the Extension Phase.
Patients must return to the study center on a monthly basis (4 weeks ± 7 days) for resupply of 
medication at which time drug dispensing information and adverse event information will be 
collected. A complete schedule of evaluations required for the Extension Phase is provided in 
Table 7-2. The procedures for patients entering the Extension Phase will proceed as follows:
Safety laboratory assessments: chemistry, hematology, urinalysis, coagulation will be 
done as clinically indicated
Treatment with assigned Cohort treatment from Core Phase will continue until lack of 
clinical benefit as assessed by Investigator at the site or any other reason for which the 
patient may be discontinued (refer to Section 7.1.5)
Every 3 months ±7 days, the investigator is required to confirm that the patient 
continues to have clinical benefit and may continue receiving study treatment. 
Although formal assessment of efficacy is not required during the Extension Phase, 
confirmation of continued treatment benefit as per standard of care is mandatory.
When patients discontinue treatment for any reason, an end of treatment visit 
following discontinuation of the medication will be performed. The 30-day Follow-up 
visit will also be performed to check on continuing AEs/SAEs or any new AEs/SAEs 
that may have occurred.
7.1.5
Discontinuation of study treatment
Patients may voluntarily discontinue from the study treatment for any reason at any time. 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 may discontinue study treatment for a given patient if he/she believes that
continuation would be detrimental to the patient’s well-being.
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the 
investigator at any time.
For patients who discontinue treatment during the Core Phase for reasons other than 
documented disease progression, death, lost to follow-up, or withdrawal of consent, tumor 
assessments must continue to be performed every 12 weeks until documented disease 
progression, death, lost to follow-up, or withdrawal of consent. This does not apply to the 


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Extension Phase; once the patient enters the Extension Phase, tumor imaging is no longer 
required per the study schedule.
Patients may be withdrawn from the study treatment if any of the following occur:

Adverse event or laboratory abnormalities as indicated in Section 6.3

Lost to follow-up

Physician decision

Progressive disease

Protocol deviation

Study terminated by sponsor

Technical problems
Patients must be withdrawn from the study treatment if any of the following occur:

Pregnancy

Death

Subject/Guardian decision
Patients who discontinue study treatment should undergo an End of Treatment (EOT) visit 
followed by a 30 day safety follow-up. At EOT (during the Core Phase), a tumor assessment 
scan should be performed if the previous scan is older than 30 days.
The investigator or his/her delegate must also contact the IRT to register the patient’s 
discontinuation from study treatment.


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7.1.5.1
Replacement policy
Patients that enter the study based on a local pathology report without PIK3CA mutational status 
confirmed or if there is discordance with results will be replaced.
7.1.6
Withdrawal of consent/ opposition to use data/biological samples
Withdrawal of consent/opposition to use data/biological samples occurs only when a patient:

Explicitly requests to stop use of their biological samples and/or data (opposition to use 
patient’s data and biological samples), and

No longer wishes to receive study treatment, and

Does not want any further visits or assessments (including further study-related contacts), 
and

Does not allow further collection of personal data.
This request should be in writing (depending on local regulations) and recorded in the source 
documentation.
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw their  consent/opposition 
to use data/biological samples and record this information.
Where consent to the use of Personal and Coded Data is not required in a certain country’s legal 
framework, the patient therefore cannot withdraw consent.  However, they still retain the right 
to object to the further collection or use of their Personal Data.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
If the patient agrees, a final evaluation at the time of the patient’s study withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table.
Further details on withdrawal of consent or the exercise of participants' data privacy rights are 
included in the corresponding informed consent form.
7.1.7
Follow-up for safety evaluations
All patients who discontinue study treatment, including those who refuse to return for an EOT 
visit in both the Core Phase and Extension Phase, 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 should have weekly follow-up for 30 days after discontinuation of study treatment or 
resolution of the AE to ≤ grade 1, whichever occurs first. Post treatment follow-up includes all 
study assessments appropriate to monitor the event.


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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).
Data collected should be added to the Antineoplastic Therapy since Discontinuation of Study 
Treatment eCRF, Adverse Events eCRF and the Concomitant Medications eCRF (during the 
Core Phase).
7.1.8
Efficacy follow-up
During the Core Phase only: 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 assessments should continue to be performed every 12 weeks until documented disease 
progression, death, lost to follow-up, or withdrawn consent to efficacy follow-up or end of study. 
At that time, the reason for study completion should be recorded on the End of Study 
Disposition eCRF page for the Core Phase.
7.1.9
Survival follow-up
All patients will be followed for survival status (after progression) every 12 weeks regardless 
of treatment discontinuation reason (except if consent is withdrawn, death or patient is lost to 
follow-up) until death, lost to follow-up, or withdrawal of consent for survival follow-up or end 
of the Core Phase. 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 eCRFs.
7.1.10
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue from study treatment or discontinue from study or withdraw 
consent/oppose to the use of their data/biological samples, the investigator must show "due
diligence" by documenting 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 eCRF.
7.1.11
End of post-treatment follow-up
Post-Treatment follow-up includes (post treatment efficacy, safety and survival). Prior to 
collecting survival follow-up information, the end of study disposition phase disposition eCRF 
page for the Core Phase will be completed once a patient has discontinued study treatment, 
completed safety follow-up, and can no longer perform efficacy assessment. During the 
Extension Phase, the end of study disposition phase disposition eCRF is completed after the 
safety follow-up is completed (Note: there is no efficacy or survival post treatment in the 
Extension Phase).


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End of post-treatment follow-up (Core Phase) 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 according to the Novartis guideline version 3.1 
(Appendix 5) based on RECIST v1.1 (Eisenhauer 2009) during the Core Phase. The imaging 
assessment collection plan is presented in Table 7-3.
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 screening and on-study interventions should be captured in the appropriate 
eCRFs.
Screening imaging assessments
Imaging assessments will be performed at screening within 21 days of start of treatment (Day -
21 to Day -1 prior to Cycle 1 Day 1).
Any imaging assessments already completed during the regular work-up of the patient within 
45 days prior to start of treatment, including before signing the main study ICF, can be 
considered as the screening images for this study. Any imaging assessments obtained after study 
treatment cannot be considered screening images. The following assessments are required at 
screening/baseline:

Chest, abdomen and pelvis CT or MRI

Brain CT or MRI, if clinically indicated

Localized bone CT, MRI or x-ray, that are not visible on the chest, abdomen and pelvis 
CT or MRI

Skin visual inspection and measurement (only if skin lesions at screening)

CT or MRI of other metastatic sites (e.g., neck), if clinically indicated
If a patient is known to have a contraindication to CT intravenous (IV) contrast media or 
develops a contraindication during the trial, a non-contrast CT of the chest (MRI is not 


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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.
Localized CT, MRI or X-rays should be acquired for all lesions, 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, lesion will be measured and visually monitored.
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 
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.
Core Phase Treatment phase imaging assessments
Imaging assessments as described in Table 7-3 should be performed using the same imaging 
modality used at screening, irrespective of study treatment interruption or actual dosing. 
Imaging assessments for response evaluation will be performed every 12 weeks (+/- 7 days) 
during the Core Phase. The 12 week interval should be followed 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 screening 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 v1.1 (Appendix 5).


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Extension Phase
During the Extension Phase there will be no per protocol efficacy assessments other than 
physician’s determination as per standard of care of whether or not the patient is continuing to 
derive clinical benefit from the study treatment.
Table 7-3
Imaging assessment collection guidance
Procedure
Screening
During Treatment/Follow-up
Chest, abdomen and 
pelvis CT or MRI (with 
intravenous contrast 
enhancement) 
Mandated
Mandated, every 12 weeks at EOT a tumor 
assessment scan should be performed if the 
previous scan is older than 30 days
Brain CT or MRI
If clinically indicated
If lesions were documented at baseline, follow 
same schedule as CT/MRI of chest, abdomen, 
and pelvis
Localized bone CT, 
MRI or x-ray
For any lesions that 
are not visible on the 
chest, abdomen and 
pelvis CT or MRI
If lesions were documented at baseline, follow 
same schedule as CT/MRI of chest, abdomen, 
and pelvis
Color photography 
(with scale/ruler)
For any skin lesions 
present
If lesions were documented at baseline, follow 
same schedule as CT/MRI of chest, abdomen, 
and pelvis
CT or MRI of other 
metastatic sites (e.g., 
neck)
If clinically indicated
If lesions were documented at baseline, follow 
same schedule as CT/MRI of chest, abdomen, 
and pelvis
7.2.1.2
Progression on next-line therapy (PFS2)
For PFS2, the disease progression will be determined based on investigator assessment of 
progression on next-line therapy. For this purpose, subsequent anti-neoplastic therapies 
including start/end date, reason for discontinuation and date of disease progression will be 
captured in the antineoplastic therapy since discontinuation of treatment eCRF during the Core 
or Extension Phase depending on which phase the patient discontinues treatment.
7.2.2
Safety and tolerability assessments
Core Phase:
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 AE collection and reporting, refer to Section 8.
If one of the study drugs is being held due to toxicity, scheduled visits and assessments should 
still be performed as described in Table 7-1.


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Extension Phase: 
Safety assessments in the Extension Phase will consist of monitoring and recording all AEs 
including SAEs, refer to Section 8.
7.2.2.1
Physical examination
A complete physical examination will be performed at screening and at subsequent time points 
as specified in Table 7-1 during the Core Phase. The physical examination at screening can be 
done at Day 1 of Cycle 1 provided that it is done before the study treatment. The physical 
examination comprises a total body examination that should include: general appearance, skin, 
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 
documented 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 eCRF. Significant new findings that begin or 
worsen after informed consent must be recorded on the adverse event page of the patient’s eCRF.
7.2.2.2
Vital signs
Vital signs include blood pressure (supine position preferred when ECG is collected), pulse 
measurement, and body temperature.
7.2.2.3
Height and weight
Height will be measured at screening.
Body weight (in indoor clothing, but without shoes) will be measured at screening and at 
subsequent time points as specified in Table 7-1 during the Core Phase.
7.2.2.4
Performance status
ECOG Performance status scale will be used as described in the Table 7-4 (during the Core 
Phase).
Table 7-4
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


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Clinical laboratory analyses (hematology, fasting biochemistry (full or partial), fasting lipase, 
fasting amylase, fasting lipid panel/glucose/c-peptide, HbA1C, coagulation, pregnancy test and 
urinalysis) are to be performed by the central laboratory. In case of urgent safety management 
of hyperglycemia, fasting or random blood glucose assessment may be done locally according 
to the schedule of assessments and collection plan outlined respectively in Table 7-1 and Table 
7-5 for the Core Phase.
Note: as hyperglycemia typically occurs within the first weeks of treatment, blood 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) during the Core Phase. 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. During the Extension Phase, 
all labs will be sent to local laboratory for testing.
The results of the local laboratory during the Core Phase 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
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 4.03. Additional analyses are left to the discretion of the 
investigator.
Visit windows of +/- 7 days are allowed. Novartis must be provided with a copy of the local 
laboratory’s certification (if applicable), and a tabulation of the normal ranges and units of each 
parameter collected in the eCRF. Any changes regarding normal ranges and units for laboratory 
values assessed during the study must be reported via an updated tabulation indicating the date 
of revalidation. Additionally, if at any time a 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 7-5
Central clinical laboratory parameters collection plan during Core 
Phase
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelets, Red blood cells, RBC 
morphology, White blood cells, - Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils)
Chemistry (Full)
Calcium, Magnesium, Potassium, Sodium, C-peptide, Alkaline phosphatase, 
ALT (SGPT), AST (SGOT), Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, 
Gamma-glutamyl-transferase (GGT), Total Protein, Albumin, Creatinine, 
Creatine kinase (CK), Blood Urea Nitrogen (BUN) or Urea, Uric Acid, Lactate 
dehydrogenase (LDH),
Chemistry 
(Partial)
Creatinine, Creatine kinase, ALT, AST, Total Bilirubin
Fasting Lipid 
panel
Total Cholesterol, LDL, HDL, Triglycerides
Coagulation 
International normalized ratio (INR) and Activated partial thromboplastin time 
(aPTT) or Partial thromboplastin time (PTT)
Pregnancy
Serum and Urine
Urinalysis
Macroscopic Panel (Dipstick) (WBC, blood, protein and glucose)
Additional tests
Amylase fasting, Lipase fasting, HbA1c, FG, RBG, FSH, estradiol
All laboratory analysis will be performed centrally during the Core Phase; however for urgent safety 
management or inclusion criteria, laboratory assessments may be allowed to be done locally and 
entered on an unscheduled local eCRF page (laboratory assessment performed locally should be 
sent to central laboratory as well for central analysis). During the Extension Phase, all laboratory 
assessments needed will be done via local laboratory testing.
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 during the Core 
Phase. Details on the collections, shipment of samples and reporting of results by the central 
laboratory are provided to investigators in the [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 during the Core Phase and 
Table 7-5. The Hematology panel specifics are listed in Table 7-5.
7.2.2.5.2 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 during the Core Phase and 
Table 7-5. The full biochemistry panel specifics are listed in Table 7-5.
7.2.2.5.3 Monitoring fasting plasma glucose, random blood glucose, c-peptide, fasting 
lipid panel, amylase, lipase and HbA1C
Fasting c-peptide, amylase, lipase, HBA1C and lipid panel will be assessed by the central 
laboratory according to the schedule of assessments and collection plan outlined respectively 


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in Table 7-1 and Table 7-5 for the Core Phase. 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 eCRF as well.
Beginning with C1D8 until EOT of Core Phase, patients can have RBG testing, at the discretion 
of the PI.
7.2.2.5.4 Coagulation
INR and PTT or aPTT will be assessed by the central laboratory according to the schedule of 
assessments and collection plan during the Core Phase outlined respectively in Table 7-1 and 
Table 7-5.
7.2.2.5.5 Urinalysis
Urinalysis dipstick analysis (WBC, blood, protein and glucose) will be performed by the central 
laboratory according to Table 7-1 during the Core Phase. The full urinalysis panel specifics are 
listed in Table 7-5.
7.2.2.5.6 Pregnancy and Hormone Levels
Pregnancy tests are to be performed according to the Visit Evaluation Schedule for the Core 
Phase and Extension Phase as outlined in Table 7-1 , Table 7-2 and Table 7-5. 
If participants cannot visit the site to have serum pregnancy tests during a Public Health 
emergency as declared by Local or Regional authorities i.e. pandemic, epidemic or natural 
disaster, that limits or prevents on-site study visits, urine pregnancy test kits may be used. 
Relevant participants can perform the urine pregnancy test at home and report the result to the 
site. It is important that participants are instructed to perform the urine pregnancy test first and 
only if the test result is negative proceed with the administration of the study treatment. A 
communication process should be established with the participant so that the Site is informed 
and can verify the pregnancy test results (e.g., following country specific measures)
A positive urine test is required to be confirmed by an immediate serum pregnancy test. A 
positive pregnancy test requires immediate interruption of study treatment until the assessment 
is confirmed. If positive, the patient must be discontinued from the study.
FSH and/or estradiol will be collected centrally and used for screening and confirmation of 
menopausal status during the Core Phase. 
A condom is required for all sexually active male participants to prevent them from fathering a 
child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, 
male participants should not donate sperm for the time period specified above’.
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements’.
Assessments of fertility:-‘Medical documentation of oophorectomy, hysterectomy, or tubal 
ligation must be retained as source documents. Subsequent hormone level assessment to 
confirm the woman is not of child-bearing potential must also be available as source 
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1. Surgical bilateral oophorectomy without a hysterectomy
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
participant regardless of reported reproductive/menopausal status at screening/baseline’.
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 in the Core Phase, additional chest CT scan or x-ray 
may be performed to follow-up on the event.


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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 during the Core Phase indicated in Table 7-6.
Table 7-6
Local ECG collection plan
Cycle
Patients
Day
Time
ECG Type
Screening
All
Day -21 to -1
Anytime
12 Lead
Cycle 1
All
Day 1
Pre-dose
12 Lead
EOT (Core 
Phase)
All
N/A
Anytime
12 Lead
Unscheduled sample as clinically indicated
Anytime
12 Lead
Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
eCRF page. Each ECG tracing should be labeled with the study number, patient initials (where 
regulations permit), patient number, date, and kept in the source documents at the study site. 
Clinically significant abnormalities present at screening should be reported on the Medical 
History eCRF page. Clinically significant findings must be discussed with Novartis 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 eCRF page.
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically significant 
findings should be collected. Local cardiologist ECG assessment may also be performed at any 
time during the study at the discretion of the investigator.
7.2.2.7.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram
The left ventricular heart function will be evaluated by ECHO or MUGA at Screening and 
according to the Visit Evaluation Schedule for the Core Phase as outlined respectively in Table 
7-1. Additional cardiac imaging during treatment is to be performed if indicated by clinical 
signs or symptoms. The same imaging modality should be used.


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Other assessments
No additional tests will be performed on patients entered into this study.
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 eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s eCRF. 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 


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diagnosis cannot be identified, each sign or symptom should be reported as a separate Adverse 
Event.
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding respectively to Grades 1 - 5, will be 
used. Information about any deaths (related to an Adverse Event or not) will also be collected 
through 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 1-5)
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 eCRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement 
to a lower grade is determined a new entry for this event should be reported in the eCRF noting 
the start date when the event improved from having been Grade 3 or Grade 4.
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 eCRF.
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 


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be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
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 eCRF. 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 SAE 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


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
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 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the 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 SAE given above 
is not a serious adverse event
8.2.2
Reporting
For patients with unknown PIK3CA status and who sign the molecular pre-screening ICF, SAE 
collection will start upon signing the molecular pre-screening ICF. SAEs will only be reported 
if the event is suspected to be causally related to a study procedure as assessed by the 
investigator (e.g. an invasive procedure such as biopsy). SAEs will be followed until resolution 
or until clinically relevant improvement or stabilization. If the main ICF is not signed 
(molecular screen failure), SAE collection ends 30 days after the last study related procedure.
For patients with known PIK3CA status who sign the main study ICF, SAE collection starts at 
time of main study informed consent whether the patient is a screen failure or not.
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis safety immediately without undue delay, but under 
no circumstances later than within 24 hours of obtaining knowledge of the events (Note: If more 
stringent, local regulations regarding reporting timelines prevail). 
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 immediately, 
without undue delay, but under no circumstances later than within 24 hours of the investigator 
receiving the follow-up information (Note: if more stringent, local regulations regarding 
reporting timelines prevail) 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 SAEs experienced after the 30 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and 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.


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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 SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Chief Medical Office and Patient Safety (CMO&PS) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
8.3
Emergency unblinding of treatment assignment
Not applicable as this is an open label study.
8.4
Pregnancies
This trial is planned for men, post-menopausal women or premenopausal women with ovarian 
suppression. No pregnancies are expected for study patients. If a female trial participant 
becomes pregnant, the study treatment should be stopped, and the pregnancy consent form 
should be presented to the trial participant.  The participant must be given adequate time to read, 
review and sign the pregnancy consent form.  The consent form is necessary to allow the 
investigator to collect and report information regarding the pregnancy.
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 Novartis Chief Medical Office and Patient Safety (CMO&PS). Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment any pregnancy outcome. Any SAE experienced 
during pregnancy must be reported on the SAE Report Form.
Pregnancy outcomes should 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.
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery.
8.5
Warnings and precautions


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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 
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
Not applicable.
8.7
Steering Committee
A Steering Committee (SC) will be established comprising investigators and Novartis personnel 
participating in the trial to ensure transparent management of the trial according to the protocol. 
The details of the steering committee, including roles will be defined in a steering committee 
charter.
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.
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 AEs) at the end of their scheduled study period.
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.
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 eCRFs with the investigators and 


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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 eCRFs, 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, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs 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 eCRF entries. Novartis monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the eCRFs 
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 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.
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 staffs 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 
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 will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Data about all study treatments dispensed to the patient and all IRT assigned dosage changes 
will be tracked using an Interactive Response Technology. The system will be supplied by a 


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vendor(s), who will also manage the database. The data will be sent electronically to Novartis 
personnel (or designated CRO).
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.
10
Statistical methods and data analysis
The primary analysis for each cohort will be performed 6 months after the last patient enrolled 
in that specific cohort has started treatment. The final analysis will be performed after LPLV of 
the study which include cumulative data (eg safety and clinical benefit) since the Core Phase 
analysis.
Prior to the final analysis, cohort specific analyses maybe performed when all patients included 
in the corresponding cohort have approximately 18 months of follow-up.  
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 
and who received one dose of study treatment. Patients will be analyzed according to the 
treatment they have been assigned to.
Modified full analysis set
The modified Full Analysis Set (mFAS) comprises all patients of the FAS population who have 
PIK3CA mutation confirmed by a Novartis designated laboratory. mFAS 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 assigned treatment if the patient took at least one dose of that treatment.
10.1.3
Per-protocol set
The Per-Protocol Set (PPS) consists of a subset of the patients in the mFAS 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 may be performed using PPS.


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10.1.4
Dose-determining analysis set
Not applicable.
10.1.5
Pharmacokinetic analysis set
Not applicable.
10.1.6
Other analysis sets
Not applicable.
10.2
Patient demographics/other baseline characteristics
The FAS will be used for the analyses below and repeated on mFAS for demographic 
characteristics.
Demographic and other baseline data including disease characteristics will be listed and
summarized descriptively.
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 continuous data.
Relevant medical histories and current medical at baseline will be summarized separately by 
system organ class and preferred term in each cohort.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
The Safety set will be used for the analyses below.
Categorical data will be summarized as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th – 75th percentiles, minimum, and maximum will be presented.
The duration of exposure (in months) to “investigational drug” and combination partner 
(fulvestrant and letrozole) as well as the dose intensity will be summarized by means of 
descriptive statistics using the safety set. The duration of exposure will also be presented for 
the study treatment by cohort. The number of subjects with dose adjustments (reduction, 
interruption, or permanent discontinuation) and the reasons will be listed and summarized by 
cohort.
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 cohort. Surgical and medical 
procedures will be coded using MedDRA and summarized by SOC and preferred term in each 
cohort. 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.


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10.4
Primary objective
The primary objective of the study is to assess the proportion of patients who are alive without 
disease progression at 6 months based on local investigator assessment per RECIST v1.1 
separately in Cohorts A and C (alpelisib in combination with fulvestrant) and Cohort B 
(alpelisib in combination with letrozole) among patients with HR+, HER2-negative aBC 
harboring a PIK3CA mutation who have progressed on or after prior treatments.
The mFAS will be used for the primary efficacy analysis.
10.4.1
Variable
The primary efficacy endpoint is the proportion of patients who are alive without disease 
progression at 6 months based on local investigator assessment using RECIST v1.1 in each 
cohort.
10.4.2
Statistical hypothesis, model, and method of analysis
A proportion of 
of patients alive without progression after 6 months is considered as a 
clinically meaningful threshold in all the cohorts for this study. Therefore, evidence of treatment 
effect will be tested using the following hypothesis:
H0:
H1:
Where p is the proportion of patients who are alive without progression at 6 months.
The primary endpoint will be presented together with two-sided  95% confidence intervals using 
Clopper and Pearson (1934) exact method for all the cohorts separately. The null hypothesis 
will be rejected and evidence of treatment effect will be demonstrated if the lower bound of the 
95% CI for observed proportion at 6 months is greater than
Table 10-1 displays the values 
of proportion of patients who are alive without any disease progression at 6 months and its 95% 
CI for selected number of patients alive without progressive disease out of 112 patients. To 
reject the null hypothesis 
 at least 44 patients need to be alive without progression at 6 
months out of 112 patients in each cohort.
Table 10-1
Exact 95% Confidence Interval
Sample size
Number of patients alive 
without PD at 6 months 
(k)
Proportion
k/N (%)
Exact 95% Confidence Interval 
(CI)
Lower (%)
Upper (%)
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10.4.3
Handling of missing values/censoring/discontinuations
Six months is defined in this study as 24 weeks ± 1 week. Therefore tumor assessments between 
week 23 and 25 will be considered for the primary analysis. For primary endpoint analysis, 
patients who progressed, died, or discontinued study before 6 months will be counted as a 
“failure”.
10.4.4
Supportive and Sensitivity analyses
The primary analysis will also be performed on the FAS and may be repeated on PPS.
The primary analysis will also be repeated in patients from mFAS harboring a PIK3CA 
mutation as determined via ctDNA.
10.5
Secondary objectives
The secondary objectives in this study are to evaluate the progression free survival (PFS), 
progression free survival 2 (PFS2), overall response rate (ORR), clinical benefit rate (CBR), 
overall survival (OS) and duration of response (DOR), and safety. For efficacy secondary 
objectives, 95% confidence intervals will be provided as needed.
The secondary efficacy analysis will also be repeated in patients harboring a PIK3CA mutation 
as determined via ctDNA.
10.5.1
Secondary efficacy objective(s)
10.5.1.1 Progression free survival
PFS is defined as the time from the date of first dose of study medication to the date of the first 
documented progression or death due to any cause occurring in the study. PFS will be assessed 
based on local investigator’s assessment according to RECIST v1.1 (see Appendix 5 for further 
details).
PFS 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 Appendix 5). It is 
not intended to censor patients for new anticancer therapy prior to documented disease 
progression in the primary analysis.
The Kaplan-Meier estimate of the PFS survival function will be estimated and displayed. The 
resulting median PFS time will be given for each cohort with 95% confidence intervals, as well 
as 25th and 75th percentiles will be reported.
10.5.1.2 Progression free survival 2
PFS2 is defined as time from the date of first dose of study medication to the date of first 
documented progression on next-line therapy or death from any cause.
The first documented progression on next-line treatment is based on investigator assessment of 
PD (i.e. as captured on the anti-neoplastic therapy after treatment discontinuation eCRF page); 


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it is not necessary to continue to collect tumor assessments data for subsequent anti-neoplastic 
therapies for the purpose of PFS2.
PFS2 will be summarized using the Kaplan-Meier method on the mFAS. The resulting median 
PFS will be given with 95% confidence intervals for each cohort.
10.5.1.3 Overall response rate
ORR is defined as the proportion of patients with best overall response (BOR) of CR or partial 
response (PR), as per local investigator’s assessment and according to RECIST v1.1 (see 
Appendix 5 for details). Patients with non-measurable lesions only at baseline will be included 
as ‘responders’ if they achieve a CR, otherwise they will be included as ‘non-responders’.
ORR will be calculated based on the mFAS. ORR and its exact 95% confidence interval 
(Clopper and Pearson 1934) will be presented for each cohort.
10.5.1.4 Clinical benefit rate
Clinical Benefit Rate is defined as the proportion of patients with a best overall response of CR 
or PR or an overall lesion response of stable disease (SD) or Non-CR/ Non-PD lasting ≥ 24 
weeks based on local investigator’s assessment according to RECIST v1.1.
CBR will be calculated based on the mFAS. The CBR and its exact 95% confidence interval 
(Clopper and Pearson 1934) will be provided for each cohort.
10.5.1.5 Duration of response
DOR is the time from the date of first documented response (confirmed CR or PR) to the date 
of first documented progression or death due to underlying cancer. DOR only applies to patients 
whose best overall response is CR or PR according to RECIST v1.1 based on tumor response 
data per local investigator’s assessment. The start date is the date of first documented response 
of CR or PR (i.e., the start date of response, not the date when response was confirmed), and 
the end date is defined as the date of the first documented progression or death due to underlying 
cancer. Patients continuing without progression or death due to underlying cancer will be 
censored at the date of their last adequate tumor assessment.
DOR will be listed and summarized for each cohort in the mFAS with confirmed BOR of CR 
or PR. DOR will be summarized using Kaplan-Meier estimates in patients with confirmed CR 
or PR within each cohort.
10.5.1.6 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”).
OS is defined as the time from date of start treatment 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.


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The analyses for OS will be based on the FAS. The distribution function of OS will be estimated 
using the Kaplan-Meier method. The median OS along with 95% confidence intervals will be 
presented for each cohort.
10.5.1.7 Extension Phase Clinical Benefit
The secondary objective related to the Extension Phase of the study is to evaluate clinical
benefit as assessed by the Investigator. Proportion of patients with clinical benefit as assessed
by the Investigator will be summarized.
10.5.2
Safety objectives
10.5.2.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented for 
each cohort.
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.
The safety summary tables will include only assessments collected no later than 30 days after 
study treatment discontinuation, with the exception of summary table for all deaths. Those 
collected later than 30 days after study treatment discontinuation will be flagged in listings.
10.5.2.2 Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment. 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 cohort.
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.


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10.5.2.3 Laboratory abnormalities
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used.
For laboratory tests where grades are not defined by CTCAE 4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges.
The following by cohort summaries will be generated separately for hematology, biochemistry 
tests and urinary laboratory tests:

Listing of all laboratory data with values flagged to show the corresponding CTCAE 
v4.03 grades if applicable and the classifications relative to the laboratory normal ranges

Listing of all notable laboratory abnormalities (i.e., newly occurring CTCAE v4.03 grade 
3 or 4 laboratory toxicities)
For laboratory tests where grades are defined by CTCAE v4.03

Number and percentage of patients with worst post-baseline CTCAE v4.03 grade 
(regardless of the baseline status). Each patient will be counted only once for the worst 
grade observed post-baseline.

Shift tables using CTCAE v4.03 grades to compare baseline to the worst on-treatment 
value
For laboratory tests where grades are not defined by CTCAE 4.03,

Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value.
 
 
Laboratory values collected later than 30 days after study treatment discontinuation will be 
flagged in the listings.
10.5.2.4 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.

ECGs: 12-lead ECGs including PR, QRS, QT, QTcF, and HR intervals will be obtained 
for each subject during the study. ECG data will be read and interpreted locally.

Categorical Analysis of QT/QTc interval data based on the number of subjects meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from 
baseline will be presented. In addition, a listing of these subjects will be produced by 
cohort.

ECOG: Shift tables to compare baseline to the worst on-treatment value.


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
Cardiac imaging: change from baseline to worst post-baseline in LVEF values.

Vital signs: Data on vital signs will be tabulated and listed, notable values will be flagged.
10.5.2.5 Supportive analyses for secondary objectives
Not applicable.
10.5.2.6 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.
10.5.3
Pharmacokinetics
Not applicable.


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10.5.5
Resource utilization
Not applicable.
10.5.6
Patient-reported outcomes
Not applicable.
10.6
Exploratory objectives
Not applicable.
10.7
Interim analysis
Three Interim Analyses (IA) are planned for this study. The first IA will be performed after at 
least
patients receiving alpelisib plus fulvestrant (cohort A) have at least 6 months of follow-
up. The second IA will be performed when approximately
patients (50% enrolled patients) 
have been treated in the study (regardless of cohort) and have at least 6 months of follow-up. 
The third IA will be performed after the Core Phase has ended.
At the time of the first two IAs, preliminary efficacy (ORR, CBR) as well as key safety data 
will be analyzed in a descriptive fashion. The primary endpoint will not be analyzed and no 
statistical hypothesis will be tested.
The third IA will include all efficacy and safety data up to the end of the Core Phase.
Details of the IAs will be specified in the analysis plan.
10.8
Sample size calculation
A median PFS of at least 6 months (or 50% of patients who are alive without progression after 
6 months) has been observed for alpelisib 300 mg plus fulvestrant 500 mg and also for 
palbociclib 125 mg plus fulvestrant 500 mg in PiK3CA mutant patients previously treated with 
AI (without CDK4/6 inhibitor) in [CBYL719X2101] and Paloma-3 (Cristofanilli 2016) studies 
respectively. Currently, there is no available clinical data in post-CDK4/6 inhibitor setting in 
PIK3CA mutant patients. Assuming that these patients after failure to CDK4/6 inhibitor will 


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have a lower median PFS than 6 months, a proportion of 
of patients alive without 
progression after 6 months is considered as a clinically meani
l threshold in both cohorts 
for this study and was used for sample size calculation.
The sample size is based on an exact Binomial test for single proportion to test the null 
hypothesis H0: 
 where p is the proportion of patients who are alive without progression 
at 6 months. With a one-sided 2.5% level of significance (two-sided 95% CI), a total sample 
size of 112 patients in each cohort is required in order to have a power of at least 90% when the 
true p ≥0.45. Table 10-2 provides the operating characteristics for N=112 and different true 
rates.
Table 10-2
Operating Characteristics
Sample size
(N)
True rate
Prob (X≥44|True rate)
112
The study will enroll a total of approximately 340 patients who have a PIK3CA mutation with 
at least 112 patients allocated into each Cohort A (alpelisib + fulvestrant), Cohort B (alpelisib 
+ letrozole) and Cohort C (alpelisib + fulvestrant).
At the time of the first two  Interim Analyses (IA) preliminary efficacy (ORR, CBR) will be 
analyzed in a descriptive fashion. The primary endpoint will not be analyzed and no statistical 
hypothesis will be tested. Therefore no multiplicity adjustment was made.
10.9
Power for analysis of key secondary variables
Not applicable.
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 


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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.
If applicable, in cases where the participant's representative(s) gives consent (if allowed
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her level of understanding. If the participant is capable of doing so, he/she 
must indicate agreement by personally signing and dating the written informed consent
document.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their eCRFs.
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 E6 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.
Information about common side effects already known about the investigational treatment can
be found in the Investigator's Brochure (IB) and Core Data Sheet (CDS) for marketed drugs. 
This information will be included in the participant consent and should be discussed with the 
participant during the study as needed. Any new information regarding the safety profile of the 
investigational drug that is identified between IB updates will be communicated as appropriate 
for example, via an investigator notification or an aggregate safety finding. New information 
might require an update to the informed consent and then must be discussed with the participant. 
The following informed consents are included in this study:

Molecular Prescreening Consent

Main study consent, which also included:

A subsection that requires a separate signature for the ‘Optional Consent for

Additional Research’ to allow future research on data/samples collected during 
this study

As applicable, Pregnancy Outcomes Reporting Consent for female participants or the

female partners of any male participants who took study treatment


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Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
Male participants must be informed that if a female partner becomes pregnant while he is
enrolled in the study, contact with the female partner will be attempted to request her consent
to collect pregnancy outcome information.
The study includes an optional sub studies/ DNA component which requires a separate signature 
if the participant agrees to participate. It is required as part of this protocol that the Investigator 
presents this option to the participants, as permitted by local governing regulations. The process 
for obtaining consent should be exactly the same as described above for the main informed
consent.
Declining to participate in these optional assessments will in no way affect the participant’s 
ability to join the main research study.
A copy of the approved version of all consent forms must be provided to Novartis after
IRB/IEC approval.
As per Section 2.6.4, during a Public Health emergency as declared by Local or Regional
authorities i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain
a standard written informed consent due to limits that prevent an on-site visit, Investigator may
conduct the informed consent discussion remotely (e.g. telephone, videoconference) if
allowable by a local Health Authority.
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs
by trial participant and person obtaining informed consent, etc.).
 
 
 
 
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


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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 on the publicly accessible database, e.g. 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 study completion (i.e., LPLV), 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.
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 case report form (eCRF) 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 eCRFs and all other required reports. Data reported 


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on the eCRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the eCRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper eCRF 
should be dated, initialed, and explained (if necessary) and should not obscure the original entry. 
For electronic eCRFs an audit trail will be maintained by the system. The investigator should 
retain records of the changes and corrections to paper eCRFs.
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.
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.


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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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14
Appendices
14.1
Appendix 1 - List of concomitant medications
In general, the use of any concomitant medication deemed necessary for the care of the patient 
is permitted in this study, except as specifically prohibited below. Combination administration 
of study drugs could result in drug-drug interactions (DDI) that could potentially lead to reduced 
activity or enhanced toxicity of the concomitant medication and/or BYL719 and/or 
fulvestrant/letrozole. Please note that all lists in Appendix 1 are not comprehensive. Please refer 
to regular updated online sources and the label of a concomitant drug to decide whether a drug 
is permitted (with caution) or prohibited based on Section 6.4. In doubt please the contact 
medical monitor with any questions.
14.1.1
Permitted Medication to be used with caution
As described in this list of CYP substrates was compiled from the University of Washington’s 
Drug Interaction Database (Updated April 2019). This list only meant to be used as a guide.
Table 14-1
List of CYP450 substrates to be used with caution
Category
Drug names
CYP2C9 substrates
Narrow Therapeutic index substrates of 
CYP2C9
(S)-Warfarin
Sensitive substrates of CYP2C9
Benzbromarone, Celecoxib, Glimepiride, 
Glipizide, (R)/(S)-Ibuprofen, Lornoxicam, 
Meloxicam, Piroxicam, Tolbutamine, (S)-
Warfarin
CYP2B6 substrates
Narrow Therapeutic index substrates of CYP2B6
Not Applicable
Sensitive substrates of CYP2B6
Bupropion, Efavirenz
Selected CYP3A4 substrates
CYP3A4 substrates which are known or 
potential auto-perpetrators
Clarithromycin, Conivaptan, Encorafenib, 
Erythromycin, Diltiazem, Mifepriston, Ribociclib, 
Telthromycin, Troleandomycin, Verapamil
Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-
administered with a known potent inhibitor.
Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that 
increases in their exposure levels by the concomitant use of potent inhibitors may lead to serious 
safety concerns (e.g. Torsades de Pointes, QT prolongation).
CYP3A4 substrates which are auto-perpetrators: Based on Novartis internal assessment
14.1.2
Prohibited Medication
Strong inducers of CYP3A4
This list of CYP inducers was compiled from the University of Washington’s Drug Interaction 
Database (Updated Nov-2020). This list only meant to be used as a guide.


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Table 14-2
List of prohibited strong inducers of CYP3A4
Category
Drug Name
Strong CYP3A Inducers
Apalutamide, Avasimibe1, Carbamazepine, 
Enzalutamide, Ivosidenib, Lumacaftor, Mitotane, 
Phenobarbital, Phenytoin, Rifabutin, Rifapentine, 
Rifampin (Rifampicin), St. John's wort 
(hypericum perforatum)1 
1 Herbal product
Inhibitors of BCRP
The table encompasses only drugs and molecular entities for which inhibition of BCRP has 
been investigated and/or formally shown in vivo in a clinical DDI study. Please note that this is 
not an exhaustive list and only meant to be used as a guide. When in doubt, refer to the 
prescribing information of the drug to assess whether a potential for BCRP inhibition is 
described.
Table 14-3
List of prohibited BCRP inhibitors
Category
Drug Name
BCRP inhibitors -
Evidence for DDI potential shown in vivo
Atazanavir/ritonavir1,2, Elvitegravir/cobicistat1,2, 
Lopinavir/ritonavir1,2, 
Tipranavir/ritonavir1,2Curcumin1,2, 
Cyclosporine1,2, Daclatasvir1,2, Eltrombopag1,2, 
Gefitinib2, Lapatinib1, Ledipasvir2, 
Pantoprazole1,2, Paritepravir2, Tipranavir2
1 Lee et al 2015
2 Novartis PK Sciences DDI List (January, 2018)


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14.2
Appendix 2: Guidelines for the treatment of alpelisib induced 
diarrhea
Mild to moderate diarrhea has been reported within the ongoing studies of single-agent alpelisib. 
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 
alpelisib 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-
4).
Table 14-4
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.


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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.
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 section of the patient record.
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 


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with any antidiarrheal agents, the patient’s response to treatment should be observed and 
appropriately documented in the source document and within the patient record.
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).
12-24 hrs later:
Diarrhea resolved

Continue instructions for dietary modification

Gradually add solid foods to diet

Discontinue loperamide after 12 hrs diarrhea-free interval
Diarrhea unresolved
Persisting diarrhea CTCAE grade 1 or 2 will be treated with addition of opium tincture or 
dihydrocodeine tartrate tablets/injections with monitoring of 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). Enteric acting steroids /systemic steroids 
may be given if clinically indicated for the management of colitis. Observe patient for 
response.
After 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.


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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.
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.
Biopsy: Histopathological examination of colonic mucosa and immunophenotyping may 
be performed to confirm the etiology of colitis.


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14.3
Appendix 3 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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14.4
Appendix 4 – Liver event and Laboratory trigger Definitions and 
Follow-up Requirements
Table 14-5
Liver event and laboratory trigger definitions
Definition/ threshold
Liver laboratory triggers
If ALT, AST and total bilirubin normal at baseline:
· ALT or AST > 5 × ULN
· ALP > 2 × ULN (in the absence of known bone 
pathology)
· Total bilirubin > 3 × ULN (in the absence of 
known Gilbert syndrome)
· ALT or AST > 3 × ULN and INR > 1.5
· Potential Hy’s Law cases (defined as ALT or 
AST > 3 × ULN and Total bilirubin > 2 × ULN 
[mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN)
· Any clinical event of jaundice (or equivalent term)
· ALT or AST > 3 × ULN accompanied by 
(general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with eosinophilia
· Any adverse event potentially indicative of a liver 
toxicity*
If ALT or AST abnormal at baseline:
· ALT or AST > 2x baseline or > 300 U/L 
(whichever occurs first)
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms ULN: upper limit 
of normal
Table 14-6
Follow-up requirements for liver laboratory triggers with liver 
symptoms
ALT
TBL
Liver Symptoms
Action
ALT increase without bilirubin increase:
If normal at baseline:
ALT > 3 x ULN
Normal
For participants with 
Gilbert’s syndrome: No 
change in baseline 
TBL
None
· No change to study 
treatment
· Measure ALT, AST, 
ALP, GGT, TBIL, INR, 
albumin, CK, and 
GLDH in 48-72 hours.
· Follow- up for 
symptoms.
If elevated at 
baseline:
ALT > 2 x baseline
or > 300 U/L 
(whichever occurs 
ﬁrst)
If normal at baseline:
ALT > 5 x ULN for 
more than two weeks
Normal
For participants with 
Gilbert’s syndrome: No 
change in baseline 
TBL
None
· Interrupt study drug
· Measure ALT, AST, 
ALP, GGT, TBIL, INR, 
albumin, CK, and 
GLDH in 48-72 hours.
· Follow- up for 
symptoms.
If elevated at 
baseline:
ALT > 3 x baseline
or > 300 U/L 
(whichever occurs 


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ALT
TBL
Liver Symptoms
Action
ﬁrst) for more than two 
weeks
· Initiate close 
monitoring and workup 
for competing 
etiologies.
· Study drug can be 
restarted only if 
another etiology is 
identiﬁed and liver 
enzymes return to 
baseline.
If normal at baseline:
ALT > 8 x ULN
Normal
None
ALT increase with bilirubin increase:
If normal at baseline:
ALT > 3 x ULN
TBL > 2 x ULN (or 
INR > 1.5)
For participants with 
Gilbert’s syndrome: 
Doubling of direct 
bilirubin
None
If elevated at 
baseline:
ALT > 2 x baseline
or > 300 U/L 
(whichever occurs 
ﬁrst)
If normal at baseline:
ALT > 3 x ULN
Normal or elevated
Severe fatigue, 
nausea, vomiting, right 
upper quadrant pain
If elevated at 
baseline:
ALT > 2 x baseline
or > 300 U/L 
(whichever occurs 
ﬁrst)
Table 14-7
Follow-up requirements for liver laboratory triggers
Criteria
Actions required
Follow- up monitoring
Total Bilirubin (isolated)
>1.5 – 3.0 ULN
· Maintain treatment
· Repeat LFTs within 48-72 
hours
Monitor LFTs weekly until 
resolutionc to ≤ Grade 1 or to 
baseline
> 3 - 10 × ULN (in the absence 
of known Gilbert syndrome)
· Interrupt treatment
· Repeat LFT within 48-72 
hours
· Hospitalize if clinically 
appropriate
· Establish causality
· Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in the 
appropriate CRF
Monitor LFTs weekly until 
resolutionc to ≤ Grade 1 or to 
baseline (ALT, AST, total 
bilirubin, Alb, PT/INR, ALP and 
GGT)
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 10 x ULN
· Discontinue the study 
treatment immediately
· Hospitalize the participant
· Establish causality
· Record the AE and 
contributing factors(e.g. 
conmeds, med hx, lab) in the 
appropriate CRF
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolutionc (frequency at 
investigator discretion)


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Criteria
Actions required
Follow- up monitoring
Any AE potentially indicative of 
a liver toxicity*
· Consider study treatment 
interruption or discontinuation
· Hospitalization if clinically 
appropriate
· Establish causality
· Record the AE and 
contributing factors (e.g., 
conmeds, med hx, lab) in the 
appropriate CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a 
maximum of 6 months, (4) liver transplantation, and (5) death.
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms 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.


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14.5
Appendix 5 - 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
List of contributors
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
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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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 2 and the definition of best response in Section 
3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions and rules for 
determination of best response. Section 3.2 is summarizing the “time to event” variables and 
rules which are mainly derived from internal discussions and regulatory consultations, as the 
RECIST criteria do not define these variables in detail. Section 4 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.
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.
Indicate the assessment schedule for tumor assessments in the protocol. Frequency of tumor re-
evaluation while on treatment should be adapted to the type and schedule of treatment, and the 
type of tumor treated. It should also be clearly stated how patients are followed for progression 
after discontinuation of study treatment.
It is assumed that all information which is considered for assessment of the tumor is captured 
in the RECIST eCRF, i.e. not merged from several sources.
2.1
Definitions
2.1.1 Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.

Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
For patients without measurable disease see Section 3.2.9.
Measurable lesions (both nodal and non-nodal)

Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.


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
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.

Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 
baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease.

Cystic lesions:

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.
If any lesion should be handled differently, this must be clearly stated and justified in the 
protocol, e.g. tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable, and the conditions under which such lesions should be considered 
must be defined in the protocol when appropriate.
2.1.2 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 
3.2.9.
2.2
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:


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
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.
If different window for baseline assessments is allowed in the protocol this must be justified in 
the protocol.

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.

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.
If head and neck tumors and those of extremities are evaluated in the study, please specify the 
methods in detail in the protocol.

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.


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
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 
obtained.

Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, 
PSA for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be 
integrated as non-target disease. If markers are initially above the upper normal limit they 
must normalize for a patient to be considered in complete clinical response when all 
lesions have disappeared.
 
If tumor markers are used in the study for the response assessment, the criteria must be clearly 
stated in the protocol and the presence of abnormality in tumor markers must be entered in the 
eCRF page for RECIST evaluations (see also Section 2.4).

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).
When pathological response is being used, the protocol must clearly state details on how 
pathological responses are documented.


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
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.
If the protocol is considering specific symptoms as objective signs of clinical progression, e.g. 
bone pain or GI bleeding, then the criteria for clear worsening of these non-measurable ‘lesions’ 
indicative of PD should be clearly specified in the protocol. In that case, the protocol should 
clearly specify that additional criteria are used to complement RECIST criteria.
2.3
Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the eCRF 
(even if it resides in the same organ).
Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 2.1.1.

Nodal target: See Section 2.1.1.
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. Each 
target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.

Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.
If the protocol is considering specific symptoms for assessment of the tumor, e.g. bone pain or 
GI bleeding, then these symptoms are to be entered as non-target lesions with either presence 
or absence or as a new lesion (based on protocol specified criteria). In that case, the protocol 
should clearly specify that additional criteria are used to complement RECIST criteria.


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For cancers which are known to metastasize to bone, the protocol should specify if and how 
bone lesions should be handled, e.g., if they should be followed throughout the study by CT, 
MRI or x-ray.
2.4
Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 2-1) and non-target lesions (Table 2-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 2-3) as well as the presence or absence of new lesions.
If tumor markers are used as non-target lesions to evaluate response, please specify criteria for 
CR, SD and PD in the protocol, e.g. CR=’Normalization of tumor marker level’, PD=’Elevation 
of tumor markers to certain level’, SD=’Not qualifying for CR or PD’. These criteria are 
indication and study specific. In that case, the protocol should clearly specify that additional 
criteria are used to complement RECIST criteria.
2.4.1 Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number.
2.4.1.1
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.


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2.4.1.2
Nodal lesions
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist.
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval.
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.
2.4.2 Determination of target lesion response
Table 2-1
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
Complete Response (CR):
Disappearance of all non-nodal target lesions. In addition, any pathological lymph 
nodes assigned as target lesions must have a reduction in short axis to < 10 mm 1
Partial Response (PR):
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of diameter of all measured target lesions, 
taking as reference the smallest sum of diameter of all target lesions recorded at 
or after baseline. In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm2.
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 2.2).
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following 
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
The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease

The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the eCRF and the tumor assessment will remain 
based on the sum of tumor measurements as presented in Table 2-1 above (i.e., a PD will 
be determined if there is at least 20% increase in the sum of diameters of all measured 
target lesions, taking as reference the smallest sum of diameters of all target lesions 
recorded at or after baseline with at least 5 mm increase in the absolute sum of the 
diameters). Proper documentation should be available to support this decision. This 
applies to patients who 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.


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
Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all 
non-nodal target lesions have disappeared.

Once a CR target lesion response has been assigned a CR will continue to be 
appropriate (in the absence of missing data) until progression of target lesions.

Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 
mm and there is at least 20% increase in sum of the diameters of all nodal target 
lesions relative to nadir with at least 5 mm increase in the absolute sum of the 
diameters.

A change in method for the evaluation of one or more lesions will usually lead to an 
UNK target lesion response unless there is progression indicated by the remaining 
lesions which have been evaluated by the same method. In exceptional circumstances 
an investigator or 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.
2.4.3 Determination of non-target lesion response
Table 2-2
Response criteria for non- target lesions
Response Criteria
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions. In addition, all lymph nodes assigned a 
non-target lesions must be non-pathological in size (< 10 mm short axis)
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.1
Non-CR/Non-PD:
Neither CR nor PD
Unknown (UNK)
Progression has not been documented and one or more non-target lesions have 
not been assessed or have been assessed using a different method than 
baseline2
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.
It is recommended that the investigator and/or central reviewer should use expert judgement 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.


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
The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e. 10 mm) the response can only be ‘Non-
CR/Non-PD’ unless there is unequivocal progression of the non-target lesions (in which 
case response is PD) or it is not possible to determine whether there is unequivocal 
progression (in which case response is UNK).

Unequivocal progression: To achieve “unequivocal progression” on the basis of non-
target disease there must be an overall level of substantial worsening in non-target disease 
such that, even in presence of CR, PR or SD in target disease, the overall tumor burden 
has increased sufficiently to merit discontinuation of therapy. A modest “increase” in the 
size of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
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 2.4.2 for assigning PD following a CR for the 
non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.
2.4.4 New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion eCRF page.

If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion

If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 2.5).

A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to 10 mm for the first time in the study plus 5 
mm absolute increase.
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 2.2.
2.5
Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in Table 2-3.


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Table 2-3
Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overall
lesion response
CR
CR
No
CR1
CR
Non-CR/Non-PD3
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR1
SD
Non-PD and not UNK
No
SD1, 2
UNK
Non-PD or UNK
No
UNK1
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1. This overall lesion response also applies when there are no non-target lesions identified at baseline.
2. Once confirmed PR was achieved, all these assessments are considered PR.
3. As defined in Section 2.4
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.
3
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 3.2.9 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
3.1
Best overall response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the 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).
The protocol should state if randomization or start of treatment is used as start date (baseline). 
This is then used in all definitions.
If a different minimum follow-up period is required to classify for best overall response= ’stable 
disease’, this must be specified in the protocol.

PD = progression 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).
If PD in a different follow-up period is considered to classify for best overall 
response=’progressive disease’, this must be specified in the protocol.
The protocol should state if discontinuation due to ‘Disease progression’ or death due to study 
indication is considered PD even if this was not accompanied by documentation of PD based 
on tumor measurements. This depends on Phase of the study and the primary endpoint (e.g. 
Phase III studies in which progression-free survival is primary endpoint should consider only 
documented PD, whereas Phase I and II studies may consider all clinical deteriorations PD). 
The following sentence therefore is only applicable if this is specified in the protocol:
Patients with symptoms of rapidly progressing disease without radiologic evidence will be 
classified as progression only when clear evidence of clinical deterioration is documented 
and/or patient discontinued due to ‘Disease progression’ or death due to study indication.

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 


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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
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.
Specify which determination of best overall response will be considered primary (and delete 
the other terms in the text). If a central blinded review is used (e.g. in an open-label study in 


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which response is the primary endpoint), the best overall response evaluated by the central 
blinded review will always be considered the primary response.
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 
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).
3.2
Time to event variables
The protocol should state which of the following variables is used in that study.
3.2.1 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.


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Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
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.
3.2.2 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.
3.2.3 Time to progression
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer.
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment.
3.2.4 PFS2
A recent EMA guidance (EMA 2012) recommends a substitute end point intermediate to PFS 
and OS called PFS2, a surrogate for OS when OS cannot be measured reliably, which assesses 
the impact of the experimental therapy on next-line treatment. The main purpose of this 
endpoint is to assess long term maintenance strategies, particularly of resensitizing agents and 
where it is necessary to examine the overall “field of influence”.
PFS2, which could be termed PFS deferred, PFS delayed, tandem PFS, or PFS version 2.0, is 
the time from date of randomization/start of treatment to the date of event defined as the first 
documented progression on next-line treatment or death from any cause. The censoring rules 
for this endpoint will incorporate the same principles as those considered for PFS in this 
document, and in addition may involve other considerations which will need to be detailed in 
the protocol.
Please note that data collection for the PFS2 is limited to the date of progression and not specific 
read of the tumor assessments.


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


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Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression.
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression.
3.2.7 Time to response
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed.
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 3.2.6. It is recommended that an 
analysis of all patients (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 
is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options.

at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV)

at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint.
Indicate in the protocol whether a subgroup analysis of responders only will be performed in 
addition to the full population analysis (which should be included as default).
3.2.8 Definition of start and end dates for time to event variables
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number.


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In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations.
Start dates
State in the protocol if date of randomization or date of start of treatment is to be used for all 
definitions. For randomized studies specify exactly where the randomization date comes from, 
e.g. from IVRS, or if start of treatment is used as randomization date. For non-randomized 
studies please specify which treatment start date is taken if more than one treatment is to be 
given.
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date.
For the calculation of duration of response the following start date should be used:

Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page).

Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease.
If applicable, if patients who discontinued due to ‘Disease progression’ are considered to be PD 
solely based on clinical deterioration, then add the following text in the protocol:
When there is no documentation of radiologic evidence of progression, and the patient 
discontinued for ‘Disease progression’ due to documented clinical deterioration of disease, the 
date of discontinuation is used as date of progression.

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 3.2.10).
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.
In comparative studies with long follow-up period and therefore extended visit schedule, it may 
be useful to collect the survival status at a pre-specified cut-off within a limited timeframe for 
all patients with no documented death. In this case, this requires a contact to be made with the 
patient or with any reliable source of information on the patient’s status, but not requiring a 
specific visit to be scheduled

Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
If this is applicable for the study, it should be specified in the protocol if new cancer therapy is 
considered an event or endpoints are censored.
3.2.9 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.
The protocol should state clearly whether patients with non-measurable disease only at baseline 
will be allowed into the study. If patients with non-measurable disease only are allowed to be 
enrolled then the statistical section should describe clearly how data from these patients will be 
incorporated into the primary analysis and main analyses of the key secondary endpoints. In 
studies where presence of measurable disease is expected to have a relatively large impact on 
the primary endpoint, this factor can even be considered as a stratification factor in the 
randomization process.
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.
For studies which specifically exclude patients with non-measurable disease only at baseline 
the pre-specified analysis plan should describe how to handle data from these types of patients 
if they are enrolled by error or if central readers do not identify measurable disease despite 
investigators having declared the contrary, or conversely perhaps they do identify measurable 
disease when it has not been identified at the local site. It is recommended for these types of 
studies that patients with non-measurable disease identified through the local site evaluation be 
included in the list of protocol violations. However, decisions on exclusion from a per protocol 
analysis should relate to whether the patient has measurable disease according to the primary 
data source. For example, if the primary data source is from a central independent review then 
patients with non-measurable disease only according to this central review should be excluded 
from the relevant per protocol analyses.


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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 non-
measurable disease is derived slightly differently according to Table 3-1.
Table 3-1
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 2.4
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”.
Study teams may also want to perform sensitivity analyses excluding patients from the analysis 
of ORR (e.g. possibly as part of a per-protocol type analysis). Similar considerations should be
given to other endpoints which rely on a clear distinction being made between a PR and a SD 
response.
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 
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.
3.2.10 Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well as addresses 
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a 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.


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Based on definitions outlined in Section 3.2.8, 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:
Table 3-2
Options for event dates used in PFS, TTP, duration of response
Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently in 
the protocol or RAP
Outcome
A
No baseline assessment
(1) Date of randomization/start of treatment3
Censored
B
Progression at or before next scheduled 
assessment
(1) Date of progression
(2) Date of next scheduled assessment2
Progressed
Progressed
C1
Progression or death after exactly one 
missing assessment
(1) Date of progression (or death)
(2) Date of next scheduled assessment2
Progressed
Progressed
C2
Progression or death after two or more 
missing assessments
(1) Date of last adequate assessment2
(2) Date of next scheduled assessment2
(3) Date of progression (or death)
Censored
Progressed
Progressed
D
No progression
(1) Date of last adequate assessment
Censored
E
Treatment discontinuation due to ‘Disease 
progression’ without documented 
progression, i.e. clinical progression based 
on investigator claim
(1) Ignore clinical progression and follow 
situations above
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
As per above 
situations
Progressed
F
New anticancer therapy given
(1) Ignore the new anticancer therapy and 
follow situations above (ITT approach)
(2) Date of last adequate assessment prior to 
new anticancer therapy
(3) Date of secondary anti-cancer therapy
(4) Date of secondary anti-cancer therapy
As per above 
situations
Censored
Censored
Event
G
Deaths due to reason other than 
deterioration of ‘Study indication’
(1) Date of last adequate assessment
Censored 
(only TTP and 
duration of 
response)
=Definitions can be found in Section 3.2.8
=After the last adequate tumor assessment.“Date of next scheduled assessment” is defined in Section 3.2.8.
=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/DoR analysis. For example, 
palliative radiotherapy given in the trial for analgesic purposes or for lytic lesions at risk of 
fracture will not be considered as cancer therapy for the assessment of BOR and PFS analyses. 
The protocol should clearly state the local treatments which are not considered as antineoplastic 
therapies in the PFS/TTP/DoR analysis.
The protocol should state that tumor assessments will be performed every x weeks until 
radiological progression irrespective of initiation of new antineoplastic therapy. It is strongly 
recommended that a tumor assessment is performed before the 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 3-2 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition:


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
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.
4
Data handling and programming rules
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates).
4.1
Study/project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation.
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock).
4.2
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 7 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


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
No longer requires treatment

Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given)
Death is a reason which “must” lead to discontinuation of the patient from the trial.
4.3
End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up.
Patients may provide study phase completion information for one of the following reasons:

Adverse event

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

Progressive disease

Study terminated by the sponsor
4.4
Medical validation of programmed overall lesion response
In order to be as objective as possible, the RECIST programmed calculated response assessment 
is very strict regarding measurement methods (i.e. any assessment with more or less sensitive 
method than the one used to assess the lesion at baseline is considered UNK) and not available 
evaluations (i.e. if any target or non-target lesion was not evaluated the whole overall lesion 
response is UNK unless remaining lesions qualified for PD). This contrasts with the slightly 
more flexible guidance given to local investigators (and to the central reviewers) to use expert 
judgement in determining response in these types 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 the 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.


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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.
4.5
Programming rules
The following should be used for programming of efficacy results:
4.5.1 Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
4.5.2 Incomplete assessment dates
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 3.2.8). If all measurement dates have no day 
recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
4.5.3 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.
4.5.4 Non-target lesion response
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’.
4.5.5 Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
4.5.6 Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page.


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For survival the following censoring reasons are possible:

Alive

Lost to follow-up
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:

Ongoing without event

Lost to follow-up

Withdrew consent

Adequate assessment no longer available*

Event documented after two or more missing tumor assessments (optional, see Table 3-2)

Death due to reason other than underlying cancer (only used for TTP and duration of 
response)

Initiation of new anti-cancer therapy
*Adequate assessment is defined in Section 3.2.8. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted:

This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when 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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5
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.

SAP_001.pdf: 
Clinical Development
BYL719 (alpelisib)
Study number: CBYL719X2402 / NCT03056755
A phase II, multicenter, open-label, three-cohort, non-comparative study to assess 
the efficacy and safety of alpelisib plus fulvestrant or letrozole in patients with 
PIK3CA mutant, hormone receptor (HR) positive, HER2-negative advanced breast 
cancer (aBC), who have progressed on or after prior treatments
Statistical Analysis Plan (SAP)
Author:
Trial statistician,
Document type:
SAP Documentation
Document status:
Amendment 4
Release date:
24-Mar-2022
Number of pages:
54
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 final version of SAP
Date
Time point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
20-Jun-2017
Prior to DB 
lock
Creation of final 
version
N/A - First version
NA
06-Dec-2018
Prior to DB 
lock
Protocol 
amendment
Change is study design 
to 
include 
premenupausal women 
Section 1.1
Addition 
of 
interim 
analysis (IA)
Section 1.1
Rule of data-cut off for 
IA was added
Section 2.1
Q1 and Q3 was added 
in the list of summary 
statistics
Section 2.1
Change of definition of 
investigational 
drug, 
Date 
of 
first 
administration of study 
treatment, Date of last 
administration of study 
treatment, Last date of 
exposure 
to 
study 
drug/treatment
Section 2.1
Child bearing status at 
baseline was added in 
demography
Section 2.3
Clarfication 
of 
few 
definition and removed 
some redundant text 
General
Removed a part of 
analysis on ANP
Section 2..2
Removed 
figure 
on 
hepatic function test
Section 2.8.3
Added section on IA 
with analysis to be 
Section 2.14


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Date
Time point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
performed during the 
IA
Updated one criteria 
number of PPS from 
TR02 to TR26.
07-Nov-
2019
Prior 
DB 
lock
Protocol 
amendment 3 & 
4
Study 
design 
was 
updated 
to 
include 
Cohort C  and second 
IA was added as per 
protocol amendment 3.
Section 1.1
Study objective was 
updated 
to 
include 
Cohort C and Overall 
survival was added as 
secondary objective.
Section 1.2
Updated the wording 
for the analysis cut-off 
date for the second 
interim analysis and for 
the primary analysis.
Second 2.1
Defintion of PPS was 
updated and deleted the 
numbering. 
Section 2.2
Subgroup analysis was 
updated to focus on 
specific variables for 
primary endpoint, PFS, 
overall response rate, 
and clinical benefit rate. 
Section 2.2.1
Updated analysis 
to 
include Cohort C.
Section 2.5
Overall survival was 
added 
to 
secondary 
objective.
Section 2.7
Second IA was added to 
IA plan.
Section 2.14
Sample size calculation 
was updated with at 
Section 3.1


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Date
Time point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
least 112 patients per 
cohort with one-sided 
2.5% significance level 
and 95% power.
03-Mar-
2021
Prior to DB 
lock
Addition   
analyses 
to 
describe 
and 
assess 
the 
impact 
of 
COVID-19 
pandemic.
Added new protocol 
deviation for COVID-
19 related PDs.
Section 
2.3 
Protocol 
deviations 
Added 
sensitivity 
analysis for primary 
endpoint and COVID-
19 related AEs table.
Section 
4.1 
Impact 
of 
COVID-19
24-Mar-
2022
Prior to DB 
lock
Protocol 
amendment 5
Study design/objectives
was updated to include 
extension phase  and 
third IA was added as 
per 
protocol 
amendment 5.
Section 
1.1, 
Table 
1-1, 
Section 
2.7, 
Section 2.14, 
Section 3.1
Data 
analysis 
was 
updated 
to 
include 
extension phase  and 
third IA was added as 
per 
protocol 
amendment 5.
Section 
2.1, 
Section 2.8.5
Updated 
List 
of 
Abbreviations.
Updated
the
“last 
contact 
date 
data 
sources” .
Table 2-1
Updated the Safety set 
and 
Safety 
set 
in 
Extension Phase
Section 
2.2, 
Section 2.4
Updated
the
Demographics 
subgroup
Section 2.2.1


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Date
Time point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
Updated the Patient 
disposition and Patient 
disposition 
in 
Extension Phase
Section 2.3
Clarified the definition 
of secondary efficacy 
endpoints
Section 2.7
Refer to the available oncology statistical guidance documents as appropriate for oncology


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Table of contents
Table of contents .................................................................................................................6
1
Introduction .......................................................................................................................11
1.1
Study design...........................................................................................................11
1.2
Study objectives and endpoints .............................................................................14
2
Statistical methods.............................................................................................................15
2.1
Data analysis general information .........................................................................15
2.1.1
General definitions................................................................................16
2.2
Analysis sets ..........................................................................................................21
2.2.1
Subgroup of interest ..............................................................................23
2.3
Patient disposition, demographics and other baseline characteristics ...................24
2.3.1
Patient disposition.................................................................................25
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................26
2.4.1
Study treatment / compliance................................................................26
2.4.2
Prior, concomitant and post therapies...................................................30
2.5
Analysis of the primary objective..........................................................................31
2.5.1
Primary endpoint...................................................................................31
2.5.2
Statistical hypothesis, model, and method of analysis..........................32
2.5.3
Handling of missing values/censoring/discontinuations.......................32
2.5.4
Supportive analyses...............................................................................32
2.6
Analysis of the key secondary objective ...............................................................33
2.7
Analysis of secondary efficacy objective(s)..........................................................33
2.7.1
Secondary endpoints .............................................................................33
2.7.2
Statistical hypothesis, model, and method of analysis..........................35
2.7.3
Handling of missing values/censoring/discontinuations.......................36
2.8
Safety analyses.......................................................................................................38
2.8.1
Adverse events (AEs)............................................................................38
2.8.2
Deaths....................................................................................................39
2.8.3
Laboratory data .....................................................................................39
2.8.4
Other safety data ...................................................................................40
2.9
Pharmacokinetic endpoints....................................................................................43
2.10
PD and PK/PD analyses.........................................................................................43
2.11
Patient-reported outcomes .....................................................................................43
43
2.13
Other Exploratory analyses....................................................................................47


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Interim analysis......................................................................................................47
3
Sample size calculation .....................................................................................................48
3.1
Primary analysis.....................................................................................................48
4
Change to protocol specified analyses ..............................................................................48
4.1
Impact of COVID-19.............................................................................................48
5
Appendix  1 .......................................................................................................................50
5.1
Imputation rules.....................................................................................................50
5.1.1
Study drug.............................................................................................50
5.1.2
AE, ConMeds and safety assessment date imputation..........................51
5.2
AEs coding/grading ...............................................................................................52
5.3
Laboratory parameters derivations ........................................................................52
5.4
Statistical models...................................................................................................53
5.4.1
Primary analysis....................................................................................53
6
Reference...........................................................................................................................54


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List of abbreviations
aBC
AE
Advanced Breast Cancer
Adverse Event
AESI
AI
ALP
ALT
AST
Adverse Event of Special Interest
Aromatase Inhibitor
Alkaline Phosphatase
Alanine Aminotransferase/Glutamic Pyruvic Transaminase/GPT
Aspartate Aminotransferase/Glutamic Oxaloacetic Transaminase/GOT
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
bid
BC
BMI
bis in diem/twice a day
Breast Cancer
Body Mass Index
BOR
Best Overall Response
CI
Confidence Interval
CBR
CDK4/6
CDKi
CLIA
Clinical Benefit Rate
Cyclin-Dependent Kinases 4 and 6
Cyclin-Dependent Kinase inhibitor
Clinical Laboratory Improvement Amendments
CR
Complete Response
CRO
Contract Research Organization
CSR
Clinical Study report
CT
Computed Tomography
CTC
Common Toxicity Criteria
CTCAE
ctDNA
Common Terminology Criteria for Adverse Events
Circulating Tumor Deoxyribonucleic Acid
DAR
Dosage Administration Record
DI
Dose Intensity
DMC
DNA
DOR
Data Monitoring Committee 
Deoxyribonucleic Acid
Duration of Response
ECG
ECHO
Electrocardiogram
Echocardiogram
ECOG
eCRF
EDC
Eastern Cooperative Oncology Group
Electronic Case Report/Record Form; the term CRF can be applied to either EDC 
or Paper
Electronic Data Capture
EOT
EOS
ER
ET
End of Treatment
End of Study
Estrogen Receptor
Endocrine Therapy
FAS
FDA
Full Analysis Set
Food and Drug Administration


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FG
FPFT
HbA1c
Fasting Glucose
First Patient First Treatment
Glycosylated Hemoglobin
HER2
Human Epidermal Growth Factor Receptor 2
HR
HR+
Hormone Receptor
Hormone Receptor Positive
IA
ICF
IHC
Interim Analysis
Informed Consent Form
Immunohistochemistry
IRT
LPFT
LPLT
LPLV
LVEF
mBC
Interactive Response Technology
Last Patient First Treatment
Last Patient Last Treatment
Last Patient Last Visit
Left Ventricular Ejection Fraction
Metastatic Breast Cancer
MedDRA
Medical Dictionary for Regulatory Activities
mFAS
MRI
MUGA
Modified Full Analysis Set 
Magnetic Resonance Imaging
Multiple Gated Acquisition
NCI
National Cancer Institute
Next Generation Sequencing
o.d.
Once Daily
ORR
OS
Overall Response Rate
Overall Survival
PD
PDI
PFS
PFS2
PgR
PI3K
PIK3CA
Progressive Disease
Planned Dose Intensity
Progression-Free Survival
Progression-Free Survival in next-line treatment
Progesterone Receptor
Phosphatidylinositol-3-kinase
Gene which encodes the p110alpha catalytic subunit of PI3K
PK
Pharmacokinetics
PPS
PR
Per-Protocol Set
Partial Response
PROS
PS
PSDS
PT
Patient-reported Outcomes
Performance Status
Post-Study Drug Supply
Preferred Term
qd
QoL
Qua’que di’e / once a day
Quality of Life
QTcF
QT interval corrected by Fridericia method
RECIST
RDI
Response Evaluation Criteria in Solid Tumors 
Relative Dose Intensity
SAE
SAP
Serious Adverse Event
Statistical Analysis Plan


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SD
SMQ
Stable Disease
Standardized MedDRA Queries
SOC
TA
TEAE
TFLs
TBL
ULN
WBC
WHO
WoC
System Organ Class
Tumor Assessment
Treatment-emergent Adverse Event
Tables, Figures, Listings
Total Bilirubin
Upper Limit of Normal
White Blood Cell
World Health Organization
Withdrawal of Consent


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the Clinical Study Report 
(CSR) of study CBYL719X2402, a phase II, multicenter, open-label, three-cohort, non-
comparative study to assess the efficacy and safety of alpelisib plus fulvestrant or letrozole in 
patients with PIK3CA mutant, hormone receptor (HR) positive, HER2- negative advanced 
breast cancer (aBC), who have progressed on or after prior treatments.
The content of this SAP is based on protocol CBYL719X2402 V05. All decisions regarding 
final analysis, as defined in the SAP document, have been made prior to database lock.
1.1
Study design
This is a phase II, multicenter, open-label, three-cohort, non-comparative study of alpelisib plus 
endocrine therapy (either fulvestrant or letrozole) in patients with HR+, HER2-negative aBC 
harboring PIK3CA mutation(s) in the tumor whose disease has progressed on or after prior 
treatments. Gonadal suppression must be achieved with either goserelin or leuprolide in men
(cohort B) and premenopausal women patients.
Patients must have the PIK3CA mutation to be eligible for the trial. Patients will be required to 
sign a molecular pre-screening consent to have their mutational status either analyzed by 
providing adequate tumor tissue or if PIK3CA status is known, providing tumor tissue to 
confirm PIK3CA mutational status using a Novartis designated central laboratory. This will be 
conducted during a pre-screening phase prior to enrolling into the trial by Day -21. 
Approximately 1300 patients are expected to be pre-screened to identify PIK3CA mutational 
status. Those patients that harbor the PIK3CA mutation are eligible for the study and will then 
have the opportunity to sign the main ICF to begin screening procedures to determine eligibility.
Overall approximately 340 patients (112 in each cohort), with HR+, HER2-negative aBC 
harboring a PIK3CA mutation in tumor tissue, that has progressed on or after prior treatments 
are expected to be enrolled.
The study will be composed of 2 phases:
Core Phase: includes treatment phase for all patients from First Patient First Treatment (FPFT) 
until 18 months post Last Patient First Treatment (LPFT) + 1 month Safety follow-up (total 19 
months post LPFT)
Extension Phase: includes treatment phase starting at the end of the treatment Core Phase until 
Last Patient Last Visit (LPLV) (up to 12 months); The extension treatment phase is only for 
patients who are continuing to benefit from treatment at the end of the Core Phase who are not 
eligible for PSDS (Post-Study Drug Supply) in their country based on local regulations. Patients 
will continue on their existing treatment assigned in the Core Phase until discontinuation or 
Last Patient Last Treatment (LPLT) of the Extension Phase. Note: If PSDS becomes available 
for a patient, the patient should be discontinued from the study and access treatment via PSDS.
Patients who are benefiting from treatment and are eligible for PSDS will exit the trial at the 
end of the Core Phase.At the start of the Core Phase, patients will be assigned to a cohort based 
on previous therapy (AI or fulvestrant) as indicated below:


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Cohort A: Patients who received any CDK 4/6 inhibitor plus any AI as immediate prior 
treatment will receive alpelisib + fulvestrant
Cohort B: Patients who received any CDK 4/6 inhibitor plus fulvestrant as immediate prior 
treatment will receive alpelisib + letrozole
Cohort C: Patients who received systemic chemotherapy or ET (as monotherapy or in 
combination with targeted treatment except CDK 4/6i + AI) as immediate prior treatment will 
receive alpelisib + fulvestrant
Note: In Cohort C, ET includes letrozole, fulvestrant and CDK4/6 inhibitor plus fulvestrant.
Figure 1-1
Study Design
Treatment crossover between cohorts will not be permitted in this study.
The primary objective of the study is to assess the proportion of patients who are alive without 
disease progression at 6 months based on local investigator assessment per RECIST v1.1
separately in Cohorts A and C (alpelisib in combination with fulvestrant) and Cohort B 
(alpelisib in combination with letrozole) among patients with HR+, HER2-negative aBC 
harboring a PIK3CA mutation who have progressed on or after prior treatments. 


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The primary analysis for each cohort will be performed 6 months after the last patient enrolled 
in that specific cohort has started treatment. The final analysis will be performed after LPLV of 
the study which include cumulative data (eg safety and clinical benefit) since the start of Core 
Phase for the patients who enter the Extension Phase.
Prior to the final analysis, cohort specific analyses maybe performed when all patients included 
in the corresponding cohort have approximately 18 months of follow-up.
Three Interim Analyses (IA) are planned for this study. The first IA will be performed after at 
least
patients receiving alpelisib plus fulvestrant (cohort A) have at least 6 months of follow 
up. The second IA will be performed when approximately
patients (50% enrolled patients) 
have been treated in the study (regardless of cohort) and have at least 6 months of follow-up.
The third IA will be performed after the Core Phase has ended.


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1.2
Study objectives and endpoints
Table 1-1
Study objectives
Objective
Endpoint
Analysis
Primary
Refer to Section 2.5
To assess the proportion of 
patients who are alive without 
disease progression at 6 months 
based on local investigator 
assessment per RECIST v1.1 in 
cohorts A and C (alpelisib in 
combination with fulvestrant) and 
cohort B (alpelisib in combination 
letrozole) among patients with 
HR+, HER2-negative aBC 
harboring a PIK3CA mutation who 
have progressed on or after prior 
treatments.
The primary endpoint of this study 
is the proportion of patients who 
are alive without disease 
progression at 6 months based on 
local investigator assessment 
using RECIST v1.1 in each cohort
Secondary
Refer to Section 2.7
To assess PFS based on local 
investigator assessment for each 
cohort.
PFS based on local investigator 
assessment using RECIST v1.1 in 
each cohort
To assess PFS on next-line 
treatment (PFS2) for each cohort.
PFS2 based on local investigator 
assessment in each cohort
To assess overall response rate 
(ORR) and clinical benefit rate 
(CBR) based on local investigator 
assessment for each cohort.
ORR based on local investigator’s 
assessment according to RECIST 
v1.1 in each cohort
Clinical Benefit Rate (CBR) based 
on local investigator’s assessment 
according to RECIST v1.1 in each 
cohort
To assess duration of response 
(DOR) in patients with confirmed 
complete response (CR) or PR for 
each cohort.
Duration of Response is the time 
from the date of first documented 
response (confirmed CR or PR) to 
the date of first documented 
progression or death
To assess Overall Survival (OS) 
for each cohort
Overall Survival is defined as the 
time of start of treatment to date of 
death or lost to follow-up.
To evaluate the safety and 
tolerability of the combination for 
each cohort.
Type, frequency and severity of 
adverse events per CTCAE v4.03
Type, frequency and severity of 
laboratory toxicities per CTCAE 
v4.03


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To evaluate clinical benefit as 
assessed by the Investigator 
during the Extension Phase
Proportion of patients with clinical 
benefit as assessed by the 
Investigator at scheduled visits
2
Statistical methods
2.1
Data analysis general information
The final analysis will be performed by Novartis and/or a designated CRO. SAS version 9.4 or 
later software will be used to perform all data analyses and to generate tables, figures and 
listings.
Data included in the analysis
The analysis cut-off date for the first interim analysis of study data will be established after at 
least
patients receiving Alpelisib + Fulvestrant (cohort A) have at least 6 months of follow-
up. The analysis cut-off date for the second interim analysis of study data will be established 
after at least 
patients have been treated (regardless of cohort) and have at least 6 months of 
follow-up on study. The third IA will be performed after the Core Phase has ended.
The analysis cut-off date for the primary analysis of each cohort will be established 6 months 
after the last patient enrolled in that cohort has started treatment. The final analysis will be 
performed after LPLV of the study which include cumulative data (eg safety and clinical benefit) 
since the start of Core Phase for the patients who enter the Extension Phase.
All statistical analyses will be performed using all data collected in the database up to the data
cutoff 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 
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All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘ongoing’. 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.
General analysis conventions
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of patients enrolled at centers, no center effect 
will be assessed. Protocol deviations, number of patients in analysis populations and 
discontinuations from study treatment will be summarized by country.
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables
separately for each cohort a missing category will be included as applicable. Percentages will 
be calculated using the number of patients in the relevant population or subgroup as the
denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e. mean, standard deviation, Q1, median, Q3, minimum, and maximum) separately 
for each cohort.
2.1.1
General definitions
Investigational drug and study treatment
Investigational drug, will refer to the alpelisib (BYL719) only. Whereas, study treatment will 
refer to the combination drugs and includes investigational drug (alpelisib) as well as fulvestrant 
or letrozole and for men (cohort B) and premenopausal women goserelin or leuprolide as 
applicable in each of the study cohorts. Cohorts A and C include alpelisib/fulvestrant and cohort 
B includes alpelisib/letrozole.
The term investigational treatment may also be referred to as study treatment which is used 
througouht this document.
The term study drug can be used to refer to investigational and components of study treatment
(fulvestrant or letrozole alpelisib and for men (cohort B) and premenopausal women goserelin
or leuprolide as applicable). 
Date of first administration of investigational drug
The date of first administration of investigational drug is defined as the first date when a non-
zero dose of investigational drug is administered and recorded on the Dosage Administration 
Record (DAR) Electronic Case Report Form (eCRF) . The date of first administration of study 
drug will also be referred as start of investigational drug.
Date of last administration of investigational drug
The date of last administration of investigational drug is defined as is the last date when a 
nonzero dose of investigational drug is administered and recorded on DAR eCRF. The date of 
last administration of investigational drug will also be referred as end of investigational drug.


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Date of first administration of study treatment 
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of any component of study treatment
(alpelisib or letrozole/fulvestrant
or 
goserelin/leuprolide for men (cohort B) and premenopausal women as applicable) was 
administered as per the Dosage Administration (e)CRF. Example: if 1st dose of alpelisib is 
administered on 05-Jan-2015, and 1st dose of fulvestrant is administered on 03-Jan-2015, then 
the date of first administration of study treatment is on 03-Jan-2015.
The date of first administration of study treatment will also be referred as start of study 
treatment.
Date of last administration of study treatment 
The date of last administration of study treatment is derived as the last date when a nonzero 
dose of any component of study treatment was administered as per Dose Administration
(e)CRF. Example: if the last alpelisib dose is administered on 15-Apr-2014, and the last dose 
of letrozole is administered on 17-Apr-2014, then the date of last administration of study 
treatment is on 17-Apr-2014. The date of first administration of study treatment will also be
referred as start of study treatment.
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 or letrozole/fulvestrant. The last date of exposure to study drugs will 
be derived as follows. 
Alpelisib and letrozole
Alpelisib and letrozole are administered daily on a continuous once daily dosing schedule.
Hence, the last date of exposure to alpelisib or letrozole is the date of last administration of
alpelisib or letrozole, respectively.
Fulvestrant
Fulvestrant is administered on 
1. Cycle 1 Day 1
2. Cycle 1 Day 15, and
3. 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)].


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
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:

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.
Goserelin and Leuprolide
Goserelin and leuprolide were administered (for pre menopausal women and men (cohort B)) 
on the first day of every cycle (e.g. Cycle 1 Day 1, Cycle 2 Day 1 etc.) 
The last date of exposure to Goserelina or leuprolide is calculated as follows:

(last date of administration of Goserelina or leuprolide) + (length of time interval -
1) i.e. [last date of Goserelina or leuprolide administration+ (28-1)].

If the patient died or was lost to follow-up within last date of administration of 
Goserelina or leuprolide + 27 days, the last date of exposure to Goserelina or leuprolide 
is the date of death or the date of last contact, respectively.
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date. 
The study day is defined as:
The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date + 1 if event is on or after the reference start date;

The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date if event precedes the reference start date.
The reference date for all assessments (safety, efficacy,  etc) is the start of any component of 
the study treatment. 


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Time unit
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375.  If duration is reported in 
years, duration in days will be divided by 365.25.
Baseline
For safety and efficacy evaluations, the last available assessment on or before the date of start 
of study treatment is defined as “baseline” assessment.
If patients have no value as defined above, the baseline result will be missing.
On-treatment assessment/event and observation periods
For adverse event reporting the overall observation period will be divided into three mutually 
exclusive segments: 

pre-treatment period: 
from day of patient’s informed consent to the day before first administration of study 
treatment.

on-treatment period: 
from date of first administration of study treatment to 30 days after date of last actual 
administration of any study treatment (including start and stop date).

post-treatment period: 
starting at day 31 after last administration of study treatment.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).  
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment and post-treatment period will be flagged.
Windows for multiple assessments 
In order to summarize laboratory parameteres, vital sign and other data collected over time 
(including unscheduled visits), the assessments will be time slotted. The following general rule
will be applied in creating the assessment windows: 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 earlier of the 2  
assessments will be used. If multiple assessments on the same date then the worst case will be 
used.  Data from all assessments (scheduled and unscheduled), including multiple assessments, 
will be listed.


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Time windows for laboratory assessments
Assessment
Target day of assessment
Time Interval
Baseline
        
≤ Day 1 
Cycle 1 Day 8
8
Day 2 to day 11
         Cycle 1 Day 15
15
Day 12 to day 21
Cycle 2 Day 1
29
Day 22 to day 42
Cycle 3 Day 1
57
Day 43 to day 63
Cycle 3 Day 15
71
Day 64 to day 77
Cycle 4 Day 1
85
Day 78 to day 98
Cycle k Day 1 (k≥5)
d=(k-1)*28+1
Day d-14 to day d+13
End of Treatment
Assessment taken at the 
end of treatment visit
Last contact date 
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the last complete date among the following:
Table 2-1
Last contact date data sources
Source data
Conditions
Date of Enrollment
No condition
Last contact date/last date patient was known to 
be alive from Survival Follow-up page 
- Patient status is reported to be alive, lost to 
follow-up or unknown.
Start/End dates from further antineoplastic 
therapy
Non-missing medication/procedure term.
Start/End* dates from drug administration record 
Non-missing dose. Doses of 0 are allowed.
End of treatment date from end of treatment 
page
No condition
Tumor (RECIST) assessment date
Evaluation is marked as ‘done’.
Laboratory/PK
collection dates
Sample collection marked as ‘done’ or non-
missing sample collection dates. 
Vital signs date
At least one non-missing parameter value
Performance Status date
Non-missing performance status
Start/End dates of AE 
Non-missing verbatim term
Withdrawal of informed consent date
No condition


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The last contact date is defined as the latest complete date from the above list on or before the 
data cut-off date. 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. 
2.2
Analysis sets
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
and who received one dose of study treatment. Patients will be analyzed according to the 
treatment they have been assigned to. 
Modified full analysis set
The modified Full Analysis Set (mFAS) comprises all patients of the FAS population who have 
PI3KCA mutation confirmed by a Novartis designated laboratory. The mFAS will be the 
primary population for the analysis of efficacy endpoints. 
Per protocol set (PPS) 
The Per-Protocol Set (PPS) consists of a subset of the patients in the mFAS who are compliant 
with requirements of the CSP.
The following list of protocol deviations will lead to exclusion of the patient from the Per-
Protocol Set:

Patient has received prior treatment with PI3K inhibitors.  

Patient does not have a PIK3CA mutation that can be confirmed by a sample that can 
be provided to a Novartis designated laboratory ( with >10% tumor tissue (15 slides 
minimum from a surgical specimen, or 20 slides minimum from a biopsy) OR Patient 
does not have a pathology report confirming PI3KCA mutation status by a CLIA 
certified laboratory (Using comparable PCR Tissue Mutation Assay) and  cannot 
provide a tumor sample (either archival or newly obtained) collected after the most 
recent progression or recurrence for PIK3CA mutation for confirmation by a Novartis 
designated laboratory. 

Unconfirmed diagnosis of HER2-negative aBC as defined by a negative in situ 
hybridization test or IHC.

Patient does not have a histologically and/or cytologically confirmed diagnosis of ER+ 
and/or PgR+ breast cancer by local laboratory. 

Patients are not: Diagnosed with aBC, with documented evidence of progression on or 
after CDK 4/ 6 inhibitor treatment. (Note: CDK 4/6 inhibitor has to be the last treatment 
regimen prior to study entry. Patients who received one prior chemotherapy for aBC 
(either in the adjuvant or metastatic setting) are allowed.  Only one other prior 
anticancer therapy, e.g. tamoxifen, fulvestrant is allowed. The maximum number of 


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prior therapies for aBC or mBC is limited to two. Patients must have recovered to grade 
1 or better from any adverse events (except alopecia) related to previous therapy prior 
to study entry). AI treatment and received systemic chemotherapy or ET are as last 
treatment regimen in cohort C. 

Patients do not have either: Measurable disease, at least one measurable lesion as per 
RECIST v1.1 criteria  or If no measurable disease is present, then at least one 
predominantly lytic bone lesion must be present

Patient has an ECOG performance status greater than 2 or ECOG missing

Patient did not provide main study informed consent

Patient enrolled in the wrong treatment cohort 

Patient who has been enrolled but not taken any dose of study drug 

Concurrent other anti-cancer therapy, or investigational therapy except palliative 
therapy, while on study treatment 

Concurrent treatment with prohibited drugs as per Protocol which puts patients under 
significant risk (please refer the Protocol section for Prohibhited Medication) 
Safety Set
The Safety set includes all patients who received at least one dose of any component of the 
study treatment. Patients will be analyzed according to the study treatment actually received.
The actual treatment received corresponds to:
1. the assigned treatment if patients took at least one dose of that treatment.
2. the first treatment received if the assigned treatment was never received.
Safety Set in Extension Phase
The Safety set in Extension Phase includes all patients who received at least one dose of any 
component of the study treatment in Extension Phase. Patients will be analyzed according to 
the study treatment actually received.
The actual treatment received corresponds to:
1. the assigned treatment if patients took at least one dose of that treatment.
2. the first treatment received if the assigned treatment was never received.
Patient Classification: 
Patients may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific patient classification rules defined in Table 
2-2.


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Table 2-2
Patient classification based on protocol deviations and non-PD 
criteria
Analysis set
Protocol deviations leading 
to exclusion
Non 
protocol 
deviation 
leading to exclusion
FAS 
No written inform consent
No dose of study treatment 
recieved.
mFAS
No written inform consent
PI3KCA 
mutation 
not 
confirmed by a Novartis 
designated laboratory and no 
dose of study treatment 
recieved.
Safety set
No written inform consent
No dose of study treatment
Safety set in Extension Phase
No written inform consent
No dose of study treatment in 
Extension Phase
Per-protocol set
Any major protocol deviation
as listed in definition of per 
protocol set (see definition of 
PP set)
Patient not evaluable for 
mFAS
Withdrawal of Informed Consent
Any data collected in the clinical database after a patients withdraws informed consent from all 
further participation in the trial, will not be included in the analysis.  The date on which a patient 
withdraws full consent is recorded in the eCRF. 
2.2.1
Subgroup of interest
The primary efficacy endpoint, progression free survival (PFS), overall response rate (ORR) 
and clinical benefit rate (CBR) will be summarized for the following subgroups. The subgroup 
analyses will be based on the mFAS:

Demography
–
Age >=65 vs age <65 years 
–
Gender (if more than 10 in men)
–
Ethnicity (white vs Asian vs black vs. other)

Prior Medication History
–
Line of advanced anti-cancer treatment in any setting (1st line vs. 2nd line)
–
Prior chemotherapy use (adjuvant vs neoadjuvant vs. no prior use)
–
Patient population based on endocrine status and line of therapy:
a.
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 (yes vs. no)


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b. 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 (yes vs. no)

Disease Characteristics
–
Number of metastatic sites (<3 vs. >=3)
–
Visceral disease (Yes vs. No)
–
Bone lesions only (Yes vs. No)
–
PTEN loss of expression (Loss of expression vs. No loss of expression) 
2.3
Patient disposition, demographics and other baseline 
characteristics
The FAS will be used for all baseline and demographic summaries. 
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed by 
cohort. Categorical data (e.g. gender, age groups: <65 and ≥ 65 years, race, ethnicity, Child 
bearing status, ECOG performance status) will be summarized by frequency counts and 
percentages; the number and percentage of patients with missing data will be provided. 
Continuous data (e.g. age, weight, height, body mass index) will be summarized by descriptive 
statistics (N, mean, median, standard deviation, Q1, Q3, minimum and maximum). BMI (kg/m²) 
will be calculated as weight[kg] / (height[m]²) using weight and height at Baseline.
Diagnosis and extent of cancer 
Summary statistics will be tabulated for diagnosis and extent of cancer. This analysis will 
include the following: primary site of cancer, details of tumor histology/cytology, histological 
grade, stage at initial diagnosis, time since initial diagnosis, time from initial diagnosis to first 
recurrence/progression (in months), time since most recent relapse/progression to start of 
treatment (in months), stage at time of study entry, presence/absence of target and non-target 
lesions, number and type of metastatic sites involved, HER2 receptor status,  estrogen receptor 
(ER) status,  progesterone receptor (PgR) status and hormone receptor (ER and/or PgR) status.  
Note: Presence/absence of target and non-target lesions will be based on the data collected on 
RECIST target/non-target lesion assessment eCRF pages. Metastatic sites will be based on 
diagnosis page.
Medical history and ongoing conditions
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
entered on (e) CRF will be summarized and listed by cohort. Separate summaries will be 
presented for ongoing and historical medical conditions.  The summaries will be presented by 
primary system organ class (SOC), preferred term (PT) and cohort. Medical history and current 
medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology. The MedDRA version used for reporting will be specified in the CSR 
and as a footnote in the applicable tables/listings.


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Other
All data collected at baseline will be listed.
2.3.1
Patient disposition
Enrollment by country will be summarized for all screened patients and also by cohort using 
the FAS and repeated on the mFAS as appropriate. The number (%) of treated patients included 
in the FAS will be presented by cohort. The number (%) of screened and not-treated patients
and the reasons for screening failure will also be displayed. The number (%) of patients in the 
FAS who are still on treatment, who discontinued the study phases and the reason for 
discontinuation will be presented by cohort.
The following summaries will be provided (with % based on the total number of FAS patients):

Number (%) of patients who are still on-treatment (based on the ‘End of Treatment 
Phase’ page not completed); 

Number (%) of patients who discontinued the study treatment phase (based on the 
‘End of Treatment Phase’ page) 

Primary reason for study treatment phase discontinuation (based on the ‘End of
Treatment Phase’ page)

Number (%) of patients who have entered the post-treatment follow-up (based on 
the ‘End of Treatment Phase’ page);

Number (%) of patients who have discontinued from the post-treatment follow-up
(based on the Study Evaluation Completion/ End of Post-treatment follow-up
page);

Reasons for discontinuation from the post-treatment follow-up (based on Study 
Evaluation Completion/ End of Post-treatment follow-up page);
Note: post-treatment follow-up for patient disposition only refers to efficacy follow-
up.
2.3.2
Patient disposition in Extension Phase
Patient disposition in Extension Phase will be summarized using the Safety Set in Extension 
Phase. The following summaries will be provided:

Number (%) of patients who are still on-treatment in Extension Phase (based on 
the ‘End of Extension Treatment Phase’ page not completed); 

Number (%) of patients who discontinued the Extension study treatment phase 
(based on the ‘End of ExtensionTreatment Phase’ page) 

Primary reason for Extension study treatment phase discontinuation (based on the 
‘End of Extension Treatment Phase’ page)
Protocol deviations
The number (%) of patients in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the study Data Handling Plan) and by cohort. Protocol 
deviations leading to exclusion from analysis sets will be tabulated separately by cohort. All 
protocol deviations will be listed.


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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.
Analysis sets
The number (%) of patients in each analysis set (defined in Section 2.3) will be summarized by 
cohort.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity
(RDI) will be summarized by cohort, separately for each component of study treatment.
Duration of exposure will be categorized into time intervals; frequency counts and percentages 
will be presented for the number (%) of patients in each interval. The number (%) of patients 
who have dose reductions, interruptions or permanent discontinuations, and the reasons, will be 
summarized by cohort. 
Patient level listings of all doses administered on treatment along with dose change reasons will 
be produced.  
The safety set will be used for all summaries and listings of study treatment in Core Phase.
The safety set in Extension Phase will be used for all summaries and listings of study treatment
for the patients who enter the Extension Phase.  
Duration of exposure to study treatment
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to the investigational drug (alpelisib) and any combination partner, if applicable:
Duration of exposure to study treatment (days) = (last date of exposure to study treatment) –
(date of first administration of study treatment) + 1.
The last date of exposure to study treatment is the latest of the last dates of exposure to 
investigational drug or any combination partner (refer to Section 2.1.1).
Summary of duration of exposure of study treatment in appropriate time units will include 
categorical summaries (<2 months, 2-<4 months, 4-<6 months etc.) and continuous summaries 
(i.e. mean, standard deviation etc.) using appropriate units of time.
Duration of exposure to investigational drug and combination partner
Duration of exposure to investigational drug (days) = (last date of exposure to investigational 
drug) – (date of first administration of investigational drug) + 1.


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Duration of exposure to fulvestrant (days) = (last date of exposure to fulvestrant) – (date of first 
administration of fulvestrant) + 1. 
Duration of exposure to letrozole (days) = (last date of exposure to letrozole) – (date of first 
administration of letrozole) + 1. 
Duration of exposure to goserilin (days) = (last date of exposure to goserilin) – (date of first 
administration of goserilin) + 1. 
Duration of exposure to leuprolide (days) = (last date of exposure to leuprolide) – (date of first 
administration of leuprolide) + 1. 
The definition of last date of study drug exposure is defined in Section 2.1.1. 
Summary of duration of exposure of investigational drug (alpelisib) will include categorical 
summaries based on monthly intervals (<2 months, 2-<4 months, 4-<6 months etc.) and using 
descriptive statistics (mean, standard deviation etc).
Cumulative dose
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized for each of the study treatment components. 
The planned cumulative dose for a study treatment component refers to the total planned dose 
as per the protocol up to the last date of investigational drug administration. 
The planned cumulative dose is not summarized/listed. It is used for relative dose intensity 
calculations.
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the patient is on the study treatment as documented in the Dose Administration eCRF.
For patients who did not take any drug the cumulative dose is by definition equal to zero.
For continuous dosing, the actual cumulative dose is the sum of the non-zero doses recorded 
over the dosing period and the planned cumulative dose is the planned starting dose summed 
over the same dosing period.
For intermittent dosing, the actual cumulative dose should be defined based on the days when 
the patient is assumed to have taken a non-zero dose during dosing periods. 
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) = Actual Cumulative dose (dosing unit) / Duration of exposure 
to study treatment (unit of time).
For patients who did not take any drug the DI is by definition equal to zero. 
Planned dose intensity (PDI) is defined as follows:
PDI (dosing unit / unit of time = Planned Cumulative dose (dosing unit) / Duration of exposure 
(unit of time).
Relative dose intensity (RDI) is defined as follows:


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RDI = DI (dosing unit / unit of time)  / PDI (dosing unit / unit of time).  
In this study DI, PDI and Relative dose intensity (RDI) are defined here below for the each 
study drugs. 
Alpelisib:
-
DI (mg/day) = Cumulative dose (mg) / duration of exposure (days)
-
PDI is 300 mg/day
-
RDI (%) = DI (mg/day) / PDI (mg/day) *100
Letrozole:
-
DI (mg/day) = Cumulative dose (mg) / duration of exposure (days)
-
PDI is 2.5 mg/day
-
RDI (%) = DI (mg/day) / PDI (mg/day) *100
Fulvestrant, goserilin or leuprolide:
-
DI (mg/day) = Cumulative dose (mg) / duration of exposure (days)
DI and RDI will be summarized separately for each of the study treatment components, but 
using the duration of exposure of each of the components.
Dose reductions, interruptions or permanent discontinuations
The number of patients who have dose reductions, permanent discontinuations or interruptions, 
and the reasons, will be summarized separately for each of the study treatment components. 
‘Dose changed’, ‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the 
Dosage Administration CRF pages (DAR) will be used to determine the dose reductions, dose 
interruptions, and permanent discontinuations, respectively.
The corresponding fields ‘Reason for dose change/dose interrupted’ and ‘Reason for permanent 
discontinuation’ will be used to summarize the reasons.
A dose change is either ‘change in prescribed dose level’ or ‘dosing error’ where actual dose 
administered/total daily dose is different from the prescribed dose.
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption that are entered on consecutive days with different reasons will be counted as 
separate interruptions. However, if the reason is the same in this mentioned multiple entries on 
consecutive days, then it will be counted as one interruption. 
The last zero dose of alpelisib/placebo or fulvestrant is not considered as a dose interruption.
Reduction: A dose change where the prescribed dose level is lower than the previous prescribed 
dose level or where the actual dose administered/total daily dose is lower than the calculated 
dose amount based on the prescribed dose. Therefore any dose change to correct a dosing error 
will not be considered a dose reduction.  Only dose change is collected in the CRF, number of 
reductions will be derived programmatically based on the change and the direction of the change.


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For alpelisib, 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 in the case of aplelisib).
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 2-3
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 letrozole and 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. The established clinical dose of goserelin or 
leuprolide will be used in men and premenopausal women patients and no dose modification is 
planned in this study.
2.4.2
Prior, concomitant and post therapies
Prior anti-cancer therapy
The number and percentage of patients who received any prior anti-neoplastic medications, 
prior anti-neoplastic radiotherapy or prior anti-neoplastic surgery will be summarized by cohort. 
Prior anti-neoplastic medications will be summarized by therapy type (e.g. chemotherapy, 
hormonal therapy etc.), setting (e.g. adjuvant, metastatic, etc.) and also by lowest ATC class, 
preferred term and treatment. Summaries will include total number of regimens, best response 
and time from last treatment to progression for the last 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’. For radiotherapy,  locations and setting of last therapy will be summarized.
For prior surgery, time since last surgery, procedure and residual disease of last therapy will be 
summarized.
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 cohort.
Separate listings will be produced for prior anti-neoplastic medications, radiotherapy, and 
surgery. 
Anti-neoplastic medications will be coded using the WHO Drug Dictionary (WHO-DD); anti-
neoplastic surgery will be coded using MedDRA. Details regarding MedDRA and WHO-DD 
version will be included in the footnote in the tables/listings. 
The above analyses will be performed using the FAS .
Post treatment anti-cancer therapy
Anti-neoplastic therapies since discontinuation of study treatment will be listed and summarized 
by ATC class, preferred term, by cohort by means of frequency counts and percentages using 
FAS.


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Concomitant medications
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a patient coinciding with the study treatment 
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. These summaries will include:

Medications starting on or after the start of study treatment but no later than 30 days 
after start of last dose of study treatment and

Medications starting prior to start of study treatment and continuing after the start of 
study treatment.
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior 
to the start of study treatment or starting more than 30 days after the last date of study treatment 
will be flagged in the listing. The safety set will be used for all concomitant medication tables 
and listings.
According to the study protocol Table 14-2, treatment with substances which are strong CYP3A 
inhibitors, or inducers of CYP3Aor medications with a known risk of QT prolongation should 
be avoided. 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. Treatment with the prohibited substances mentioned above will be 
identified in the database as protocol deviations.
2.5
Analysis of the primary objective
The primary objective of the study is to assess the proportion of patients who are alive without 
disease progression at 6 months based on local investigator assessment per RECIST v1.1 
separately in Cohorts A and C (alpelisib in combination with fulvestrant) and Cohort B 
(alpelisib in combination with letrozole) among patients with HR+, HER2-negative aBC 
harboring a PIK3CA mutation who have progressed on or after prior treatments. 
2.5.1
Primary endpoint
The primary efficacy endpoint is the proportion of patients who are alive without disease 
progression at 6 months based on local investigator assessment using RECIST v1.1 in each 
cohort.
The mFAS will be used for the primary efficacy analysis.


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2.5.2
Statistical hypothesis, model, and method of analysis
In post CDK 4/6 inhibitor progression setting a
response rate is considered as a clinically 
meaningful threshold in each cohort. Therefore, evidence of treatment effect will be tested using 
the following hypothesis:
H0:
H1:
Where p is the proportion of patients who are alive without progression at 6 months.
The primary endpoint will be presented together with two-sided 95% confidence intervals using 
Clopper and Pearson (1934) exact method for both cohorts separately. The null hypothesis will 
be rejected and evidence of treatment effect will be demonstrated if the lower bound of the 95% 
CI for observed proportion at 6 months is greater than
Table 2-4 displays the values of 
proportion of patients who are alive without any disease progression at 6 months and its 95% 
CI. To reject the null hypothesis 
at least 44 patients need to be alive without 
progression at 6 months out of 112 patients in each cohort.
Table 2-4
Exact 95% Confidence Interval
Sample size
(N)
Number of 
patients alive 
without PD at 6 
months (k)
Proportion
k/N (%)
Exact 95% Confidence Interval (CI)
Lower (%)
Upper (%)
112
2.5.3
Handling of missing values/censoring/discontinuations
Six months is defined in this study as 24 weeks ± 1 week. Therefore tumor assessments between 
week 23 and 25 will be considered for the primary analysis. For primary endpoint analysis, 
patients who progressed, died, or discontinued study before 6 months will be counted as a 
“failure”.
2.5.4
Supportive analyses
The primary analysis will also be performed on the FAS and may be repeated on PPS, if 
hypothesis on the primary endpoint for the mFAS is met.
The primary analysis will also be repeated in patients from mFAS harboring a PIK3CA 
mutation as determined via ctDNA. This analysis will be conducted using the same analytical 
conventions as the primary analysis.


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2.6
Analysis of the key secondary objective
Not applicable. 
2.7
Analysis of secondary efficacy objective(s)
The secondary objectives in this study are to evaluate the progression free survival (PFS), 
progression free survival 2 (PFS2), overall response rate (ORR), clinical benefit rate (CBR), 
overall survival (OS),  duration of response (DOR), and safety. For efficacy secondary 
objectives, 95% confidence intervals will be provided.
The secondary efficacy analyses will also be repeated in patients harboring a PIK3CA mutation 
as determined via ctDNA at baseline and conducted using the same analytical conventions. 
2.7.1
Secondary endpoints
The mFAS will be used for the secondary efficacy analyses.
Progression free survival
Seconday endpoints include PFS, defined as the time from the date of start of treatement to the 
date of the first documented progression or death due to any cause. PFS will be based on local 
investigators review of tumor assessments and using RECIST 1.1 criteria (see Appendix 5 of 
the study protocol).  If a patient has not progressed or died  at the analysis cut-off date, PFS 
will be censored at the date of the last adequate tumor evaluation date before the cut-off date.
PFS events documented after the initiation of new anti-neoplastic therapy (i.e. RECIST 1.1. 
documented disease progression or death) will be considered for the primary analysis provided 
tumor assessments continue after initiation of new cancer therapy.  Discontinuation due to 
disease progression (collected on the ‘End of treatment’ and ‘End of post treatment follow up’ 
disposition pages) without supporting objective evidence satisfying progression criteria per 
RECIST 1.1 will not be considered disease progression for PFS derivation. Clinical 
deterioration will not be considered as a qualifying event for progression.
Overall response rate
ORR is defined as the proportion of patients with best overall response (BOR) of complete 
response (CR) or partial response (PR) according to RECIST 1.1 (see Appendix 5 of the study 
protocol).  ORR will be calculated based using local investigators  review of tumor assessment 
data in patients with measurable disease at baseline. 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. Tumor assessments performed before the start of any further 
antineoplastic therapy (i.e. any additional secondary antineoplastic therapy or surgery) will be 
considered in the assessment of BOR. 
Clinical benefit rate (CBR) 
CBR is defined as the proportion of patients with a best overall response of CR or PR, or an 
overall lesion response of stable disease (SD) lasting 24 weeks or longer or Non-CR/ Non-PD 
lasting 24 weeks or longer, 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 23 weeks or later from 


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enrollment, 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 start of study treatment. CBR will be calculated using the mFAS based on 
the investigators’ tumor assessments. 
Duration of response 
Duration of response (DOR) only applies to patients whose best overall response is complete 
response (CR) or partial response (PR) according to RECIST 1.1 based on local investigators 
review of tumor assessment data. The start date is the date of first documented response of CR 
or PR (i.e., the start date of response, not the date when response was confirmed), and the end 
date is defined as the date of the first documented progression or death due to underlying cancer. 
Patients continuing without progression or death due to underlying cancer will be censored at 
the date of their last adequate tumor assessment using the censoring rule described for PFS 
analysis (options A(1), C2(1), D(1), E(1), F(1-3) and G(1) from Table 3-2 in Appendix 5 of the 
study protocol). 
Overall Survival
OS is defined as the time from date of start treatment 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.
PFS after next-line of treatment (PFS2)
PFS2 is defined as time from date of start of treatment to the first documented disease 
progression (clinical or radiologic) on next-line therapy or death from any cause, whichever 
occurs first. The first documented progression on next-line treatment will be based on
investigator assessment of PD (i.e. as captured on the anti-neoplastic therapy after treatment 
discontinuation CRF page).
1.
Next-line therapy is defined as the first new (systemic) anti-neoplastic therapy initiated
after discontinuation of study treatment regardless of EoT reason. Drugs given as part 
of the same regimen should be grouped as one line (i.e. part of the next-line therapy). In 
addition, continuation of the study treatment after the initial radiologic disease 
progression will not be considered as next-line therapy.
2.
PFS2 will be censored if no PFS2 event (progression or death) is observed during next-
line therapy before the analysis cut-off date; the censoring date will be the last contact 
date. 
3.
However, in case a second new anti-neoplastic therapy is introduced without prior PFS2 
event, then PFS2 will be censored at the end date of the first new anti-neoplastic therapy 
(i.e. next line therapy).
4.
PFS2 will be censored at last contact date if a patient is still ongoing on study treatment 
irrespective of the disease progression status or second progression while being on study 
treatment, or patient has discontinued study treatment but has not started next-line 
therapy and is still alive.


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5.
Any death prior to initiation of next-line therapy will be considered as an event for PFS2. 
6.
PFS and PFS2 may be identical if a patient did not experience an event (i.e. progression) 
prior to initiation of next-line therapy, and adequate tumor assessments continue until 
RECIST 1.1-documented disease progression after initiation of next-line therapy.
Extension Phase Clinical Benefit
The secondary objective related to the Extension Phase of the study is to evaluate clinical
benefit as assessed by the Investigator. Proportion of patients with clinical benefit is defined by 
the number of patients with clinical benefit as assessed by investigator during Extension Phase 
(begins after the end of the Core Phase) divided by the number of patients in Extension Phase
(Safety set in Extension Phase). 
2.7.2
Statistical hypothesis, model, and method of analysis
PFS 
The survival distribution of PFS will be estimated using the Kaplan-Meier method. The results 
will be plotted graphically (Kaplan-Meier curves) by cohort. The plots will display the number 
of patients at risk at equidistant time points. The median, 25th and 75th percentiles for PFS for 
each cohort will be provided with associated 95% confidence intervals (Brookmeyer and 
Crowley 1982). The survival probabilities at 6, 12, 18 months, and the associated 95% 
confidence intervals will be summarized by cohort. 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.
ORR and CBR 
ORR and CBR will be calculated based on the mFAS. ORR and CBR will be summarized using 
descriptive statistics (N, %) separately for each cohort along with two-sided exact binomial 
95% CIs [Clopper and Pearson 1934]. As sensitivity analysis, CBR  will be calculated and 
summarized for patients with only measurable disease at baseline.
Duration of Response
DOR will be listed and summarized by cohort for all patients in the mFAS with confirmed BOR 
of CR or PR. The distribution of time to response will be estimated using the Kaplan-Meier 
method and the median time to response will be presented along with 95% confidence interval 
only if a sufficient number of responses is observed. A responders-only analysis will also be 
performed in this case. 
OS
OS will be analyzed in the mFAS population. The distribution of OS will be estimated using 
the Kaplan-Meier method. The median OS along with 95% confidence intervals will be 
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PFS2
PFS2 will be analyzed in the mFAS population. The PFS2 distribution will be estimated using          
the Kaplan-Meier method, and the Kaplan-Meier curves, medians and 95% confidence intervals 
of the medians will be presented separately for each cohort. 
Extension Phase Clinical Benefit
Proportion of patients with clinical benefit as assessed by the investigator will be summarized 
at scheduled visits. Clinical benefit will be summarized using the Safety Set in Extension 
Phase.
2.7.3
Handling of missing values/censoring/discontinuations
PFS 
PFS will be censored at the date of the last adequate tumor assessment if no PFS event is 
observed prior to the analysis cut-off date.
PFS events documented after the initiation of new anti-neoplastic therapy (i.e. RECIST 1.1. 
documented disease progression or death) will be considered for the primary analysis provided 
tumor assessments continue after initiation of new cancer therapy.
The date of last adequate tumor assessment is the date of the last tumor assessment with overall 
lesion response of CR, PR or SD before an event or a censoring reason occurred. In this case 
the last tumor evaluation date at that assessment will be used. If no post-baseline assessments 
are available (before an event or a censoring reason occurred) then the date of 
randomization/start date of treatment will be used.
In particular, PFS will be censored at the last adequate tumor assessment if one of the following 
occurs: absence of event, the event occurred after two or more missing tumor assessments. The 
term “missing adequate tumor assessment” is defined as a tumor assessment (TA) not 
performed or tumor assessment with overall lesion response of “UNK”. The rule to determine 
number of missing TAs is based on the time interval between the date of last adequate tumor 
assessment and the date of an event. If the interval is greater than  twice the protocol-specified 
interval between the TAs and 2 times the protocol-allowed time window around assessments, 
then the number of missing assessments will be 2 or more.
Refer to Table 2-5 for censoring and event date options and outcomes for PFS.
Table 2-5
Outcome and event/censor dates for PFS analysis
Situation
Date
Outcome
No baseline assessment
Date of start of treatment 
Censored
Progression or death at or 
before next scheduled 
Assessment
Date of progression (or 
death)
Progressed


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Situation
Date
Outcome
Progression or death after 
exactly one missing assessment
Date of progression (or 
death)
Progressed
Progression or death after two or 
more missing assessments
Date of last adequate 
assessment prior to 
missed assessment 
Censored
No progression (or death)
Date of last adequate 
assessment 
Censored
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression, i.e. 
clinical progression based on 
investigator claim
Date of last adequate 
assessment 
Censored
New anticancer therapy given 
prior to protocol defined 
progression 
Ignore the new 
anticancer therapy and
follow situations above 
As per above situations
Death before first PD 
assessment
Date of death
Progressed
ORR 
Patients with unknown or missing best overall response (BOR) will be counted as failures. If 
there is no baseline tumor assessment, all post-baseline overall lesion responses are expected 
to be ‘Unknown’. If no valid post-baseline tumor assessments are available, the best overall 
response must be “Unknown” unless progression is reported. For the computation of ORR, 
these patients will be included in the mFAS and will be counted as ‘failures’.
PFS 2 
For PFS2, refer to Table 2-6 for censoring and event date options and outcomes.
Table 2-6
Outcome and event/censor dates for PFS2 analysis
Situation
Event/Censoring Date
Outcome
No baseline assessment
Date of start of treatment
Censored
Progression or death during the 
next-line therapy
Date of progression (or 
death)
Event
Death prior to initiation of next-
line therapy
Date of death
Event
No progression (or death) during 
the next-line therapy and no 
second new anti-neoplastic 
therapy is initiated
Last contact date 
Censored
No progression (or death) during 
the next-line anticancer therapy 
and a second new anti-
neoplastic therapy is initiated 
End date of the next-line 
therapy
Censored
No next-line therapy initiated 
with patient known to be alive
Last contact date
Censored


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2.8
Safety analyses
All safety analyses will be based on the safety set. All listings and tables will be presented for 
each cohort.
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.
2.8.1
Adverse events (AEs)
AE summaries will include all AEs occurring during on treatment period (treatment-emergent
AEs). All AEs collected in the AE (e)CRF page will be listed along with the information 
collected on those AEs e.g. AE relationship to study drug, AE outcome etc. AEs with start date 
outside of on-treatment period will be flagged in the listings. 
AEs will be summarized by number and percentage of patients having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT)
using MedDRA coding. A patient with multiple occurrences of an AE will be counted only 
once in the respective AE category. A patient with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event.
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables.
In AE summaries, the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency in the investigational drug .
The following adverse event summaries will be produced by cohort: overview of adverse events 
and deaths, AEs by SOC and PT, summarized by relationship, seriousness, leading to treatment 
discontinuation, leading to dose interruption/adjustment, requiring additional therapy and 
leading to fatal outcome. In addition, a summary of serious adverse events with number of 
occurrences will be produced (an occurrence is defined as >1 day between start and prior end 
date of record of same preferred term).
2.8.1.1
Adverse events of special interest / grouping of AEs
Data analysis of AESIs
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound BYL719. These groupings are defined using MedDRA 
terms, SMQs (standardized MedDRA queries), HGLTs (high level group terms), HLT (high 
level terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA queries, NMQ)
may also be used. A NMQ is a customized group of search terms which defines a medical 
concept for which there is no official SMQ available or the available SMQ does not completely 
fit the need. It may include a combination of single terms and/or an existing SMQ, narrow or 
broad. For each specified AESI, number and percentage of patients with at least one event of 
the AESI occurring during on treatment period will be summarized.


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A Case Retrieval Sheet (CRS; an Excel file) with the exact composition of the adverse events 
groupings is to be used to map reported adverse events to the AESIs groupings (termed Specific 
Event Categories (SECs) in the CRS). This file may be updated (i.e. it is a living document) 
based on review of accumulating trial data. The latest version of the CRS document available 
at the time of the analyses will be used.
Summaries of these AESIs will be provided by cohort (specifying grade, SAE, relationship, 
leading to treatment discontinuation, leading to dose adjustment/interruption, hospitalization, 
death etc.). If sufficient number of events occurred, analysis of time to first occurrence will be 
applied.
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 specific groupings. 
Median time to onset and 95% CI will be summarized. Ascending Kaplan-Meier lots will be 
generated. 
A listing of all grouping levels down to the MedDRA preferred terms used to define each 
AESI will be generated. 
2.8.2
Deaths
Separate summaries for on-treatment and all deaths will be produced by cohort, system organ 
class and preferred term. 
All deaths  will be listed, post treatment deaths will be flagged. A separate listing of deaths prior 
to starting treatment will be provided for all screened patients .
2.8.3
Laboratory data
On analyzing laboratory, data from all sources (central and local laboratories) will be combined. 
The summaries will include all assessments available for the lab parameter collected no later 
then 30 days after the last study treatment administration date (see Section 2.1.1).
The following summaries will be produced for hematology, biochemistry and urinary 
laboratory data (by laboratory parameter and treatment):

Worst post-baseline CTC grade (regardless of the baseline status). Each patient will be 
counted only for the worst grade observed post-baseline.

Shift tables using CTC grades to compare baseline to the worst on-treatment value.

For laboratory tests where CTC grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-treatment
value.

Trends of lab parameter values over time (baseline and selected on-treatment timepoints) 
might be displayed via boxplots 
based on time windows and corresponding tables 
displaying the statistics used for the box plots by the selected time points.

In addition, HbA1c, fasting 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 


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HbA1c/glucose/C-peptide levels with two-sided 95% confidence intervals over time by 
cohort may also be produced to view the trends over time.
The following listings will be produced for the laboratory data:

Listings of all laboratory data, with CTC grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged.  

Listing of all CTC grade 3 or 4 laboratory toxicities
Liver function parameters 
Liver function parameters of interest are total bilirubin (TBL), ALT, AST and alkaline 
phosphatase (ALP). The number (%) of patients with worst post-baseline values as per 
Novartis Liver Toxicity guidelines will be summarized:
The following summaries will be produced:

ALT or AST > 3xULN 

ALT or AST > 5xULN

ALT or AST > 8xULN

ALT or AST > 10xULN

ALT or AST > 20xULN

TBL > 2xULN

TBL > 3xULN

ALT or AST > 3xULN & TBL > 2xULN

ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN  (potential Hy’s law)   
Potential Hy’s Law events are defined as those patients with concurrent occurrence of AST or 
ALT > 3xULN and TBL > 2xULN and ALP < 2xULN  in the same assessment sample during 
the on-treatment period. 
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
Data handling
In case the study requires ECG replicates at any assessment, the average of the ECG parameters 
at that assessment should be used in the analyses.
Data analysis
12-lead ECGs including PR, QRS, QT, QTcF, and HR intervals will be obtained for each patient
during the study. ECG data will be read and interpreted locally.
The number and percentage of patients with notable ECG values will be presented by cohort. 


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
QT, QTcF, or QTcB
–
New value of > 450 and ≤ 480 ms
–
New value of > 480 and ≤ 500 ms
–
New value of > 500 ms
–
Increase from Baseline of > 30 ms to ≤  60ms
–
Increase from Baseline of > 60 ms

HR
–
Increase from baseline >25% and to a value > 100 bpm
–
Decrease from baseline >25% and to a value < 50 bpm

PR
–
Increase from baseline >25% and  to a value > 200 ms
–
New value of > 200 ms

QRS
–
Increase from baseline >25% and  to a value > 120 ms 
–
New values of QRS > 120 ms 
Categorical Analysis of QT/QTc interval data based on the number of patients meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline 
will be presented. In addition, a listing of these patients will be produced by cohort.
A listing of all ECG assessments will be produced by cohort and notable values will be flagged. 
In the listing, the assessments collected during the post-treatment period will be flagged.
2.8.4.2
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body temperature (°C), heart 
rate (beats per minute), systolic and diastolic blood pressure (mmHg).
Data handling
Vital signs collected on treatment will be summarized. Values measured outside of on treatment 
period will be flagged in the listings.
Data analysis
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-7
below.
Table 2-7
Clinically notable changes in vital signs
Vital sign (unit)
Clinically notable criteria
above normal value 
below normal value
Weight (kg)
increase >= 10% from Baseline
decrease  >= 10% from Baseline
Systolic blood 
pressure 
(mmHg)
>=180 with increase from baseline 
of >=20
<=90 with decrease from baseline 
of >=20


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Vital sign (unit)
Clinically notable criteria
above normal value 
below normal value
Diastolic blood 
pressure 
(mmHg)
>=105 with increase from baseline 
of >=15
<=50 with decrease from baseline 
of >=15
Pulse rate (bpm)
>=100 with increase from baseline 
of >25%
<=50 with decrease from baseline of 
> 25%
Body 
temperature
>= 39.1
-
The number and percentage of patients with notable vital sign values (high/low) will be 
presented  by cohort.         
A listing of all vital sign assessments will be produced by cohort and notable values will be 
flagged. In the listing, the assessments collected outside of on-treatment period will be flagged. 
2.8.4.3
Cardiac imaging (MUGA / ECHO)
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 cohort.
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.
2.8.4.4
ECOG performance status
ECOG Performance status (PS) is assessed to attempt to quantify the impact of disease on daily 
life activities of patients.
ECOG PS scale is used to assess physical health of patients, ranging from 0 (most active) to 5 
(least active) (see Table 7-4 of the study protocol for details). 
Shift tables will be produced to compare baseline to the worst on-treatment value.
2.8.4.5
Additional Analyses
Time to first occurrence of any AESI with CTC grade > 2 event
Time to first occurrence of an event is defined as time from start of study treatment to the date 
of first occurrence of this event (or first event within an AESI grouping), i.e. time in days is 
calculated as (start date of first occurrence of event ) – (start 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


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
start date of new antineoplastic therapy before experiencing any CTC grade > 2 event. 

data cut-off date.

withdrawal of informed consent date
The corresponding censoring reason will be used: death, new anti cancer therapy, treatment 
discontinuation, ongoing at cut-off date or consent withdrawal.
Failure curves (ascending Kaplan-Meier curves) will be constructed by cohort. Median together 
with 95% confidence interval as well as 25th percentile and 75th percentile will be presented 
for each cohort. 
In addition, the median time to occurrence for the subset of patients who experienced the event 
of interest will be calculated. Simple descriptive statistics, median, min and max as well as 25th 
percentile and 75th percentile, will be presented.
The same analysis might be repeated for events of grade 3 and grade 4.
2.8.5
Safety data for Extension Phase
Safety analyses for the Extension Phase will be performed on the Safety Set in Extension Phase. 
The assessment of safety will be based mainly on the duration of exposure and dosage. The 
following summaries will be provided since the start of Core Phase:

Duration of exposure to study treatment;

Dose of study treatment received;

Dose adjustments and discontinuation of study treatment.
2.9
Pharmacokinetic endpoints
Not applicable.
2.10
PD and PK/PD analyses
Not applicable. 
2.11
Patient-reported outcomes
Not applicable.


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2.13
Other Exploratory analyses
Not applicable.
2.14
Interim analysis
The first Interim Analysis (IA) is planned after at least 
patients receiving alpelisib plus 
fulvestrant (cohort A) have at least 6 months of follow up. Once
patients will be recruited,  
the interim analysis data cutoff will be the last patients first visit plus 6 months. The second IA 
is planned after
patients have been treated (regardless of cohort) and have at least 6 months 
of follow-up on study. The third IA will be performed after the Core Phase has ended.
At the time of the first two IAs, preliminary efficacy (ORR, CBR) as well as key safety data 
will be analyzed in a descriptive fashion. The primary endpoint will not be analyzed and no 
statistical hypothesis will be tested.
The third IA will include all efficacy and safety data up to the end of the Core Phase.
Primary endpoint will not be analysed and no formal statistical hypothesis testing will be done 
at the time of IA and therefore no multiplicity adjustment will be made. 
Preliminary efficacy as well as key safety data will be analysed in a descriptive fashion
separately in each cohort.
The following endpoints will be summarized at the time of the first two IAs:
-
Overall response rate (ORR)
-
Clinical Benefit rate (CBR)
-
Average daily dose, cumulative dose, relative dose intensity
-
Duration of exposure
-
Dose reduction/interupptions 
-
Adverse events
-
Serious adverse events
-
Deaths
-
Adverse event of special interest (AESI)
-
Laboratory parameters


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3
Sample size calculation
3.1
Primary analysis
A median PFS of at least 6 months (or 50% of patients who are alive without progression after 
6 months) has been observed for alpelisib 300 mg plus fulvestrant 500 mg and also for 
palbociclib 125 mg plus fulvestrant 500 mg in PiK3CA mutant patients previously treated with 
AI (without CDK4/6 inhibitor) in [CBYL719X2101] and Paloma-3 (Cristofanilli 2016) studies 
respectively. Currently, there is no available clinical data in post-CDK4/6 inhibitor setting in 
PIK3CA mutant patients. Assuming that these patients after failure to CDK4/6 inhibitor will 
have a lower median PFS than 6 months, a proportion of 
of patients alive without 
progression after 6 months is considered as a clinically meaningful threshold in both cohorts 
for this study and was used for sample size calculation.
The sample size is based on an exact Binomial test for single proportion to test the null 
hypothesis H0:
 where p is the proportion of patients who are alive without progression 
at 6 months. With a one-sided 2.5% level of significance (two-sided 95% CI), a total sample 
size of 112 patients in each cohort is required in order to have a power of at least 90% when the 
true p ≥0.45. Table 3-1 provides the operating characteristics for N=112 and different true rates.
Table 3-1
Operating Characteristics
Sample size
(N)
True rate
Prob (X≥44|True rate)
112
The study will enroll a total of approximately 340 patients who have PIK3CA mutation with at 
least 112 patients allocated into each Cohort A (alpelisib + fulvestrant), Cohort B (alpelisib + 
letrozole) and Cohort C (alpelisib + fulvestrant).
At the time of the first two Interim Analysis (IA) preliminary efficacy (ORR, CBR) will be 
analyzed in a descriptive fashion. The primary endpoint will not be analyzed and no statistical 
hypothesis will be tested. Therefore no multiplicity adjustment was made.
4
Change to protocol specified analyses
4.1
Impact of COVID-19
Due to pandemic COVID in year 2020, some extra analyses will be performed outside protocol 
specified. 


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Operational impact: Specified protocol deviation categories will be assigned to important 
deviations related to COVID-19 (e.g., missing efficacy assessments) and these will be 
summarized and listed separately. A summary table of the COVID-19 related deviations by 
relationship category will be provided. 
Safety: To help to evaluate the impact of the pandemic on safety, the incidence of COVID-19 
related adverse event preferred terms will be presented incorporating COVID-19 related 
adverse events with an onset date in the year of 2020.
Efficacy: If there are >=10% patients with missed visits due to COVID-19, an additional 
sensitivity analysis for primary endpoint will be performed to address the potential impact of the 
COVID-19 pandemic, using local investigator assessment using RECIST v1.1 on the mFAS and 
considering the visit labeled by “missed visits due to COVID-19” has the same assessment value 
as in previous scheduled visit.


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5
Appendix  1
5.1
Imputation rules
All imputation rules will be provided in full details in the PDS and the most updated rules as 
mentioned in the PDS will be followed.
5.1.1
Study drug
The following rule should be used for the imputation of the dose end date for a given study 
treatment component:
Scenario 1: If the dose end date is completely missing and there is no EOT page and no death 
date, the patient is considered as on-going:
The patient should be treated as on-going and the cut-off date should be used as the dose end
date. 
Scenario 1 should not applicable for final CSR. All patients should have EOT page complete 
before the Database lock for Final CSR
Scenario 2: If the dose end date is completely or partially missing and the EOT page is 
available:
Case 1: The dose end date is completely missing, and the EOT  completion 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 dose end date, and yyyy  = the 
year of EOT date and mm < the month of  EOT date: 
Use last day of the Month (mm)
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:
Use the treatment start date
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed.


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5.1.2
AE, ConMeds and safety assessment date imputation
Table 5-1
Imputation of start dates (AE, CM) and assessments (LB, EG, VS)
Missing 
Element
Rule
day, month, 
and year

No imputation will be done for completely missing dates
day, month

If available year = year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY
o
Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY

If available year < year of study treatment start date then 01JulYYYY
day

If available month and year = month and year of study treatment start 
date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start 
date then 01MONYYYY  

If available month and year < month year of study treatment start date 
then 15MONYYYY  
Table 5-2
Imputation of end dates (AE, CM) 
Missing 
Element
Rule
(*=last treatment date plus 30 days not > (death date, cut-off date, 
withdrawal of consent date))
day, month, 
and year

Completely missing end dates (incl. ongoing events) will be 
imputed by the end date of the on-treatment period* 
day, month

If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period * 
day

If partial end date contains month and year, set end date = earliest 
of last day of the month or end date of the on-treatment period*
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings.
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided. 


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5.1.2.1
Other imputations
Incomplete date of initial diagnosis of cancer and  date of most recent 
recurrence 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan. 
Incomplete assessment dates for tumor assessment
All investigation dates (e.g. MRI scan, CT scan) must be completed with day, month and year. 
If one or more assessment 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 the latest of all investigation dates (e.g. MRI scan, CT scan) if 
the overall response at that assessment is CR/PR/SD/UNK. Otherwise – if overall response is 
progression – the assessment date is calculated as the earliest date of all investigation dates at 
that evaluation number.  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.
Applying the cut-off to tumor assessment
For tumor related assessments, if an evaluation has some assessments done prior to cut-off date 
and others after the cut-off date, then the evaluation is considered post-cut-off date and will be 
excluded from analysis.
5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 .
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1). 
5.3
Laboratory parameters derivations
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 (specify version used in the 
RAP). The calculation of CTCAE grades will be based on the observed laboratory values only, 
clinical assessments will not be taken into account. The criteria to assign CTCAE grades are 
given in Novartis internal criteria for CTCAE grading of laboratory parameters. The latest 
available version of the document based on the underlying CTCAE version 4.03 at the time of 


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analysis will be used. The Novartis internal CTC grading document has been added as appendix
2 to the present document. For laboratory tests where grades are not defined by CTCAE v 4.03, 
results will be graded by the low/normal/high (or other project-specific ranges, if more suitable)
classifications based on laboratory normal ranges.
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia.
Imputation Rules  
CTC grading for blood differentials is based on absolute values. However,  this data may not 
be reported as absolute counts but rather as percentage of WBC. 
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. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential
xxx count = (WBC count) * (xxx %value / 100)
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]
In order to apply the above formula, albumin values in g/L will be converted to g/dL by  
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium.
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading
5.4
Statistical models
5.4.1
Primary analysis
The methodology is described in Section 2.5
Kaplan-Meier estimates
An estimate of the survival function in each cohort will be constructed using Kaplan-Meier
(product-limit) method as implemented in PROC LIFETEST with METHOD=KM option. The
PROC LIFETEST statement will use the option CONFTYPE=LOGLOG.
Median survival for each cohort will be obtained along with 95% confidence intervals
calculated from PROC LIFETEST output using the method of [Brookmeyer and Crowley
1982]. Kaplan-Meier estimates of the survival function with 95% confidence intervals at
specific time points will be summarized. The standard error of the Kaplan-Meier estimate


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will be calculated using Greenwood’s formula [Collett 1994].
Analysis of Binary Data
Responses will be summarized in terms of percentage rates with 95% CIs. An exact binomial 
confidence interval (implemented using SAS procedure FREQ with EXACT statement for one-
way tables) will be calculated [Clopper and Pearson 1934]
SAS procedure FREQ will be used to estimate the proportion of responders (binary outcome = 
1 or “Yes”), along with the associated 95% (=100 × (1 – two-sided alpha level)) two-sided 
Pearson-Clopper CI and exact one-sided p-value for the hypothesis test of the null proportion
(0.xx). 
6
Reference
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time.
Biometrics, 38, 29 - 41. 
Clopper CJ and Pearson ES (1934).  The use of confidence or fiducial limits illustrated in the 
case of the binomial.  Biometrical, 26, 404-413.
Collet D (1994). Modelling survival data in medical research. London, Chapman & Hall.
Dodd EL, Korn LE, Freidlin B, Gray R, Bhattacharya S. An audit strategy for progression-
free survival. Biometrics, 2011, 67 (3): 1092-99.
FDA briefing Document Oncologic Drugs Advisory Committee Meeting, July 24, 2012, 
Evaluation of radiologic review of progression-free survival in Non-hematologic 
malignancies. 
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/oncol
ogicdrugsadvisorycommittee/ucm311141.pdf
Kalbfleisch JD and Prentice RL. The Statistical Analysis of Failure Time Data (2002). Wiley 
Series in Probability and Statistics.