Clinical trial NCT01923168
Conditions: Breast Cancer
Keywords: BYL719 alpelisib Breast Cancer BKM120 buparlisib Pathological Complete Response neoadjuvant hormone receptor-positive HER2 negative Objective Response Rate
Sponsor: Novartis Pharmaceuticals
Start date: 2014-03-11; Completion date: 2017-07-08
Enrollment: 340 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study was to determine whether treatment with a PI3K inhibitor plus letrozole led to an increase in pathologic clinical response and Objective Response Rate compared to treatment with placebo plus letrozole in patients with Breast cancer.

Detailed description:

Arms: arm 1: Participants took alpelisib 300 mg once daily plus letrozole 2.5 mg once daily. arm 2: Participants took buparlisib 100 mg once daily or 5 days on/2 days off plus letrozole 2.5 mg once daily. arm 3: Participants took matching Placebo (of alpelisib 300 mg once daily/buparlisib 100 mg once daily or 5 days on/2 days off) plus Letrozole 2.5 mg once daily.
Interventions: intervention 1: alpelisib intervention 2: buparlisib intervention 3: Placebo
Intervention descriptions: intervention 1: BYL719 + Letrozole intervention 2: BKM120 + Letrozole intervention 3: Placebo (of BYL719 or BKM120) + Letrozole

Protocol documents:
Prot_001.pdf: 
Clinical Development
Alpelisib (BYL719)
Protocol CBYL719A2201 / NCT01923168
A phase II randomized, double-blind placebo controlled, 
study of letrozole with or without BYL719 or buparlisib, for 
the neoadjuvant treatment of postmenopausal women with 
hormone receptor-positive HER2-negative breast cancer
Authors
Document type
Amended Protocol Version (Clean)
EUDRACT number
2013-001862-41
Version number
07
Development phase
II
Document status
Final
Release date
18-Oct-2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents .................................................................................................................2
List of appendices................................................................................................................7
List of figures ......................................................................................................................7
List of tables ........................................................................................................................8
List of abbreviations..........................................................................................................10
Glossary of terms...............................................................................................................13
Amendment 7 (18-Oct-2016) ............................................................................................14
Amendment 6 (04-May-2016)...........................................................................................16
Amendment 5 ....................................................................................................................16
Amendment 4 ....................................................................................................................25
Amendment 3 ....................................................................................................................29
Amendment 2 ....................................................................................................................29
Amendment 1 ....................................................................................................................38
Protocol summary:.............................................................................................................44
1
Background........................................................................................................................47
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............47
1.1.1
Hormone receptor-positive breast cancer..............................................47
1.1.2
PI3K Pathway........................................................................................48
1.1.3
PI3K pathway activation in HR+ Breast Cancer...................................49
1.2
Introduction to investigational treatment(s) and other study treatment(s).............50
1.2.1
Overview of BYL719............................................................................50
1.2.2
Overview of buparlisib (BKM120).......................................................59
1.2.3
Overview of letrozole............................................................................66
1.2.4
Overview of BYL719/buparlisib plus letrozole....................................67
2
Rationale............................................................................................................................70
2.1
Study rationale and purpose...................................................................................70
2.2
Rationale for the study design ...............................................................................71
2.2.1
Rationale for study design and inclusion of wild-type patients ............72
2.2.2
Rationale for the stratification factors...................................................72
2.3
Rationale for dose and regimen selection..............................................................73
2.4
Rationale for choice of combination drugs............................................................74
2.5
Rationale for choice of comparators drugs............................................................74
2.6
Risks and Benefits .................................................................................................75
3
Objectives and endpoints...................................................................................................75
4
Study design ......................................................................................................................79


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4.1
Description of study design ...................................................................................79
4.2
Timing of interim analyses and design adaptations...............................................82
4.3
Definition of end of the study................................................................................82
4.4
Early study termination..........................................................................................82
5
Population..........................................................................................................................82
5.1
Patient population..................................................................................................82
5.2
Inclusion criteria ....................................................................................................83
5.3
Exclusion criteria...................................................................................................84
6
Treatment...........................................................................................................................87
6.1
Study treatment......................................................................................................87
6.1.1
Dosing regimen .....................................................................................87
6.1.2
Instructions for administration..............................................................88
6.1.3
Guidelines for continuation of treatment ..............................................88
6.1.4
Treatment duration................................................................................89
6.2
Dose escalation guidelines.....................................................................................89
6.3
Dose modifications ................................................................................................89
6.3.1
Dose modification and dose delay ........................................................89
6.3.2
Follow-up for toxicities.........................................................................98
6.4
Concomitant medications ....................................................................................104
6.4.1
Permitted concomitant therapy ...........................................................104
6.4.2
Prohibited concomitant therapy ..........................................................108
6.5
Patient numbering, treatment assignment or randomization ...............................109
6.5.1
Patient numbering ...............................................................................109
6.5.2
Treatment assignment or randomization.............................................109
6.5.3
Treatment blinding..............................................................................110
6.6
Study drug preparation and dispensation.............................................................110
6.6.1
Study drug packaging and labeling.....................................................110
6.6.2
Drug supply and storage......................................................................110
6.6.3
Study drug compliance and accountability .........................................111
6.6.4
Disposal and destruction .....................................................................111
7
Visit schedule and assessments .......................................................................................111
7.1
Study flow and visit schedule..............................................................................111
7.1.1
Molecular pre-screening......................................................................118
7.1.2
Screening.............................................................................................118
7.1.3
Treatment period .................................................................................121
7.1.4
Discontinuation of Study Treatment ...................................................121


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7.1.5
Withdrawal of Consent .......................................................................122
7.1.6
Follow up for Safety Evaluations........................................................123
7.1.7
Lost to follow-up.................................................................................123
7.1.8
Breast Cancer Surgery.........................................................................123
7.2
Assessment types.................................................................................................124
7.2.1
Efficacy assessments...........................................................................124
7.2.2
Safety and tolerability assessments.....................................................124
7.2.3
Pharmacokinetics ................................................................................130
7.2.4
Biomarkers ..........................................................................................133
8
Safety monitoring and reporting......................................................................................137
8.1
Adverse events.....................................................................................................137
8.1.1
Definitions and reporting ....................................................................137
8.1.2
Laboratory test abnormalities..............................................................138
8.1.3
Adverse events of special interest.......................................................139
8.2
Serious adverse events.........................................................................................139
8.2.1
Definitions...........................................................................................139
8.2.2
Reporting.............................................................................................140
8.3
Emergency unblinding of treatment assignment .................................................141
8.4
Pregnancies..........................................................................................................141
8.5
Warnings and precautions....................................................................................141
8.6
Data Monitoring Committee................................................................................142
8.7
Steering Committee .............................................................................................142
9
Data collection and management.....................................................................................142
9.1
Data confidentiality .............................................................................................142
9.2
Site monitoring ....................................................................................................143
9.3
Data collection.....................................................................................................143
9.4
Database management and quality control..........................................................144
10 Statistical methods and data analysis ..............................................................................144
10.1
Analysis sets ........................................................................................................145
10.1.1
Full Analysis Set .................................................................................145
10.1.2
Safety Set ............................................................................................145
10.1.3
Per-Protocol Set ..................................................................................145
10.1.4
Pharmacokinetic analysis set...............................................................145
10.1.5
Other analysis sets...............................................................................146
10.2
Patient demographics/other baseline characteristics ...........................................146
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................147


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10.4
Primary objective.................................................................................................147
10.4.1
Variable...............................................................................................148
10.4.2
Statistical hypothesis, model, and method of analysis........................148
10.4.3
Handling of missing values/censoring/discontinuations.....................149
10.4.4
Supportive and sensitivity analyses ....................................................149
10.5
Secondary objectives ...........................................................................................150
10.5.1
Key secondary objective(s).................................................................150
10.5.2
Other secondary efficacy objectives ...................................................150
10.5.3
Safety objectives .................................................................................150
10.5.4
Pharmacokinetics ................................................................................152
10.5.5
Resource utilization.............................................................................154
10.5.6
Patient-reported outcomes...................................................................154
10.6
Exploratory objectives.........................................................................................154
10.6.1
Biomarkers ..........................................................................................154
10.6.2
Efficacy ...............................................................................................156
10.7
Interim analysis....................................................................................................156
10.8
Sample size calculation........................................................................................156
10.9
Power for analysis of key secondary variables....................................................157
11 Ethical considerations and administrative procedures ....................................................157
11.1
Regulatory and ethical compliance......................................................................157
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................157
11.3
Informed consent procedures...............................................................................157
11.4
Discontinuation of the study................................................................................158
11.5
Publication of study protocol and results.............................................................158
11.6
Study documentation, record keeping and retention of documents.....................158
11.7
Confidentiality of study documents and patient records .....................................159
11.8
Audits and inspections.........................................................................................159
11.9
Financial disclosures............................................................................................159
12 Protocol adherence ..........................................................................................................160
12.1
Amendments to the protocol................................................................................160
13 References (available upon request)................................................................................161
14 Appendices ......................................................................................................................167
14.1
Appendix 1 - List of concomitant medications....................................................167
14.1.1
Cytochrome P450 Substrates ..............................................................167
14.1.2
Cytochrome P450 Inhibitors and Inducers..........................................169


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14.1.3
Drugs that prolong the QT interval and/or induce Torsades de 
Pointes.................................................................................................169
14.1.4
BCRP inhibitors ..................................................................................173
14.2
Appendix 2: Guidelines for response, duration of overall response, TTF, TTP, 
progression-free survival and overall survival (based on RECIST 1.1)..............175
14.2.1
Introduction.........................................................................................177
14.2.2
Efficacy assessments...........................................................................177
14.2.3
Definitions...........................................................................................177
14.2.4
Eligibility based on measurable disease..............................................178
14.2.5
Methods of tumor measurement - general guidelines.........................178
14.2.6
Baseline documentation of target and non-target lesions ...................180
14.2.7
Follow-up evaluation of target and non-target lesions........................181
14.2.8
Follow-up and recording of lesions.....................................................181
14.2.9
Non-nodal lesions................................................................................181
14.2.10
Nodal lesions.......................................................................................182
14.2.11
Determination of target lesion response..............................................182
14.2.12
Determination of non-target lesion response ......................................184
14.2.13
New lesions .........................................................................................185
14.2.14
Evaluation of overall lesion response .................................................185
14.2.15
Efficacy definitions .............................................................................186
14.2.16
Best overall response...........................................................................186
14.2.17
Time to event variables .......................................................................188
14.2.18
Progression-free survival ....................................................................188
14.2.19
Overall survival...................................................................................188
14.2.20
Time to progression.............................................................................189
14.2.21
Time to treatment failure.....................................................................189
14.2.22
Duration of response ...........................................................................189
14.2.23
Time to response .................................................................................190
14.2.24
Definition of start and end dates for time to event variables ..............191
14.2.25
Handling of patients with non-measurable disease only at baseline...192
14.2.26
Sensitivity analyses .............................................................................193
14.2.27
Data handling and programming rules................................................194
14.2.28
Study/project specific decisions..........................................................195
14.2.29
End of treatment phase completion.....................................................195
14.2.30
End of post-treatment follow-up (study phase completion)................195
14.2.31
Medical validation of programmed overall lesion response ...............196
14.2.32
Programming rules..............................................................................196


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14.2.33
Calculation of ‘time to event’ variables..............................................196
14.2.34
Incomplete assessment dates...............................................................196
14.2.35
Incomplete dates for last known date patient alive or death ...............197
14.2.36
Non-target lesion response..................................................................197
14.2.37
Study/project specific programming...................................................197
14.2.38
Censoring reason.................................................................................197
14.2.39
References (available upon request) ...................................................198
14.3
Appendix 3: Guidelines on Calculating PEPI Score ...........................................199
14.4
Appendix 4: Patient Self-Reported Mood Questionnaires ..................................200
14.4.1
Scoring the PHQ-9 and GAD-7 ..........................................................200
14.5
Appendix 5: Guidelines for the treatment of study drug combination induced 
diarrhea ................................................................................................................204
List of appendices
Appendix 1: List of concomitant medications
Appendix 2: RECIST guidelines
Appendix 3: PEPI Score
Appendix 4: Patient Self-Reported Mood Questionnaires
Appendix 5: Guidelines for the treatment of study drug combination induced diarrhea
List of figures
Figure 1-1
Schematic representation of the PI3K pathway ....................................49
Figure 1-2
Frequency of PIK3CA, PTEN and INPP4B alterations in breast 
cancer ....................................................................................................50
Figure 1-3
Pharmacodynamic profile of NVP-BYL719 after multiple 
treatments in NCI-H596 tumor bearing nude rats.................................52
Figure 1-4
Supporting evidence for pathway inhibition in preclinical model of 
breast carcinoma (T47D) by NVP-BYL719 at 50 mg/kg.....................52
Figure 1-5
Single agent activity of BYL719 in ER+ breast cancer models............68
Figure 1-6
Apoptosis rate with BKM120 in MCF7, MCF7-long term 
oestrogen deprived (LTED) and MCF7-estrogen retreated LTED 
cell lines ................................................................................................68
Figure 1-7
Activity of BKM120 as single agent in ER+ breast cancer model; 
HE staining and IHC for Ki67 and cleaved caspase-3/7 (analysis of 
tumor tissue from animals treated with either fulvestrant (2nd row), 
BKM120 (3rd row) or a combination of both (bottom panel)).............69
Figure 4-1
Description of study design...................................................................79


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136
201
203
List of tables
Table 1-1
PI3K signaling pathway mutations and alterations in breast cancer.....49
Table 3-1
Objectives and related endpoints ..........................................................76
Table 6-1
Dose and treatment schedule.................................................................87
Table 6-2
Dose reduction sequential steps for BYL719/placebo..........................90
Table 6-3
Dose reduction sequential steps for buparlisib/placebo........................90
Table 6-4
Criteria for interruption and re-initiation of BYL719/placebo or 
buparlisib/placebo .................................................................................91
Table 6-5
Management of pneumonitis...............................................................100
Table 6-6
Packaging and labeling .......................................................................110
Table 6-7
Supply and storage of study treatments ..............................................111
Table 7-1
Visit evaluation schedule ....................................................................113
Table 7-2
Imaging collection plan.......................................................................124
Table 7-3
ECOG performance status...................................................................126
Table 7-4
Central Clinical laboratory parameters collection plan.......................127
Table 7-5
Local ECG collection plan..................................................................129
Table 7-6
Patient self-reported mood questionnaire collection plan 
(buparlisib/placebo+letrozole arms only) ...........................................130
Table 7-7
Classification of severity based on depression and/or anxiety 
questionnaire scores ............................................................................130
Table 7-8
Pharmacokinetic blood collection log.................................................132
Table 7-9
Biomarker sample collection plan.......................................................133
136
Table 10-1
Non-compartmental PK parameters....................................................153
Table 14-1
List of CYP450 substrates to be used with caution.............................167
Table 14-2
List of moderate CYP3A4 inducers and inhibitors used with 
caution (buparlisib treatment arm)......................................................169
Table 14-3
List of prohibited strong CYP3A4 inducers and inhibitors 
(buparlisib treatment arm)...................................................................169
Table 14-4
List of prohibited QT prolonging drugs..............................................170
Table 14-5
List of QT prolonging drugs to be used with caution .........................171
Table 14-6
BCRP inhibitors to be used with caution ............................................174
Table 14-7
Response criteria for target lesions .....................................................182


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Table 14-8
Response criteria for non-target lesions..............................................184
Table 14-9
Overall lesion response at each assessment ........................................185
Table 14-10
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................192
Table 14-11
Options for event dates used in PFS, TTP, duration of response........193
Table 14-12
The preoperative endocrine prognostic index (PEPI) score................199
Table 14-13
NCI CTCAE version 4.03 grading of diarrhea for patients without 
colostomy............................................................................................204


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List of abbreviations
ADA
American Diabetes Association
AE
Adverse Event
AI
Aromatase inhibitor
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
aPTT
Activated Partial thromboplastin time
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
ARA
Acid Reducing Agents 
b.i.d./BID
bis in diem/twice a day
BC
Breast cancer
BSA
Body Surface Area
BUN
Blood Urea Nitrogen
CBC
Cells Blood Count
ctDNA
Circulating tumor DNA
CDP
Clinical Development Plan
CPK
Creatine Phosphokinase
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CSR
Clinical study report
CT
Computed Tomography
CTT
Clinical Trial Team
CYP
Cytochrome P
DDI
Drug-Drug Interaction
DILI
Drug-induced liver injury
DLCO
Carbon monoxyde diffusing capacity
DLT
Dose Limiting Toxicity
DS&E
Drug Safety and Epidemiology
EBV
Epstein-Barr Virus
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report/Record Form
EDC
Electronic Data Capture
EIAED
Enzyme-inducing anti-epileptic drug
EOT
End of Treatment
ER
Estrogen receptor
FAS
Full Analysis Set
FPG
Fasting plasma glucose
FSH
Follicle-stimulating hormone
GAD-7
General Anxiety Disorder
GCP
Good Clinical Practice
GGT
Gamma-glutamyltranspeptidase
GLP
Good Laboratory Practice
HbA1c
Glycosylated Hemoglobin
HBsAg
Hepatitis B surface Antigen


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HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HDL
High density lipoprotein
HER2
Human epidermal growth factor receptor 2
HER2-
Human epidermal growth factor receptor 2 negative
HFHC
High-fat high-calorie 
Hgb
Hemoglobin
HIV
Human immunodeficiency virus
HR
Hormone Receptor 
HSV
Herpes Simplex Virus
i.v.
intravenous(ly)
IC50
Half maximal Inhibitory Concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IGF-1
Insulin-like growth factor 1
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IHC
Immunohistochemistry
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
ITT
Intent-to-treat
LDH
Lactate dehydrogenase
LDL
Low density lipoprotein
LFLC
Low-fat low-calorie 
LFT
Liver Function Tests
LLOQ
Lower Limits of Quantitation
LTED
Long Term Estrogen Deprivation
LVEF
Left Ventricular Ejection Fraction
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
mTOR
Mammalian target of rapamycin
MUGA
Multiple Gated acquisition scan
ORR
Overall Response Rate
p.o.
per os/by mouth/orally
pCR
pathologic complete response
PEPI
Preoperative endocrine prognostic index
PgR
progesterone receptor 
PHI
Protected Health Information
PHQ-9
PHQ-9 Patient Health Questionnaire
PI3K
PI3K Phosphatidylinositol-3-kinase
PIK3CA
PIK3CA Gene which encodes the p110alpha catalytic subunit
PK
Pharmacokinetics
PLT
Platelets


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PPS
Per Protocol Set
PTEN
Phosphatase and tensin homolog
PTT
partial thromboplastin time 
QD
once a day
QTcF
Q-T interval in the ECG (corrected according to the formula of Fredericia)
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses
REB
Research Ethics Board
RECIST
Response Evaluation Criteria In Solid Tumors
RP2D
Recommended phase two dose
SAE
Serious Adverse Event
SC
Steering Committee
TBL
Total bilirubin
UDPGA
Uridine 5'-diphospho-glucuronic acid
UGT1A4
UDP-glucuronosyltransferase 1 family, polypeptide A4
ULN
Upper Limit of Normal
WBC
White Blood Cell
WHO
World Health Organization
WNL
Within Normal Limits


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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 
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.)
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.
Premature
patient
withdrawal
Point/time when the patient exits from the study prior to the planned completion of all study 
treatment administration and/or assessments; at this time all study treatment administration 
is discontinued and no further assessments are planned 
Randomization 
number
A unique treatment identification code assigned to each randomized patient, corresponding 
to a specific treatment arm assignment
Stage related to 
study timeline
A major subdivision of the study timeline; begins and ends with major study milestones such 
as enrollment, randomization, completion of treatment, etc.
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of the tumor, 
whether lymph nodes contain cancer, and whether the cancer has spread from the original 
site to other parts of the body
Stop study 
participation
Point/time at which the patient came in for a final evaluation visit or when study treatment 
was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the patient 
(subject) as part of the required study procedures, including placebo and active drug run-ins.
In specific examples, it is important to judge investigational treatment component relationship 
relative to a study treatment combination; study treatment in this case refers to the 
investigational and non-investigational treatments in combination.
Study treatment 
discontinuation
Point/time when a patient permanently discontinues study treatment for any reason;
Treatment group
A treatment group defines the dose and regimen or the combination, and may consist of 1 or 
more cohorts. Cohorts are not expanded, new cohorts are enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from data collected using 
specified assessments at specified timepoints
Withdrawal of 
Consent
Withdrawal of consent occurs only when a patient does not want to participate in the study 
any longer, and does not want any further visits or assessments, and does not want any 
further study related contact 


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Amendment 7 (18-Oct-2016)
As of October 14, 2016, 325 patients have been randomized in study CBYL719A2201 of 
these, 121 patients have been randomized to buparlisib/buparlisib-placebo arms, and 204
patients have been randomized to BYL719/BYL719 (Alpelisib)-placebo. All patients 
randomized to buparlisib/buparlisib-placebo arm have discontinued study treatment. 66
patients are taking study treatment in BYL719/BYL719 (Alpelisib)-placebo arm. PIK3CA 
wild-type cohort enrollment was completed on August 23, 2016 and 7 patients remain to be 
enrolled in the PIK3CA mutant cohort.
The purpose of this protocol amendment is:

To provide more detailed treatment guidance for AE of hyperglycemia and update on AE 
management for skin toxicity following an advisory-board meeting recommendation

To update the general administration guidelines for alpelisib/placebo based on a food 
effect and acid reducing agents (ARA) drug-drug interaction (DDI) study: alpelisib must 
be taken with a meal regardless of composition or overall calorie intake. A staggered 
approach for co-administration of alpelisib with acid reducing agents is no longer required
Amendment 7 rationale
Updated guidance for the management of hyperglycemia and skin toxicity Adverse 
Events
In 2016, a program-wide assessment of available data on alpelisib-induced hyperglycemia and 
skin toxicity was conducted and results were shared and discussed with an advisory board 
consisting of oncologists, endocrinologists and a dermatopathologist. The management 
guidelines were reviewed and more detailed guidance for the management of alpelisib 
induced hyperglycemia and skin toxicity has been developed. For skin toxicity of any grade, 
treatment with topical steroids 3-4 times daily is recommended. Oral anti-histamines are 
indicated in case of skin toxicity accompanied with burning, stinging or pruritus or 
prophylactic in case of hypersensitivity in patients’ medical history, e.g. seasonal allergy, 
allergic asthma, drug-induced exanthema in the past. Consultation with a dermatologist is 
highly recommended for better assessment and management of alpelisib-induced skin toxicity.
Table 6.4, Criteria for interruption and re-initiation of alpelisib/placebo treatment, has been 
updated to provide more detailed guidance than the previous version of the protocol.  
Update of general administration guidelines for alpelisib/placebo 
Based on in vitro solubility data, alpelisib has been administered after a light meal breakfast in 
most clinical trials including the first-in-man trial CBYL719X2101. The impact of food on the 
absorption of alpelisib was recently investigated in a clinical trial in healthy volunteers (Study 
CBYL719A2103) after a single 300 mg oral dose of alpelisib. Compared to the fasted state a 
high-fat high-calorie (HFHC) meal increased – on average – AUCinf by 73% and Cmax by 
84%, and a low-fat low-calorie (LFLC) meal increased AUCinf by 77% and Cmax by 145%, 
confirming a positive food effect on absorption of alpelisib. No significant difference was 
found for AUCinf between LFLC and HFLC meals. Overall, data from study 
CBYL719A2103 confirmed that alpelisib must continue to be given with a meal. However as 


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neither composition nor overall calorie intake have shown an effect, the light meal restriction 
can be lifted, allowing also some further flexibility with regards to alpelisib intake during the 
day if dose administration has been forgotten in the morning. 
In vitro, alpelisib demonstrates a pH-dependent solubility profile, with a >100-fold drop in 
thermodynamic solubility between pH 1 (> 5 mg/ml) and pH 6.8 (0.02 mg/ml). Therefore acid 
reducing agents (ARAs, e.g. proton-pump inhibitors, H2-antagonists and antacids) may alter 
the solubility of alpelisib and hence its bioavailability. Co-administration of an acid-reducing 
agent (ARA) in presence or in absence of a meal was investigated in the same clinical trial. 
The co-administration of the H2 receptor antagonist ranitidine in combination with a single 
300 mg oral dose of alpelisib slightly reduced the bioavailability of alpelisib and decreased 
overall exposure of alpelisib. In the presence of a LFLC meal, AUCinf was decreased – on 
average – by 21% and Cmax by 36% with ranitidine. In the absence of food, the effect was 
more pronounced with a 30% decrease in AUCinf and a 51% decrease in Cmax with 
ranitidine compared to the fasted state without co-administration of ranitidine. As the study
showed a non-clinically relevant 21% decrease in exposure of alpelisib in combination with 
ranitidine when given with a LFLC meal, ARAs can be administered concomitantly and do 
not have to be administered in a staggered manner. Hence, the restriction about the staggered 
administration of H2-receptor antagonists as well as the avoidance of proton-pump inhibitors 
has been removed.
For more information, please refer to the [Alpelisib (BYL719) Investigators Brochure Edition 
9].
Protocol Changes: 
The changes are outlined as follows in order of appearance:

List of abbreviations has been updated

Section 2.6 Risks and Benefits has been added to the protocol

Section 6.1.2.1 general guidelines on alpelisib/placebo dosing instructions and 
recommendations have been updated based on the results of a food effect and ARA DDI 
study for alpelisib

Section 6.3.1.1, Table 6-4 has been updated to provide more guidance for hyperglycemia,
skin toxicity management and in case of acute pancreatitis

Section 6.3.2.3.2 has been updated per update of Table 6-4

Section 6.3.2.3.5 has been updated per update of Table 6-4

Section 6.4.1.3 has been updated as per approved program standard language

Section 6.4.1.9 has been updated to reflect the changes with respect to the co-
administration of acid reducing agents, lifting the restriction for the use of proton-pump-
inhibitors and staggered dosing of other gastric protection agents

Section 7.2.3 has been updated based on the results of a food effect and ARA DDI study 
for alpelisib

Section 8.1.1 Adverse events Definitions and reporting has been updated to match with 
Novartis' updates processes

Section 8.1.3 Adverse events of special interest has been added to the protocol 


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
Section 8.2.2 SAE reporting has been updated to match with Novartis' updates processes

Section 8.4 Pregnancies has been added to match Novartis' protocol template language
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
IRB/IEC/HA
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 6 (04-May-2016)
As of March 22nd, 2016, 241 patients have been randomized in the study CBYL719A2201 Of 
these, 121 patients have been randomized to buparlisib/buparlisib-placebo arms, and 120 
patients have been randomized to BYL719/BYL719-placebo. As of this date no patients have 
been enrolled into amendment 5 of the trial pending local approvals. 
Amendment rationale
The purpose of this protocol amendment is to correct a technical publishing issue identified in 
Protocol Amendment V05:

Table 6-4 “Cardiac-QTC prolongation” adverse drug reaction text was hidden, not 
expanded in the PDF version. Consequently, the full wording for the dose adjustment and 
related management recommendations for Cardiac – QTC prolongation appeared as 
missing, only partial wording. This issue is corrected in Amendment 6.
Protocol Changes: 
Table -6-4: Formatting error of Cardiac QTC prolongation row is corrected.
IRB/IEC/HA
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 are non-substantial and do not require 
IRB/IEC approval prior to implementation.
Amendment 5
As of December 31, 2015, 241 patients have been randomized in the study CBYL719A2201
Of these, 121 patients have been randomized to buparlisib/buparlisib-placebo arms, and 120 
patients have been randomized to BYL719/BYL719-placebo.


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Amendment rationale
The purpose of this protocol amendment is:

To update the clinical study protocol according to the decision made by the Sponsor on 
Dec 22, 2015 to stop permanently the accrual in the buparlisib/buparlisib-placebo 
treatment arms, 

To change the assessment of the anti-tumor activity of buparlisib/buparlisib-placebo plus 
letrozole into an exploratory objective.

To change the Overall Response Rate (ORR) from being secondary to primary endpoint.

To change the assessment of the anti-tumor activity of BYL719 plus letrozole versus 
letrozole alone on pCR and ORR by PIK3CA status based on circulating tumor DNA 
(ctDNA), from exploratory to secondary objective. 

To stop the conduct of the central review for pathological response.

To implement regular safety review of unblinded data performed by a Data Monitoring 
Committee (DMC) 

To update the inclusion criteria with regards to baseline glucose metabolism parameters, 
potassium, and values of amylase and lipase. 

To retire the exclusion criteria related to psychiatric disorders and viral hepatitis, and 
update the exclusion criterion on uncontrolled medical conditions.

To update the safety monitoring and guidance for the management of hyperglycemia, skin 
toxicity, and pancreatitis

To revise and update the Appendix 14-1 “List of concomitant medications” due to a recent 
re-classification of drugs with QT prolongation

To update the language of some protocol sections as part of a general update implemented 
across the program (e.g. safety monitoring for liver toxicity; language for Adverse Events 
reporting)
Rationale for stopping accrual in buparlisib/buparlisib-placebo treatment arms
As part of a program-wide assessment of Buparlisib (BKM120) in breast cancer across 
different indications, and considering the modest efficacy observed in the Belle-2 study 
(Baselga, 2015), Novartis has decided not to pursue further the development of buparlisib in 
early-stage breast cancer. On December 8, 2015 a pre-planned blinded pooled safety analysis 
of the CBYL719A2201 study (N=178) was performed for both treatment arms, i.e. 
Buparlisib/placebo + Letrozole and BYL719/placebo + Letrozole.  Eighty-nine patients had 
been allocated to each of the two treatment arms. There were no new or unexpected safety 
findings compared with a prior analysis performed in June 2015.  The results of these analyses 
and the decision to discontinue the development of buparlisib in early-stage breast cancer 
were presented and endorsed by the study Steering Committee. Ongoing patients receiving 
buparlisib/buparlisib-placebo and letrozole may continue the treatment based on the 
investigator’s clinical judgement. Patients recruited under buparlisib/buparlisib-placebo will 
still be part of the statistical analysis. However, the assessment of the anti-tumor activity of
buparlisib/buparlisib-placebo plus letrozole will now become an exploratory objective.


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Rationale for adding ORR as a primary objective
The rationale for changing ORR from secondary to primary endpoint in this study is 
supported by the high clinical relevance of ORR in the neoadjuvant setting of hormone 
receptor-positive breast cancer (Benda 2004). In addition, in order to be aligned with the most 
recent neoadjuvant endocrine treatment clinical trials where ORR has been selected as the 
primary objective (Saura 2014, Fontein 2014), this study will now also assess ORR as primary 
objective. Thus, this study will now have both pCR rate and ORR as primary endpoints.
Rationale for assessing efficacy based on PIK3CA mutational status 
determined on ctDNA
Circulating tumor DNA is a new tool for mutation identification. A recent study demonstrated 
that assessments in ctDNA allowed capturing the heterogeneity and real-time status of the 
tumor by detecting all mutations identified in either the primary tumor or in the metastatic 
lesions (De Mattos-Arruda 2014). Technology evolution allows for a reliable detection of 
molecular alterations in ctDNA, specifically for PIK3CA mutations which were successfully 
detected in ctDNA from metastatic breast cancer patients (Board 2010, Higgins 2012). In 
addition, data reported recently suggest a relationship between PIK3CA mutations detected in 
ctDNA and response to BYL719 (Shah 2015).
Hence, exploring the role of ctDNA in the context of neoadjuvant treatment is critical and the 
previously exploratory objective of PIK3CA mutation analysis in ctDNA will now become a
secondary objective in order to assess the association between ctDNA PIK3CA mutational
status and clinical outcome. 
 
 
 
Rationale for stopping the conduct of central review for pathological response
As of Dec 31, 2015, one hundred and five patients had undergone surgery. Samples for central 
review of pathological response had been received for only 35 (33%) of them. In addition, the 
central review has been performed in 25 (24%) of the cases; in the remaining it was not 
possible due to insufficient material sent from the sites.
Therefore, given the substantial operational challenges encountered, the central assessment of 
pathological responses will no longer be conducted and the corresponding supportive analysis 
will not be done. The assessment of pathological response performed by the local investigator
remains the primary endpoint of the study. Therefore removing the central review will not 
affect the primary endpoint.
Rationale for implementing a Data Monitoring Committee
Safety evaluations across the BYL719 program are regularly conducted. In order to evaluate 
also unblinded safety data from the current study, CBYL719A2201, a Data Monitoring 
Committee (DMC) will be implemented. The DMC will be composed of Novartis personnel 
who are not directly involved in the BYL719 program and will review ongoing safety data 
from the study (National Health Service [NHS]. National Patient Safety Agency. National 


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Research Ethics Service (2010): Data monitoring committees in clinical trials. Guidance for 
Research Ethics Committees). The recommendations of the internal DMC will be regularly 
shared with the study Steering Committee members.
Rationale for updating the inclusion/exclusion criteria and management of 
hyperglycemia 
An overall assessment of the incidence and potential risk factors for BYL719-induced 
hyperglycemia has recently been conducted across the program in more than 1000 patients 
treated with BYL719 at different doses, in different tumor types, and as part of different 
treatment regimens. A higher risk to develop grade 3/4 hyperglycemia was observed in 
patients with HbA1c between 6.5 and 8.0% (Novartis Internal Data). In addition, and 
according to the American Diabetes Association (ADA) guidelines with regards to glycemic 
targets in patients with diabetes mellitus, a value of HbA1c >6.5% may represent a status of 
not-optimally controlled diabetes. The equivalent FPG values for an HbA1c of 6.5% are 
around 140 mg/dl. Therefore, in an attempt to reduce the risk of BYL719-induced 
hyperglycemia and in alignment with ADA guidelines, the inclusion criterion #13 for FPG 
and HbA1c has been modified as follows: FPG ≤ 140 mg/dl and HbA1c < 6.5%
Further recommendations for management of hyperglycemia have also been added in the 
additional follow-up for selected toxicities section. 
Rationale for updating the inclusion and exclusion criteria, and the 
management of pancreatitis 
One case of life threatening acute pancreatitis has recently been reported in the study 
CBYL719A2301 (SOLAR-1), where postmenopausal women with advanced breast cancer are 
randomized to receive BYL719 (300 mg, once daily) and fulvestrant or BYL719 and placebo. 
No preclinical evidence for this risk has been observed. An overall assessment of the risk of 
BYL719 to induce acute pancreatitis has been conducted at the end of November 2015 across 
the development program (details reported in the IN PHHO2015IL018569). The key findings 
of such evaluation indicate that asymptomatic elevations of pancreatic enzymes may occur in 
patients treated with BYL719. Clinical data suggest that a small percentage (< 1%) of patients 
treated with BYL719 may develop acute clinical pancreatitis (Tenner et al 2013).
Therefore, in the current protocol and across the BYL719 development program, the 
following changes have been implemented: modification of the inclusion criteria; now 
including fasting amylase and lipase added to the panel of investigations at screening; 
frequent monitoring of amylase and lipase; and detailed dose modification guidelines in case 
of asymptomatic increases of amylase and/or lipase or clinical signs of pancreatitis included.
Rationale for the modification of the potassium inclusion criterion
A concentration-effect-analysis for BYL719 (single agent) showed a limited but positive trend 
of increase in QT. While no clinical significant QT prolongation (< 10 ms) is expected at a 
300 mg dose, potassium levels should be within normal range at study entry to limit the risk 
of cardiac adverse events, as hypokalemia has been shown to increase QT prolongation and 
hyperkalemia can lead to faster repolarization of the cardiac action potential. During study 
conduct, any potassium related adverse event will be monitored.


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Rationale for retiring the exclusion criteria related to psychiatric disorders and 
to viral hepatitis 
As psychiatric disorders and viral hepatitis re-activation risk have not been observed so far in 
BYL719 studies (BYL719 Investigator’s Brochure), and these risks were expected to be 
related only to buparlisib, the exclusion criteria #11 (PHQ-9 questionnaire and related score), 
#12 (response to question “9” on PHQ-9 questionnaire), #13 (GAD-7 questionnaire and 
related score), #14 (psychiatric disorders), and #15 (anxiety); and exclusion criteria #28
(screening for viral hepatitis), have been retired.
Rationale for updating the exclusion criterion related to uncontrolled medical 
conditions
Exclusion criteria #10 explains that patients with uncontrolled medical conditions, based on 
investigator’s clinical judgment, are to be excluded, and some examples are given in 
parenthesis. Those medical situations, given as examples in parenthesis, but already outlined 
in individual stand-alone exclusion criteria, such as pancreatitis (exclusion criterion #28), 
have been deleted. For uncontrolled hypertension, a new exclusion criterion has been added 
(#29) to provide more clarity on the blood pressure values required for study entry.
Rationale for updating the skin toxicity management section
An overall assessment of the incidence of skin toxicity and potential preventive actions has 
recently been conducted across the alpelisib program. Some improvement in the severity of 
rash has been observed with the prophylactic use of non-sedating oral anti-histamines (Dickler 
2014, Mayer 2014), however conclusive data are not yet available. Thus, the use of 
prophylactic oral non-sedating anti-histamines (e.g. cetirizine or equivalent), is now 
recommended based on investigators’ clinical judgment.
Protocol Changes
Protocol summary section: Addition of ORR from secondary to primary objective and of 
PIK3CA ctDNA from exploratory to secondary endpoint.
Section 2.2: Addition of ORR from secondary to primary objective.
Section 2.2.1: Clarification on the material used for assessment of mutation status (tumor 
tissue).
Section 3, Table 3-1: Change of ORR from secondary to primary objective and related 
endpoint; and of PIK3CA ctDNA from exploratory to secondary objective and related 
endpoints. Change for safety analysis by PIK3CA cohort to safety analysis overall.
Figure 4-1: Description of study design was updated to reflect the stop of the recruitment in 
the the buparlisib/buparlisib-placebo treatment arm.
Section 4.1: Deletion of the central review of surgical specimen as supportive measure of 
primary endpoint assessment. Clarification of C1D15 biopsy time-point. Clarification on 


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treatment phase section (update randomization number). Clarification on study treatment 
continuation for patients randomized to buparlisib/buparlisib-placebo treatment arms. 
Section 4.2: Timing of interim and design adaptations section has been added. 
Section 5.2: Inclusion criterion #13 has been updated to reflect the changes in baseline FPG, 
Hb1Ac, amylase, lipase and potassium.
Section 5.2: Inclusion criterion #14: Clarification of study starting point.
Section 5.3: Exclusion criteria #3: update of compounds to be received by the patient.
Section 5.3: Exclusion criterion #5: Clarification of discontinuation of systemic therapy, 
radiotherapy, or hormone-replacement therapy.
Section 5.3: Exclusion criterion #6 on diabetes mellitus has been updated for more clarity.
Section 5.3: Exclusion criterion #10 has been updated for more clarity.
Section 5.3: Exclusion criterion #11, 12, 13, 14, 15 and 28 have been retired.
Section 5.3: Exclusion criterion #29 has been added for more clarity.
Section 5.3: Exclusion criterion # 30, related to uncontrolled hypertension, has been added for 
more clarity.
Section 6.1: Study treatment phase has been updated to reflect the discontinuation of the 
buparlisib/buparlisib-placebo treatment arm.
Section 6.1.4: Definition of treatment cycle is clarified for frequency.
Section 6.3.1.1 – Table 6.4: Criteria for interruption and re-initiation of BYL719/placebo or 
buparlisib/placebo table has been updated for the following adverse event reactions:
AST/ALT, hyperglycemia, and pancreatitis. Rash, rash maculopapular, rash generalized, and 
pruritushave been grouped under Skin Toxicities in order to provide consistent and uniform 
management recommedations. 
Section 6.3.2.1: The follow-up guidance on potential drug-induced liver injury (DILI) cases 
section has been added.
Section 6.3.2.2: The follow-up guidance on amylase or lipase elevation (≥ CTCAE Grade 3) 
has been added.
Section 6.3.2.3.2: The follow-up guidance on BYL719-induced hyperglycemia has been 
added.
Section 6.3.2.3.4: Guidelines for the treatment of study drug induced skin toxicity has been 
updated for more clarity.
Section 6.4: Clarification has been made with regards to the collection of the information with 
regards to the breast cancer diagnostic biopsy under the “Prior antineoplastic therapy eCRF”.


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Section 6.4.1.5: Changes in the wording for more detailed explanation of coagulation.
Section 6.4.1.6: Removal of Contraceptives section as it is not applicable for the study 
population (postmenopausal women).
Section 6.4.2.3: Drugs with a known risk of QT prolongation or of causing Torsades de 
Pointes section has been updated.
Section 6.5.2: The treatment assignment or randomization section has been updated on 
discontinuation buparlisib/placebo arm and randomization number.
Section 6.5.3: The treatment blinding section has been updated.
Section 7.1: Table 7.1 -Update the category from “D” to “S” for the PIK3CA mutation and 
Ki67 status results entered in IRT item. Fasting amylase analysis was added, as well as
collection of antineoplastic therapy data after discontinuation of study treatment for more 
clarity. The tumor biopsy at screening, at C1D15, and post-treatment follow up phase has 
been added to the Visit Evaluation Schedule table for more clarity. Clarification of the 
acknowledge of receipt of adequate tumor tissue has been added.
Fasting plasma amylase has been added on day of every cycle.
Section 7.1.1: Clarification on the material used for assessment of mutation status (tumor 
tissue).
Section 7.1.2, Section 7.1.2.1 and Section 7.1.3: Removal of buparlisib/placebo from 
screening section.
Section 7.1.2.2: Information to be collected on screen failures has been updated for clarity.
Section 7.1.2.3: Patients demographics and other baseline characteristics section has been 
updated for clarity and viral hepatitis serology (with the change of Exclusion criteria #28) and 
patient self-rating mood questionnaires have been removed.
Section 7.1.6: The follow up safety evaluation has been updated for clarity to mention that 
any antineoplastic therapy given until the surgery will be recorded in the eCRF.
Section 7.1.8: Deletion of the central review of surgical specimen.Section 7.2.1: Addition of 
ORR from secondary to primary efficacy endpoint and subsequent update in the pCR 
assessment.
Section 7.2.2.2: The wording for vital signs was refined for consistency with CRF page name.
Section 7.2.2.5: The hepatotoxixity testing was reworded for more clarity.
Section 7.2.2.5: Table 7-4: Biochemistry section was reviewed for consistency with table 7.1.
Section 7.2.2.5.6: The viral hepatitis serology test was reviewed for more clarity.


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Section 7.2.2.6: Patient self-reported mood questionnaires and footnotes of table 7-6 have 
been updated for clarity for patients still under buparlisib/placebo treatment.   
Section
7.2.3: Pharmacokinetics section has been updated with the removal of 
buparlisib/placebo wording per protocol changes.
Section 7.2.4.1: Table 7-9: Biomarker collection plan has been clarified (tumor DNA).
Section 7.2.4.3.1: Change in the timelines for sending the tumor tissue collected to laboratory 
based on actual study logistic experience.
Section 7.2.4.3.2: Blood collection plan was clarified.
Section 7.2.4.3.3: Central review of pCR was deleted and additional wording on surgical 
specimen has been added for more clarity.
Section 7.2.4.4: Reworded for more clarity.
Section 8.5: Data monitoring committee section added per protocol changes.
Section 9.4: Data management and quality control section updated with fasting lipase and 
amylase, ALP and Creatinine to align with the eCRF.
Section 10.1.2: Update of the safety set definition without considering at least one post-
baseline safety assessment and of the treatment received as per new protocol template.
Section 10.1.3: Addition of RECIST evaluation in the PPS definition for consistency with the 
new added primary endpoint ORR and clarification as per new protocol template.
Section 10.1.4: The pharmacokinetic analysis set was clarified.
Section 10.1.4.2: Revision due to current course of the study in the BYL719 Full Sampling 
Pharmacokinetic Analysis Set (BYL719 FPAS).
Section 10.1.4.4: Revision due to current course of the study in the Buparlisib Full Sampling 
Pharmacokinetic Analysis Set (BKM120 FPAS).
Section 10.1.4.6: Revision due to current course of the study in the Letrozole Full Sampling 
Pharmacokinetic Analysis Set (LZ FPAS).
Section 10.1.5: Other analysis sets section added as per protocol template.
Section 10.2.2: Clarifications added regarding analysis sets used to describe demographics, 
analysis pooled on cohorts and description of relevant medical histories and current medical 
condition at baseline.
Section 10.3: Clarifications added regarding analysis set and methods used for descriptions of 
treatments, and that the duration of exposure to study treatment, the number of dose 
adjustements and reasons will also be described.
Section 10.4: Addition of the primary objective related to ORR and removal of buparlisib 
from the primary objectives as it is now an exploratory objective.
Section 10.4.1: Addition of ORR as a primary efficacy endpoint and of its definition.


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Section 10.4.2: Addition of the statistical hypothesis, model, and method of analysis for ORR
and of the Proof-of-Concept based on pCR and ORR. Deletion of the possibility to analyze 
one cohort if it completes the study earlier. Updates due to the assessment of the anti-tumor 
activity of buparlisib which is now an exploratory objective.
Section 10.4.3: Description of the rules applying for handling of missing values / censoring /
discontinuations for ORR and reminder on the rules for pCR mentioned in section 10.4.1.
Section 10.4.4: Update of the supportive analyses section with additional supportive analyses 
to be performed if appropriate with specifications given in the RAP.
Section 10.5.2: Deletion of analysis related to ORR from the secondary objective section 
(since upgraded to primary efficacy endpoint) and addition of secondary analysis by PIK3CA 
status based on ctDNA.
Section 10.5.3.1: Deletion of safety analysis by cohort and addition of safety analysis 
separately for the continuous schedule and for the 5 days-on / 2 days-off schedule of 
buparlisib. Addition that selected safety outputs will be produced for the DMC.
Section 10.5.3.2: Adverse events section has been updated for clarification: summary tables 
for non-serious adverse events and AESI, all deaths both on-treatment and post-treatment, 
deletion of some details on SEC. 
Section 10.5.3.3 Deletion of the use of clinical meaningful limits for laboratory 
abnormalitiesand addition of summary tables regardless of baseline value.
Section 10.5.3.4: ECG table type is changed to correct a mistake (“shift table of ECG” to 
“notable ECG parameter changes”) and analysis for cardiac imaging is specified.
Section 10.5.3.5: Tolerability section has been updated for clarity.
Section 10.5.4: Update of a technic reference in the pharmacokinetics section. Addition that 
T1/2 will be applicable to BYL719 only and that effective half-life will be provided instead 
for buparlisib, as T1/2 cannot be properly estimated for buparlisib due to its long half-life. 
Section 10.5.5: Resource utilization section has been renumbered. 
Section 10.5.6: Patient-reported outcomes section has been renumbered.
Section 10.6: Exploratory objectives section has been moved in order to have the Biomarker 
section in the exploratory objectives section for consistency with the objectives section.
Section 10.6.1.3.2: Addition that the concordance/discordance on PIK3CA mutation status 
between ctDNA and tumor tissue at study entry may be performed. Clarification added on 
exploratory analyses.
Section 10.6.2: Addition of the assessment of the anti-tumor efficacy for buparlisib as an 
exploratory analysis. Addition of a missing analysis related to the exploratory efficacy 
objective regardless of PIK3CA mutational status and deletion of analysis using other pCR 
definitions.
Section 10.8: Update of the sample size section taking into account the inclusion of ORR as a 
primary efficacy endpoint.
Section 13: Update of references.


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Section 14.3-Appendix 3: Deletion of the “BCSS score” in the preoperative endocrine 
prognostic index (PEPI) score Table 14-12 as it will not be used for the PEPI analysis.
IRB/IEC/HA
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. A separate ICF “BYL719 only” will be signed by the newly screened 
patients, and an updated ICF will be signed by patients enrolled prior to the current Protocol 
Amendment implementation.
Amendment 4
As of July 20th, 2015, 146 patients have been randomized in the study CBYL719A2201.
Amendment rationale
The main purpose of this protocol amendment is to provide additional guidance to 
investigators around management of liver toxicities.
Alterations in liver function tests (LFTs) have been commonly observed in clinical trials with 
buparlisib as an investigational agent. These include mostly transient increases in 
transaminase enzymes (ALT and/or AST), which often occur during the first 6 to 8 we eks of 
buparlisib treatment, and rarely are associated with signs/symptoms of impaired liver function. 
Current buparlisib protocols have conservative inclusion criteria for baseline LFTs with close 
monitoring guidelines to be followed during the treatment and stringent dose 
modification/interruption criteria.
In March 2015, a search for potential drug-induced liver injury (DILI) cases in buparlisib
Novartis-sponsored trials using conservative biochemical criteria (e.g. AST/ALT >3.0x ULN 
and TBL>2.0xULN at any time during the treatment period, regardless of causality) identified 
21 potential DILI candidates in the blinded pivotal breast cancer trials CBKM120F2302 and 
CBKM120F2303 conducted in combination with fulvestrant (HR-positive HER2-negative
disease). No cases were identified in the unblinded CBKM120F2202 study in combination 
with paclitaxel (HER2-negative disease). Upon medical review, most of these occurred in the 
context of disease progression in terminally-ill advanced cancer patients and/or were 
confounded by other causes. However, for some of the DILI candidates causal relationship 
with study treatment is possible. The liver abnormalities generally have been transient and 
reversible; so far, no fatal case has been reported across any of the buparlisib studies as a 
result of study drug(s) related liver toxicity.
Six of the DILI candidates were further consistent with Hy’s law criteria and probable causal 
relationship to blinded study medication (all enrolled in CBKM120F2302 study); two of these 
six patients had liver metastasis at baseline, one patient took concurrent herbal medications, 


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and one patient had >50% unconjugated peak bilirubin suggesting a component of Gilbert’s 
syndrome or hemolysis as possible contributing or confounding factors (the latter was 
considered equivocal Hy’s law based on external expert review). All Hy’s Law candidates 
have recovered upon treatment discontinuation except one patient for whom outcome is not 
available because the patient refused to return for safety follow-up.
In May 2015 one additional DILI candidate was identified in the study CBYL719A2201, in a 
patient randomized to the buparlisib/placebo treatment arm. Briefly, a 55-year-old woman 
diagnosed with early-stage, non-metastatic breast cancer, and without any prior significant 
medical history or pre-existing risk factors for liver disease, presented on cycle 2 day 1 with 
elevated ALT (grade 3) and elevated AST (grade 2).The study treatment was stopped five 
days after the transaminases increase occurred. ALT and AST continued to increase (grade 4), 
and this was accompanied by grade 4 bilirubin elevation. Alkaline phosphatase was also 
elevated (grade 1). The patient remained asymptomatic during the entire period. Viral 
hepatitis serology and liver imaging did not reveal any findings. All previously elevated 
laboratory values returned to normal after six weeks.
Updated liver safety including the identified DILI/Hy’s law candidates in studies 
CBKM120F2302 and CBKM120F2303 were presented to the Data Monitoring Committee 
(DMC) for these trials on 9-April-2015; the DMC noted no change or additional liver safety 
concerns and recommended continuing the respective studies as planned.
An Aggregated Safety Finding Report was submitted to Health Authorities and all 
investigators participating in buparlisib studies informing them about the liver findings. In 
addition, Novartis decided to update the current liver-related safety measures in ongoing 
protocols to enhance patient safety. Therefore, the main purpose of this protocol amendment 
is to provide additional guidance to investigators around management of liver toxicities as 
outlined below.
Changes in the background section:

Update of the clinical background section on liver toxicity to align with the protocol 
amendment rationale.

Changes in the exclusion criteria:

Exclusion of patients with an acute viral hepatitis or with a history of chronic or active 
HBV or HCV infection (testing not mandatory).

Changes in the section on management and follow-up for selected toxicities:

Addition of hepatotoxicity management guidelines.

Changes to the visit schedule and assessments:

Clarification of laboratory parameters collection plan and viral hepatitis testing.

In addition, clarifications have been made with regards to the definition of 
postmenopausal status at study entry and hormone-replacement therapy. The rationale for 
these clarifications is based on the fact that bilateral oophorectomy can effectively render 
patients postmenopausal, and has a therapeutic effect in hormone-sensitive breast cancer. 
Therefore, it can be considered an endocrine treatment in its own right. In those patients 
where bilateral oophorectomy was performed, this procedure must have been performed at 
least 6 months prior to study entry and prior to the diagnosis of breast cancer, in order to 


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ensure that women are truly menopausal at study entry, and to avoid any potential 
influence of bilateral oophorectomy in the study treatment effect (Neven et al, 2015). 
Similarly, hormone-replacement therapy in postmenopausal women can also influence the 
biology of hormone receptor positive breast cancer and its response to endocrine treatment. 
Therefore, a minimum wash out period of 28 days is mandated for those women who were 
taking hormone replacement therapy.

Changes in the inclusion criteria #3: Patient must be postmenopausal at the time of breast 
cancer diagnosis. For those women that have had a prior bilateral oophorectomy, this 
procedure must have been performed at least 6 months before the diagnosis of breast 
cancer in order to be considered post-menopausal.

Changes in the exclusion criteria #5: Patients receiving hormone-replacement therapy 
must have discontinued such therapy 28 days before study entry.

In accordance to the Summary of Product Characteristics of letrozole clarifications have 
also been made with regards to the patient population of the study (i.e. patients for whom 
immediate chemotherapy or immediate surgery is indicated are not eligible).

Changes in the patient population: clarification that patients for whom immediate 
chemotherapy or immediate surgery is indicated are not eligible.

Changes to the protocol

The following sections have been changed in the amended protocol:

Section 1.2.1.2 Clinical experience: addition of the outcome from a recent medical review 
for the liver toxicity.

Section 5.3 Exclusion criteria:

Addition of exclusion criterion #28 to exclude patients with an acute viral hepatitis or a 
history of chronic or active HBV or HCV infection.

Section 6.3.1.1 - Table 6-4 (Criteria for interruption and re-initiation of BYL719/placebo 
or buparlisib/placebo): Clarification of the management of AST or ALT side effects.

Section 6.3.2.1.5 Additional management and follow-up for selected toxicities: New 
section added “Management of hepatotoxicity (ALT and/or AST >3.0x ULN and total 
bilirubin >2.0x ULN) in patients receiving BYL719/placebo or buparlisib/placebo” 
including detailed liver event follow-up assessments and close monitoring measures.

Section 7.1 Study flow and visit schedule - Table 7-1 (Visit evaluation schedule): addition 
of hepatotoxicity follow-up testing/procedures.

Section 7.1.2.3 Patient demographics and other baseline characteristics: addition of viral 
hepatitis serology.

Section 7.2.2.5 Laboratory evaluations and Table 7-4 (Clinical laboratory parameters 
collection plan): addition of hepatotoxicity follow-up testing and procedures (Note: testing 
not mandatory). Updated full and partial biochemistry collections and parameters. 
Clarification on tests to be done fasting.

Section 7.2.2.5.6: New section added “Viral hepatitis serology and other tests for 
hepatotoxicity follow-up”.

Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.


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
Additional ChangesSection 5.1: Patient population has been clarified in alignment the 
therapeutic indications of letrozole laid out in the Summary of Product Characteristics.

Section 5.2: Inclusion criteria: clarification in inclusion criterion #3 in those patients must 
be postmenopausal at the time of breast cancer diagnosis. For those women that have had 
a prior bilateral oophorectomy, this procedure must have been performed at least 6 months 
before the diagnosis of breast cancer in order to be considered post-menopausal.
Clarification in inclusion criterion #4.
Clarification in inclusion criterion #6.

Section 5.3: Addition in the exclusion criterion #5 that patients receiving hormone-
replacement therapy must have discontinued such therapy 28 days before study entry.

Section 6.1.4: Clarification on treatment duration, including timing of surgery after 
finishing study treatment that includes letrozole.

Section 6.3.1.1, Table 6-4: Dose adjustment and management recommendations for 
hyperglycemia have been described in more detail.

Section 6.4.1.7 (Buparlisib paragraph): Reference was corrected.

Section 6.4.2.3 Clarification that paragraph is also applicable for buparlisib and that either 
BYL719 or buparlisib need to be discontinued if study treatment is interrupted for > 28 
days.

Section 7.1 Table 7.1: Timing of assessment HbA1c, fasting lipase, fasting lipid profile, 
grouped under the time window of day -7 to day-1 to minimize patient visits and facilitate 
receipt of batched results from the central lab to the investigator at once.

Section 7.1.1: Precision is brought for postmenauposal definition.

Clarification on PIK3CA mutation status and Ki67 status procedure.

Radiographic tumor assessments clarification in case of former source document.

Section 7.1.2.3 and Table 7-1: Corrected section reference numbers for Laboratory 
evaluation, ECG and Cardiac imaging.

Section 7.1.8: Breast Cancer Surgery: clarification that letrozole will be maintained until 
surgery when either BYL719/placebo or buparlisib/placebo has been prematurely 
discontinued.

Section 7.2.1: Radiographic tumor assessments clarification in case of former source 
document Clarification on MRI/US procedure.

Addtion of the FDA definition for pathological complete response.

Section 7.2.2: ECG/MUGA clarification in case of former source document.

Section 7.2.4: Biomarkers: Clarifications and renaming of tissue requirements and 
biopsies have been made to facilitate understanding and protocol compliance with regards 
to tumor tissue requirements and shipping. “Specimen 3” is now named “Cycle 1 Day 15 
biopsy”. Figure 7-1 has been updated accordingly.

Section 7.2.2.5, Table 7-4: Fasting and full biochemistry were defined.

Section 7.2.2.5.2 Clarification on Biochemistry.

Section 7.2.2.5.4: Clarification on INR.


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
Section 7.2.4.1, Table 7-9 and section Section 7.2.4.3.2 and Section 7.2.4.4, Figure 7-1: 
Tumor tissue identification was changed for more clarity.

Section 7.2.4.3.1: Clarification on tumor identification and on biomarker assessment 
procedure.

Section 7.2.4.3.3: Rewording for more clarity.

Section 7.2.4.4, Table 7-10: Rewording for more clarity.

Section 13: Updated References.

Section 14: Appendix 1 has been updated due to recent re-classification of the risk of 
certain QT prolonging drugs from possible / conditional risk to known risk. All other 
tables were also updated based on their sources.
IRB/IEC/HA
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 3
Amendment rationale
The main purpose of this protocol amendment is to correct a typo identified in Inclusion 
criteria #4 and #13.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

Section 5.2: correct Inclusion criteria #4 from “T1c-Tc” to “T1c-T3”.

Formatting issues identified in Inclusion criteria #13, INR and AST were re-aligned to be 
separate sub bullets as per the original protocol.
Amendment 2
Amendment rationale
As of January 23, 2015, 76 patients have been randomized in the study CBYL719A2201.
The main purpose of this protocol amendment is:

To revise the dosing schedule of buparlisib, from 100 mg QD to 100 mg QD 5 days on/2 
days off.

To modify the guidelines for pneumonitis management that has been revised based on the 
Urgent Safety Measure released on Dec 19, 2014 following accumulation of pneumonitis 
ases up to nine (including three with fatal outcome) within the BYL719 development 


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program. The most recent fatal case was reported from the CLJM716X2103 trial 
(BYL719 in combination with the anti-HER-3 monoclonal antibody LJM716).”

To modify and clarify some of the inclusion/exclusion criteria.

To update clinical efficacy and safety data of both buparlisib and BYL719 as a result of 
new available data and in alignment with the latest Buparlisib and BYL719 Investigators’ 
Brochure updates.

To make administrative changes for clarification and typographical errors have been 
corrected.
Rationale for the change in the dosing schedule of buparlisib
The dosing schedule will change from 100 mg QD daily to 100 mg QD 5 days on/2 days off.
And recommended dose reductions for

dose level -1: from 80 mg QD daily to 80 mg QD 5 days on/2 days off

dose level -2: from 60 mg QD daily to 60 mg QD 5 days on/2 days off
The first blinded safety review of the CBYL719A2201 study (planned by protocol) was 
conducted on the first 27 patients enrolled (data cut off Oct 1 st 2014). In the 
buparlisib/buparlisib placebo arms, among the 15 patients enrolled, 7 discontinued the study 
treatment: 5 for subject decision, and 2 for an adverse event (in both cases due to grade 4 
transaminases increase). The overall aim of these changes is to improve tolerability and 
decrease severe side effects in buparlisib/buparlisibplacebo arms.
The intermittent dosing schedule of buparlisib (i.e. 5 days on/2 days off) has been investigated 
in two phase Ib studies conducted in HR-positive HER2-negative metastatic breast cancer 
(BC), showing less incidence of severe adverse events of the intermittent schedule when 
compared to continuous dosing. (Please refer to Section 1.2.2. and Section 1.2.4. for further 
details).
In addition, simulation by means of a Population PK model for buparlisib has also shown that 
the intermittent regimen has the benefit of decreasing Cmax while maintaining an efficacious 
level of exposure (Section 1.2.2.2.3).
Therefore, based on the abovementioned data and the preliminary safety findings in the 
current study in buparlisib/buparlisibplacebo arms, the present amendment buparlisib alters 
the current dosing schedule to intermittent administration 5 days on/2 days off.
Intermittent schedule is to be implemented for new patients after the amendment approval.
Rationale for the modifications in pneumonitis management
On 12, December 2014, Novartis issued an Investigator Notification regarding a patient on 
study CLJM716X2103 (combination of BYL719 and LJM716) with a serious, unexpected, 
possibly related adverse event of fatal pneumonitis. Subsequently, an Urgent Safety Measure 
(USM) was put in place for the overall BYL719 program assessment. A letter was sent to all 
sites and investigators participating in BYL719 studies on 19th December 2014, requiring 
them to implement the USM immediately to adequately protect the patients. Therefore, safety 
management guidelines have been updated (Section 6.3).


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Rationale for the changes in the inclusion/exclusion criteria

Inclusion criterion #4 (tumor stage) has been clarified: patients with the diagnosis of either 
multifocal or multicentric BC are allowed to participate. Similarly, patients with 
synchronous bilateral BC can also take part on the study provided only one unilateral 
tumor lesion is considered for study purposes (i.e. assessment of pathological complete 
response [pCR]). In addition, patients with cM0 (i+) staging are required to provide 
radiological evidence of no gross metastatic disease in order to qualify for study entry.

The rationale for these clarifications reflects current clinical practice and international 
clinical guidelines for the use of neoadjuvant hormonal treatment in BC ([NCCN 2013
Guidelines].

Inclusion criterion #13 has been modified to: ANC ≥1.5 x 109 /L

The rationale for this change is to ensure adequate bone marrow function and to align 
with NCI CTCAE v4.03.

Potassium, calcium (corrected for serum albumin) and magnesium have to be within 
normal limits or ≤ grade 1 severity according to NCI CTCAE version 4.03 if judged 
clinically not significant by the investigator, as these values are considered acceptable 
for the purpose of the study.
The rationale for this change is to facilitate patient enrolment and is based on the 
exercise of clinical judgement in minimal electrolyte alterations (≤ grade 1 as per NCI 
CTCAE version 4.03) that otherwise would not pose any safety risk to the patient.

The upper limit of normal (ULN) for AST/ALT will be increased to allow 1.5 x ULN for 
study inclusion.

The rationale for this change is that mild and asymptomatic transaminase elevations at 
baseline are a common finding in this patient population (e.g. related to concomitant 
medications, fatty liver, etc.), and are currently one of the most common reasons for 
screening failure in this study.
Patient’s safety will continue to be ensured given the weekly monitoring of 
transaminases during the two first 2 cycles. Based on recently reported and published
data, a lower incidence and severity of transaminases increase is expected with the 
change from continuous to intermittent dosing schedule of 
buparlisib/buparlisibplacebo (Section 1.2.2).

Exclusion criterion #6 (diabetic patients) has been clarified in such a way that only 
patients with diabetes mellitus type 1 and steroid-induced diabetes mellitus are excluded.

The rationale for this change is to gain alignment and consistency with current 
inclusion criterion #13, where HbA1c ≤8% is required for study entry. Since Hb1Ac 
values above 6.5% are considered in its own right a diagnostic criterion for diabetes 
mellitus (American Diabetes Association Position Statement 2010), patients with type 
2 diabetes mellitus and values of HbA1c ≤8% will now be allowed to participate. This 
change also follows the the formal recommendation of the study Steering Committee.

Exclusion criteria #11, #12, and #13 (criteria related to the PHQ-9 and GAD-7 
questionnaires) will only apply to buparlisib/buparlisib placebo treatment arms. Patients 
meeting one of these criteria will be randomized to BYL719/BYL719 placebo arm.


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
The rationale for this change is based on the fact that BYL719 does not cross the blood-
brain barrier and no clinically relevant and/or severe (i.e. grade ≥3) treatment-related 
psychiatric side effects have been reported to date [BYL719 Investigators’ Brochure].

Exclusion criteria #23 (corticosteroid use) has been updated to reflect the recent finding of 
minor impact of corticosteroids on buparlisib metabolism (see Buparlisib Investigator’s 
Brochure). However, patients on chronic corticosteroids or other immunosuppressive 
agents continue to be excluded from the study entry.

Exclusion criterion #24 (warfarin use) has been retired based on changes with regards to 
the Conmed Section (see below).
Changes in the background section
Clinical background sections have been updated to align with the latest Invetigators’ Brochure 
of each compound (buparlisib and BYL719), and to reflect the newly reported clinical data of 
buparlisib and BYL719, particularly in combination with endocrine therapy (e.g. letrozole, 
fulvestrant) in HR-positive BC.
Changes in the skin toxicity management section
More detailed guidance for management of skin toxicity has been added given that it is one of
the most common side effects observed with buparlisib and BYL719. Such guidance is aimed 
at optimizing the treatment of this side effect. In particular, additional guidance is provided 
for different types of skin toxicity including specific recommendations for therapeutic 
approaches.
Changes in the concomitant medications section
Section 6.4 “Concomitant medications” and Appendix 14.1 “Concomitant medications” have 
been changed to simplify understanding of concomitant medications permitted and prohibited 
for both treatments arms.
In addition, some of the criteria were reworded based on the current knowledge on the 
pharmacology of BYL719, buparlisib and letrozole as follows:

As it has been shown by the human ADME that the metabolism and clearance of BYL719 
in vivo is not dependent on CYP3A4 (Section 1.2.1.1.2) and the label of letrozole does not 
require the exclusion of any CYP3A4 inhibitors or inducers (Femara Prescribing 
Information), strong inhibitors or inducers of CYP3A4/5 are now permitted to use with 
caution for the BYL719/placebo + letrozole arm. They are still prohibited for the 
buparlisib/placebo + letrozole arm due to the dependence of the metabolism of buparlisib
on CYP3A4/5.

Sensitive substrates of CYP3A4/5 and/or substrates of CYP3A4 that have a narrow 
therapeutic window are now permitted to be used with caution for both treatment arms in 
line with other BYL719 or buparlisib studies, where those have not been restricted. While 
BYL719 is a time-dependent inhibitor of CYP3A4 in vitro (KI,u=5.2 μM, kinact 0.011 
min-1), recent data has shown that it is also an inducer of CYP3A4 (Section 1.2.1.1.2). 
Based on available clinical data and PBPK modelling both opposing effects seem to 


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balance each other out. As buparlisib is only a weak, reversible inhibitor of CYP3A4 (Ki,u 
= 13.4 μM) restriction of these substrates is not necessary.

Warfarin and coumarin derivatives are now permitted with caution in both arms but 
should be avoided whenever possible (6.4.1.5). While both BYL719 and buparlisib have 
shown some inhibitory potential towards CYP2C9, the major metabolizing enzyme of S-
warfarin, as well as other 2C-family enzyme, inhibition was weak (Section 1.2.1.1.2 and 
1.2.2.1.2). The median Cmax values observed at steady state in the first in man trials at the 
respective MTDs were around 8.1 µM (0.9 µM unbound) for BYL719 and 4.3 µM (0.7 
µM unbound) for buparlisib. A risk assessment based on the mechanistic static model (or 
a “net effect model”) by Fahmi et al, 2008 assuming fraction metabolized (fm) by 
CYP2C9 to be 1 for warfarin and no gut metabolism (FG = 1), predicted an AUCR to be 
<1.1. Hence it is unlikely that inhibition of CYP2C9 or other CYP2C-family enzymes, 
which showed an even less inhibitory potential, translates into a clinical interaction with 
warfarin (R-warfarin is metabolized by multiple CYP enzymes). A clinical interaction 
study between letrozole and warfarin showed no clinically significant effect of letrozole 
on warfarin pharmacokinetics.
Changes in the discontinuation of study treatment section
Clarifications regarding the discontinuation of clinical trial protocol elements have been 
added throughout the protocol. Updated language in this protocol amendment is aimed at 
differentiating between patients who:

discontinue certain clinical trial protocol (CTP) elements (discontinue study treatment, or 
some or all visits etc.);

patients who withdraw consent;

and patients who are lost to follow-up.
Changes in the treatment assignment and randomization section

PIK3CA mutation status and Ki67 results will not be communicated to the site at the time 
of randomization to avoid any potential bias.

As exclusion criteria #11 and/or #12, and/or #13, will now be applicable only to 
buparlisib/buparlisib placebo treatment arms, patients meeting any of these exclusion 
criteria will be randomized to BYL719/BYL719 placebo plus letrozole arm through the 
interaction response technology (IRT) system.
Changes in visit schedule and assessments

The receipt of PIK3CA mutation status and Ki67 results by the site before randomization 
has been changed to indicate that these results will not be communicated to the 
site.Ophtalmologic evaluations will no longer be necessary at screening, based on the 
latest clinical safety information provided in the updated edition of the [BYL719 
Investigators’ Brochure].

Instructions for sites have been added to capture pCR information of those patients who 
discontinued earlier than planned (i.e. before 24 weeks) study treatment (without 
withdrawal of consent) and opt for immediate surgery (i.e. within 30 days post-
discontinuation) in order to fully assess treatment efficacy.


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Changes in the biomarker section
Additional circulating DNA collections were added to assess feasibility of circulating DNA 
for monitoring for disease progression and correlation with tumor molecular profiling.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

Section 1.2.1.1.2: added new information regarding induction of CYP3A4 by BYL719 in 
vitro.

Section 1.2.1.2 (based on current BYL719 Investigators’ Brochure version):

Updated list of ongoing BYL719 studies, and the new data collected since the last 
version of the protocol.

Updated clinical safety and efficacy of BYL719 to include new data acquired after the 
study has begun.

Section 1.2.1.3: updated Cmax and Racc information.

Section 1.2.1.4: added new supportive information regarding interaction of BYL719 
with Letrozole.

Section 1.2.2.2: updated section to include new clinical data (based on current Buparlisib 
Investigators’ Brochure version).

Updated clinical safety and efficacy of Buparlisib to include new data acquired after 
the study has begun.

Section 1.2.2.2.1: Updated with current program information based on current Buparlisib 
Investigators’ Brochure:

Hyperglycemia language.

Psychiatric mood disorders and clarified who should do psychiatric consultation.

Liver Toxicity language with more current information.

Skin rash and hypersensitivity with more current information.

Lung Toxicity language with more current information.

Section 1.2.2.2.2. Added preliminary results of an ongoing phase Ib study; updated
references are provided.

Section 1.2.4:

Added sub-headings to clarify if data provided is preclinical or clinical.

Updated Buparlisib + Letrozole information based on the preliminary results recently 
reported.

Updated BYL719+Letrozole information based on the preliminary results recently 
reported.

Section 2.3:

Updated CBYL719X2101 study data.

Updated CBYL719ZUS03T study data.

Updated buparlisib dosing schedule and provided rationale for the change.


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
Section 2.5: provided updated references.

Section 3.1 Table 3-1:

Primary Objective: added “(QD continuous or QD 5 days on/2 days off)” to clarify 
that patients on a continuous regimen and intermittent regimen will be analyzed for 
the primary objective.

Updated Buparlisib administration schedule as “QD continuous or QD 5 days on/2 
days off”.

Replaced “Investigator” with “local”.

Section 4.1:

Updated the tumor requirements at screening for clarification.

Added “for any other reason than documented disease” in 5th paragraph for 
clarification.

Modified to clarify the tissue requirements for molecular prescreening/screening.

Explained logistical changes of receiving the PIK3CA mutation status and Ki67 
results at screening.

Treatment Phase: change the buparlisib frequency from “QD” to “5 days on/2 days 
off”.

Section 4.2: deleted ‘approximately” before 30 days for clarity.

Section 4.3: Deleted “prematurely” and added “discontinued or” before” withdrawn 
patient”.

Section 5.2 (Inclusion Criteria):

Provided clarifying language to #3 for the definition of post-menopausal status.

Provided clarifying language to #4 of the types of breast cancer allowed into the study.

Updated requirements for potassium, calcium, magnesium, AST and ALT in #13.

Section 5.3 (Exclusion Criteria):

Updated #6 to allow for diabetes mellitus type 2 patients to be now allowed into the 
study.

Updated language to #11, #12, and #13; to indicate that these criteria are applicable to 
the buparlasib/buparlisib placebo arm only.

Updated the use of corticosteroid use to #23.

Retired criterium #24.

Section 6.1.1: Updated Table 6-1 with updated buparlisib dosing schedule.

Section 6.1.2.1: Clarified dosing frequency of BYL719 and buparlisib and added that 
patients are allowed to drink water after administration of BYL719/placebo or 
buparlisib/placebo.

Section 6.1.4: Updated language and provided new study drug dosing frequency.

Section 6.3.1: clarified that patients must be
permanently
discontinued from 
BYL719/buparlisib if withheld for more than 28 days.

Section 6.3.1.1:


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
Provided new buparlisib dosing frequency and timing of re-introduction in the event 
of a buparlisib interruption.

Updated Table 6-3 with buparlisib dosing frequency.

Clarified that if patients discontinue from BYL719/placebo or buparlisib/placebo that 
patients can continue on letrozole until study completion.

Updated Table 6-4 with clarifying language throughout, and adjusted dose 
modification for rash maculopapular (Grades 1-3).

Section 6.3.2.1.1: Added new management of pneumonitis language per Dec. 19, 2014 
Urgent Safety Measure and updated Table 6-5.

Section 6.4: Updated entire section to include more specific instructions on the use of 
permitted (section 6.4.1) and the exclusion of prohibited (section 6.4.2) concomitant 
medications.

Section 6.5.2: added that PIK3CA mutation and Ki67 status results will be not be 
communicated to study sites and that patients meeting exclusion criteria #11 and/or #12, 
and/or #13, and/or #15 will be randomized to BYL719+letrozole or placebo+letrozole and 
will be assigned to BYL719 or BYL719 matching placebo.

Section 6.6.1: Updated Table 6-6 with new buparlisib dosing frequency.

Section 7.1 added “Visit windows of +/- 3 days are allowed (except at cycle 1 Day 1 and 
where specified in Table 7-1).”

Section 7.1 Table 7-1 removed “Receipt of” from “Receipt of PIK3CA mutation and Ki67 
status results” from list of evaluations and added “entered into IRT” after “Ki67 status 
results”; updated frequency of vital signs evaluation by removing C1D8 and C1D22; 
deleted Ophthalmologic Evaluations; updating buparlisib administration schedule from 
“Daily Continuous Dosing” to “5 days on/2 days off”.

Section 7.1.1 removed all references to receipt of PIK3CA mutation and Ki67 status 
results by sites; specified that no previous treatment has been received for “current 
diagnosis”; updated the logistics of patient randomization.

Section 7.1.2 specified that re-screening can be done only one time.

Section 7.1.2.2 removed all references to receipt of PIK3CA mutation and Ki67 status 
results by sites.

Section 7.1.2.3 added Ki67 results and deleted reference to Ophthalmologic examination.

Section 7.1.4 added that patients who discontinue but do not withdraw study informed 
consent and go for surgery will have pCR results communicated to Novartis.

Sections 7.1.4, 7.1.5, and 7.1.7 replaced Sections 7.1.3.1 and 7.1.3.2 to differentiate 
between patients who: discontinue study treatment, or some or all visits etc., withdraw 
consent, or are lost to follow-up.

Sections 7.1.6 updated section title to clarify type of follow up visit.

Section 7.2.1 indicated that pCR must be performed following pCR guidelines distributed 
by Novartis and timelines for pCR submission via eCRF and material to be sent to 
Genoptix after surgery and local pCR assessment is complete within recommended 
timeframes.


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
Section 7.2.2.5 was removed as ophthalmologic exam is no longer required for this study
as per latest BYL719 Investigators’ Brochure update.

Section 7.2.2.6 was replaced with 7.2.2.5 and updated to remove visit window language, 
which was moved to section 7.1.

Sections 7.2.2.5 Table 7-4 removed calcium from Biochemistry collection panel and 
added “Prothrobin Time (PT)” and aPTT to Coagulation.

Section 7.2.2.5.4 added “prothrombin time (PT)” and “or aPTT”.

Section 7.2.2.7 Table 7-6 removed word mandated from Visit/Cycle column; indicated 
that patients meeting exclusion criteria 11-13 or 15 will be excluded from the buparlisib 
arm.

Section 7.2.2.8 updated PHQ-9 and GAD-7 language.

Section 7.2.4 was adapted to add new collections of circulating DNA collections and 
tumor tissue requirements at surgery.

Section 7.2.4.1 Table 7-9 was updated to capture the changes in the circulating DNA 
collection schedule.

Section 7.2.4.2.1 updated the number of slides required for the diagnostic biopsy.

Section 7.2.4.3.1 updated language for the collection of Specimen 2 and circulating DNA.

Section 7.2.4.3.2 added language specific for blood collection.

Section 7.2.4.3.3 added instructions for tumor tissue collection: “4 samples from the 
surgical specimen (2 of these samples should be formalin fixed and shipped in ethanol the 
other 2 should be snap frozen and shipped on dry ice)”.

Section 7.2.4.4 Figure 7.1 was updated to capture the changes in the circulating DNA 
collection schedule.

Section 7.2.4.4 Figure 7.1 under Surgery updated language from “24 weeks (± 2 weeks)” 
to read “24 weeks (up to 26 weeks)”.

Section 7.2.4.4 Table 7-10 removed all references to additional biopsy informed consent 
as there is no additional biopsy ICF for this study; this biopsy is mandatory and hence part 
of the main ICF.

Section 7.2.4.4 added “Optional additional biomarker studies” statement to indicate length 
of biomarker sample storage and potential usage of samples.

Section 9.3: added “recommended to be” before “performed” and “within 5 days of the 
visit” after “performed”.

Section 10.1.4.4: replaced “for the last consecutive 7 days” with “on 10 days out of 14 
days”.

Section 10.4: updated Buparlisib administration schedule as “QD continuous or QD 5 
days on/2 days off”, added ‘QD” after “letrozole”.

Section 10.4.2: added “mean” after “estimated” to second bullet point for clarity.

Section 10.4.4: added a supportive analysis using the subpopulation of patients who 
receive the intermittent schedule if the proof of concept is established with buparlisib plus 
letrozole in at least one cohort.


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
Section 10.5.4 Table 10-1: Deleted CL and Vss and their definitions and updated units as 
appropriate throughout the table.

Section 10.5.4.1.1: corrected LLOQ of 1.00 ng/ml to 5.0 ng/ml.

Section 13: Added 5 new references.

Section 14.1: Clarified the list of concomitant medications; replaced Tables 14-1, 14-2, 
14-3 and 14-4 and added Tables 14-5 and 14-6.
Amendment 1
Amendment rationale
The recruitment of first patient will occur after implementation of the following amendment.
The purpose of this protocol amendment is:

To revise the starting dose of BYL719 from 350 mg QD to 300 mg QD and corresponding 
dose reduction guidelines.

To change study inclusion/exclusion criteria, concomitant medications, dose adjustments 
and follow up of toxicities.

To include additional analyses for safety.
Administrative changes are made for 
clarification and typographical errors have been corrected.
Change in starting dose of BYL719/placebo and corresponding dose reduction 
guidelines:
CBYL719ZUS03T is a phase I trial conducted to establish the recommended dose for the 
combination of BYL719 and letrozole in ER+ HER2- advanced/metastatic breast cancer. 
Updated results from this study have shown that the administration of BYL719 given at the 
dose of 350mg together with letrozole at the standard dose of 2.5mg was limited by the 
occurrence of adverse events and mainly rash: although only 1 patient experienced a DLT at 
this dose, 4 out of 6 patients required dose reduction. The 300mg dose was administered to a 
total of 5 patients so far: none of these patients presented DLT during cycle 1 nor needed a 
dose reduction due to adverse events, and 2 confirmed partial responses were observed. Based 
on these findings, 300 mg QD can be considered an acceptable starting dose for the 
combination of BYL719 and letrozole 2.5 mg (Communication from CBYL719ZUS03T 
principal investigator, Ingrid Mayer, October 2013).
As a consequence of the change in the starting dose of BYL719, dose reduction levels for 
BYL719/placebo are modified as follows: first dose reduction will consist of 
BYL719/placebo given at the dose of 250 mg QD daily and the second dose reduction will 
consist of BYL719/placebo given at the dose of 200 mg QD daily.
Changes in inclusion/exclusion criteria and concomitant medications:
To take into consideration the curative intent of neoadjuvant treatment - in the absence of any 
new safety signal within BYL719 and BKM120 programs - and to integrate new emerging 
findings, the following Inclusion/Exclusion criteria have been modified, as well as chapter 6.4 
“concomitant medications”:


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
Inclusion criteria # 4:
Patients with T1c breast cancer tumors are allowed to enroll in the trial per investigator’s 
discretion.
The inclusion criterion is modified as these patients may benefit from neoadjuvant endocrine 
therapy. In a clinical trial where letrozole was given as neoadjuvant treatment (duration 3 -12 
months), clinical responses and benefit were seen in patients with T2 or T3 tumors, as well as 
in patients with T1 tumors (Dixon 2009).

Exclusion criteria # 10 and addition of a new exclusion criteria (# 20):
Patients with a history of ‘acute pancreatitis’ and ‘patients with a history of pneumonitis o r 
interstitial lung disease’ are excluded from the study per modified exclusion criteria # 10. 
‘Patients with congenital long QT syndrome or family history of unexpected sudden cardiac 
death’ are excluded as per added exclusion criteria # 20.
The following are known adverse events for both BYL719 and buparlisib:

Amylase/lipase increases have been observed in patients receiving either BYL719 or 
buparlisib, although the majority of these events were of mild to moderate severity.

Cases of lung toxicity and pneumonitis have been observed with the administration of 
buparlisib and to a lesser extent, BYL719.
In addition, pre-clinical, clinical data and PK-QT modeling from study first in man single 
agent dose escalation trial CBKM120X2101 showed no effect of buparlisib on QT. From 
preclinical cardiac BYL719 safety studies, no relevant electrophysiological effect was seen 
and the only effect considered significant was an increase in systolic and diastolic blood 
pressure, observed in a dog telemetry study. In addition, as of May 2013, two patients in the 
single agent treatment (1.4%) experienced drug-related QTc prolongation/cardiac 
dysrhythmias/cardiac ischemia events; neither of these drug-related events was assessed as 
Grade 3 or 4, and BYL719 did not cause any clinically evident arrhythmia. PKQT modeling 
will be done in BYL719 first in man dose-escalation study CBYL719X2101 and results 
provided as they become available.
Monitoring of these potential adverse events and specific dose adjustments are already 
included in the protocol and no new safety findings have been seen within BYL719 and 
buparlisib programs.
Hence exclusion criteria #10 and #20 are modified/added to remain conservative in the 
curative setting of neoadjuvant treatment.

Exclusion criteria # 25 is changed as well as Concomitant medication chapter (6.4):
The use of moderate CYP3A4 inhibitors and inducers is now allowed for patients entering the 
study: recent results from a buparlisib drug-drug interaction study conducted with a strong 
CYP3A4 inhibitor (ritonavir) [CBKM120C2111] have shown a lower than anticipated 
involvement of the CYP3A4 in the metabolism of buparlisib. This is also in line with the 
results of a drug-drug interaction study with dexamethasone (a weak CYP3A4 inducer) 
[CBKM120C2106] which showed no significant change in buparlisib pharmacokinetics. Thus, 
moderate CYP3A4 inhibitors and inducers can be used with caution with buparlisib on the 
basis of these trials.


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As CYP3A4 inhibitors and inducers are per se not prohibited by the Femara label nor for 
BYL719, moderate CYP3A4 inhibitors and inducers will also be allowed for the BYL719 
combination arm. Based on the potential risk of an interaction between letrozole and BYL719 
due to time-dependent CYP3A4 inhibition by BYL719 and letrozole pharmacology, strong 
CYP3A4 inhibitors and inducers are still excluded. Hence the exclusion criteria # 25 has been 
modified to exclude only patients receiving strong inhibitors or inducers of isoenzyme 
CYP3A and not those receiving moderate inhibitors or inducers. The patient must have 
discontinued strong inducers for at least one week and must have discontinued strong 
inhibitors before the start of treatment. Switching to a different medication prior to 
randomization is allowed.
Changes in dose adjustment guidelines:
In the absence of any new safety signal within BYL719 and BKM120 programs, to ensure the 
most appropriate safety management in the current study, the following changes are made to 
implement more conservative dose modification adjustments:

Patients who interrupt treatment due to febrile neutropenia or grade 4 neutropenia and 
who decide to continue on study should restart study drug at a lower dose level.

Patients with symptomatic decline in ejection fraction or with an ejection fraction 20-39% 
or a >20% drop from baseline should permanently discontinue study drug.

Patients with a grade 3 elevation of bilirubin or of AST/ALT who subsequently recover to 
grade ≤ 1 and who decide to continue on study should restart study drug at a lower dose 
level, and

Patients with a grade 4 elevation of AST/ALT should permanently discontinue study drug.

Management of grade 3 hyperglycemia adverse events is changed to be more stringent as 
permanent discontinuation of the study drug is now recommended when there is no 
recovery of the event to a grade 1 within 14 days (instead of 28 days originally), despite 
study drug omission.

Management of skin toxicities has been updated and specific paragraphs for 
corresponding type of skin toxicities have been added to allow for a better management of 
this side effect.
Change in the follow up for toxicities:
In addition, as pneumonitis and skin rash are events that could be associated to PI3K 
inhibitors class, and not only specific for buparlisib only, the management and follow-up of 
them is applied to both buparlisib/placebo and BYL719/placebo. More detailed information 
on co-medications that can be used for the management of skin toxicities is added.
Changes in the statistical section:
Periodic review of safety data aggregated by blinded treatment group (BYL719/placebo or 
buparlisib/placebo) will be performed and results will be shared with Study Steering 
Committee.


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Change in End of treatment phase completion and End of post-treatment 
follow-up
Pregnancy is not a criterion for End of treatment phase completion and End of post-treatment 
follow-up; as it is post-menopausal patient population.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

Updated information related to the phase Ib clinical study of BYL719+letrozole 
(CBYL719ZUS03T) throughout the document: Sections 1.2.1.2, 1.2.4 and 2.3.

Starting dose reduced from 350 mg to 300 mg throughout the protocol.

Section 1.2.1.4: added rationale for decreased likelihood of letrozole plasma exposure 
when combined with BYL719 at 300 mg dosing.

Section 1.2.2.1.2: replaced “(estimated fraction metabolized >0.9)” with “in vitro” to 
indicate how metabolism of buparlisib was obtained.

Section 1.2.2.2.3: added rationale for allowing the use of moderate CYP3A4 inhibitors 
and inducers.

Section 2.3: added “for 24 weeks” to read “BYL719 300 mg QD will be given in 
combination with letrozole 2.5 mg QD for 24 weeks.”

Section 2.3: added rationale for 24 week treatment.

Section 5.1 and Section 5.2 (Inclusion Criteria #4): “T2-T3” is replaced by “T1c-T3”

Section 5.3 (Exclusion Criteria):

Exclusion Criteria #10: Added “acute or” and “pneumonitis or interstitial lung 
disease”.

Added Exclusion Criteria #20.

Exclusion Criteria # 25: Deleted “moderate” inhibitors of isozyme CYP3A.

Section 6.1.1 Table 6.1 Dose and Treatment Schedule footnote #2 changed “300” to “250” 
and “2 X 50 mg” to “1 X 50 mg” to reflect changes in dose reductions.

Section 6.3.1.1: updated the lowest dose which subjects can be administered before study 
treatment discontinuation to 200 mg and updated Table 6.2 (Dose reduction sequential 
steps for BYL719/placebo) with updated dosing schedule.

Section 6.3.1.1: Updated Table 6.4 (Criteria for interruption and re-initiation of 
BYL719/placebo or buparlisib/placebo) to indicate study drug to be dose adjusted 
throughout the table and provide more conservative language to the Dose adjustment and 
Management Recommendations for hematology, cardiac, hepatic, hyperglycemia and rash 
maculopapular. Added dose adjustment and management recommendations for Pruritus 
and Rash (Acneiform).

Section 6.3.2.1.1 broadened language to include treatment of patients for pneumonitis on 
either buparlisib or BYL719.


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
Section 6.3.2.1.1 Table 6.5 Management of pneumonitis in patients receiving 
buparlisib/placebo added “is recommended and” to Grade 3 Required Investigations as no 
guidance was previously given in the protocol.

Section 6.3.2.1.4 added “sunscreen” as an additional means to protect against study drug 
induced skin toxicities, recommendation to take photographs and biopsies of rashes, and 
added description of types of skin toxicities and suggested treatments.

Section 6.4.1: removed “and moderate” throughout section to indicate only strong 
CYP3A4 inhibitors and inducers are prohibited.

Section 6.4.2: added “or moderate” throughout section to indicate use of moderate CYP3A 
inhibitors and inducers are permitted.

Section 7.2.2.5 added “or a qualified health care specialist.” to make it easier for the sites 
to meet the requirement.

Section 7.2.4.4 Figure 7.1 under Surgery updated language from “24 weeks (± 2 weeks)” 
to read “24 weeks (up to 26 weeks)”.

Section 7.2.4.4 Table 7-10 removed all references to additional biopsy informed consent 
as there is no additional biopsy ICF for this study; this biopsy is mandatory and hence part 
of the main ICF.

Section 7.2.4.4 added “Optional additional biomarker studies” statement to indicate length 
of biomarker sample storage and potential usage of samples.

Section 10.5.3.1 added periodic safety analysis in which results will be shared with the 
study steering committee.

Section 13 added references supporting 24 week treatment duration.

Section 14.1.1, Table 14.1 List of prohibited medications during BYL719+letrozole 
combined treatment, and Table 14.2 List of prohibited medications during 
buparlisib+letrozole combined treatment the following medications are deleted.
Moderate CYP3A 
Inhibitors 
Amprenavir, aprepitant, atazanavir, casopitant, cimetidine, ciprofloxacin, cyclosporine, 
darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fosamprenavir, grapefruit 
juice (citrus paradisi fruit juice), imatinib, Schisandra sphenanthera2, tofisopam, verapamil
Moderate CYP3A 
Inducers 
Bosentan, efavirenz, etravirine, genistein, modafinil, nafcillin, ritonavir, talviraline, 
thioridazine, tipranavir

Section 14.1.1, Table 14.3 List of medications to be used with caution during 
BYL719+letrozole combined treatment, and Table 14.4 List of medications to be used 
with caution during buparlisib+letrozole combined treatment: the following medications 
are added.
Moderate CYP3A 
Inhibitors 
Amprenavir, atazanavir, casopitant, cimetidine, ciprofloxacin, cyclosporine, darunavir, 
diltiazem, dronedarone, erythromycin, fluconazole, fosamprenavir, grapefruit juice (citrus 
paradisi fruit juice), imatinib, Schisandra sphenanthera2, tofisopam, verapamil
Moderate CYP3A 
Inducers 
Bosentan, efavirenz, etravirine, genistein, modafinil, nafcillin, ritonavir, talviraline, 
thioridazine, tipranavir

Section 14.2.16 removed bullet “Central Blinded Review overall lesion response.” or any 
reference to a central review.

Section 14.2.29, removed Pregnancy as a criterion for End of treatment phase completion.

Section 14.2.30, removed Pregnancy as a criterion for End of post-treatment follow-up.


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IRB/IEC/HA
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. In addition, if 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 amended protocol.


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Protocol summary:
Protocol number
CBYL719A2201
Title
A phase II randomized, double-blind placebo controlled, study of letrozole with or 
without BYL719 or buparlisib, for the neoadjuvant treatment of postmenopausal women 
with hormone receptor-positive HER2-negative breast cancer
Brief title
Study of safety and efficacy of neoadjuvant treatment with BYL719 or buparlisib plus 
letrozole in postmenopausal women with hormone receptor-positive HER2-negative breast 
cancer patients 
Sponsor and
Clinical Phase
Novartis
Phase II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
● The purpose of the study is to determine whether treatment with a PI3K inhibitor (either 
alpha specific: BYL719 or pan PI3K inhibitor: buparlisib) plus letrozole leads to an increase 
in pathologic response and Objective Response Rate compared to treatment with placebo 
plus letrozole in patients with hormone receptor-positive HER2-negative breast cancer for 
the following populations: i) in patients with tumors harboring a mutation in the PIK3CA 
gene ii) in patients with tumors harboring a wild type PIK3CA gene.
● The addition of a PI3K-AKT-mTOR inhibitor to letrozole has already been shown to lead 
to improved clinical outcomes when compared to letrozole alone in a randomized phase II 
trial in neoadjuvant treatment of postmenopausal women (Baselga 2009). Promising pre-
clinical data showing potential for cell death in addition to decreased proliferation have 
been observed when PI3K inhibitors are given in combination with hormonal therapy 
(Sanchez 2011). Furthermore, clinical activity has been observed with single agent BYL719 
and buparlisib and combination of buparlisib and letrozole when given to pretreated 
metastatic breast cancer patients.
● Hence the use of BYL719 or buparlisib in combination with letrozole may improve 
letrozole single agent outcomes by increasing the rate of of pathologic complete response 
or Objective Response Rate and might prove to be an effective treatment in neoadjuvant 
treatment for postmenopausal HR+ HER2- BC patients.
Primary 
Objectives
● To assess the anti-tumor activity of BYL719 QD plus letrozole QD versus letrozole alone 
in increasing the pathologic complete response (pCR) rate during neo-adjuvant treatment 
among postmenopausal patients with HR+, HER2-negative breast cancer for each of the 
two cohorts: i) PIK3CA mutated and ii) PIK3CA wild type tumors based on tumor tissue.
and
● To assess the anti-tumor activity of BYL719 QD plus letrozole QD versus letrozole alone 
in increasing the Objective Response Rate (ORR) during neo-adjuvant treatment among 
postmenopausal patients with HR+, HER2-negative breast cancer for each of the two 
cohorts: i) PIK3CA mutated and ii) PIK3CA wild type tumors based on tumor tissue.
Secondary 
Objectives
● To assess the anti-tumor activity of BYL719 QD plus letrozole versus letrozole alone in 
increasing the pCR rate and ORR for each of the two cohorts: i) PIK3CA mutated and ii) 
PIK3CA wild tumor types, based on ctDNA.- To evaluate the safety and tolerability of the 
drug combinations, and separately for buparlisib continuous and intermittent schedules
● To estimate the rate of breast conserving surgery for each of the two cohorts, namely, i) 
PIK3CA mutated and ii) PIK3CA wild type based on tumor tissue
● To evaluate the association between changes in Ki67 from baseline to day 15, and 
baseline to surgery, with pCR for each of the two cohorts, namely, i) PIK3CA mutated and 
ii) PIK3CA wild type based on tumor tissue
● To assess Preoperative endocrine prognostic index (PEPI) score for each of the two 
cohorts, namely, i) PIK3CA mutated and ii) PIK3CA wild type based on tumor tissue
● To characterize the pharmacokinetics of BYL719/buparlisib and letrozole when given in 
combination


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Study design
● This is a multi-center randomized, double-blind, placebo controlled phase II study 
comparing, oral tablets of BYL719 300 mg daily in combination with daily letrozole 2.5 mg 
and oral capsules of buparlisib 100 mg 5 days on/2 days off in combination with daily 
letrozole 2.5 mg to placebo in combination with letrozole 2.5 mg as neoadjuvant treatment 
in postmenopausal patients with HR-positive HER2-negative breast cancer.
● Recruitment in the buparlisib/buparlisib placebo arm was stopped on December 22, 
2015. The buparlisib/buparlisib placebo patients ongoing at the time of the end of patient 
recruitment in this buparlisib arm may continue to be treated under their assigned 
treatment if they benefit from the treatment according to investigator’s clinical judgment.
● Patients will undergo screening phase including molecular pre-screening to establish the 
PIK3CA mutation status, and assess the Ki67 status for stratification and randomization.
● A total of approximately 320 patients will be grouped into two cohorts (i.e. PIK3CA 
mutated and PIK3CA wild-type). Within each cohort, patients will be randomized in one of 
the treatment arms, after stratification according to Ki67% (<14% vs. ≥14%, as measured 
by Novartis designated central lab) and lymph node status (positive or negative).Following 
the permanent stop of the enrollment in the buparlisib arm, the target number of 60 patients 
per arm in each cohort remains unchanged for the BYL719 and placebo arms. However a 
lower number of patients will be randomized to buparlisib.
● Patients will be treated for 24 weeks until surgery, progression, unacceptable toxicity or 
discontinuation from the study treatment for any other reason. Definitive breast surgery will 
be performed as early as possible after treatment, no later than 14 days after the last dose 
of BYL719/placebo or buparlisib/placebo. Surgical breast and axillary node resection 
specimens will be evaluated for pathologic tumor response.
● Tumor evaluations will be performed at baseline, at cycle 4 day 1 (with a window of +/- 7 
days) and at maximum 7 days before surgery. At least 15 patients in each treatment arm 
will have PK sampling performed in order to characterize the PK of buparlisib and BYL719 
when given in combination with letrozole as well as the PK of letrozole.
● Safety follow-up assessments should be completed 30 days after the last dose of the 
study treatment.
Population
The patient population consists of postmenopausal women with HR-positive, 
HER2negative, T1c-T3 breast cancer, whose disease has never been treated with local nor 
systemic treatment, and are eligible for endocrine neoadjuvant treatment.
Key Inclusion 
criteria
● Patient has T1c-T3, any N, M0, operable breast cancer
● Patients must have measurable disease
● Patient has diagnostic biopsy available for the analysis of PIK3CA mutation and Ki67 
level.
● Patient has estrogen receptor (ER) and/or progesterone receptor (PgR)-positive breast 
cancer as per local laboratory testing
● Patient has HER2-negative breast cancer defined as a negative in situ hybridization test 
or an IHC status of 0 or 1+ as per local laboratory testing
● Patient has known PIK3CA mutation status (mutated or wild-type), based on tumor tissue 
analysis, as defined by a Novartis designated laboratory. (Patients with unknown PIK3CA 
mutation status will not be enrolled)
● Patient has Ki67 level status determined centrally
● Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 
which the investigator believes is stable at the time of screening
Key Exclusion 
criteria
● Patient has locally recurrent or metastatic disease
● Patient has received any systemic therapy (e.g. chemotherapy, targeted therapy, 
immunotherapy) or radiotherapy for current breast cancer disease before study entry.
● Patient with type 1 diabetes mellitus, and/or not adequately controlled diabetes mellitus 
type 2
Investigational 
and reference 
therapy
● BYL719+letrozole
● Buparlisib+letrozole
● Letrozole
Efficacy 
assessments
● pCR
● Tumor response (ORR according to RECIST v1.1)


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Safety 
assessments
● Adverse events (AEs)
● Laboratory Evaluations (biochemistry, hematology, coagulation, insulin, fasting plasma 
glucose, urinalysis, C-Peptide, and HbA1c)
● ECOG Performance status
● ECG, vital signs, weight, physical exam and cardiac Imaging
● Patient’s self-reported mood questionnaires
Other 
assessments
● Plasma concentration time profiles of BYL719/buparlisib and appropriate individual PK 
parameters (e.g. AUCtau, Cmax, Tmax and other PK parameters if deemed appropriate)
● Plasma concentration time profiles of letrozole and appropriate individual PK parameters 
(e.g. AUCtau, Cmax, Tmax and other PK parameters if deemed appropriate)
● Ki67 and markers of cell death 
● Molecular analysis of the diagnostic biopsy and surgical specimen
Data analysis
● The primary analysis will be performed after all patients in each cohort have completed 
24 weeks of treatment and pCR evaluation is completed or after ALL patients have 
discontinued due to any reason.
● The pCR rates and ORR in each of the treatment arms will be summarized by cohort 
using descriptive measures including 90% confidence intervals using Clopper and Pearson 
(1934) exact method. The pCR rates and ORR will also be summarized by each stratum. 
Patients receiving letrozole plus BYL719 placebo and letrozole plus buparlisib placebo in 
the control arm will be combined together for all analyses. Efficacy of treatment with either 
of the combination arms will be declared if Proof of Concept (PoC) criteria on pCR or ORR 
are met in the respective cohorts. 
Keywords
Postmenopausal women, HR-positive, HER2-negative, treatment naive, T1c-T3 breast 
cancer, endocrine treatment, AI, neoadjuvant treatment, PIK3CA mutation status


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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 form of malignant tumor in women worldwide, and 
incidence rates are as high as 99.4 per 100,000 women (World Health Organization 2013). 
Subtypes of BC 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 2009). Within these subtypes 60-70% of breast 
tumors are HR+ (ER and/or PgR-positive) HER2-.
Therapies that interfere with ER functions such as tamoxifen or aromatase inhibitors (AI) 
have significantly contributed to mortality reduction in advanced breast cancer. Among the 
AIs, letrozole, anastrozole (non-steroidal AIs) and exemestane (steroidal AI) are also 
indicated for the adjuvant treatment of postmenopausal women with hormone receptor-
positive early breast cancer.
In locally advanced breast cancer, treatment options include surgery, radiation therapy, and 
systemic treatment such as chemotherapy and endocrine therapy, given in adjuvant and/or 
neoadjuvant setting. Neoadjuvant treatment was historically reserved for large inoperable 
locally advanced breast cancers and used with the intent to make these breast cancers operable. 
This approach has also demonstrated its potential in allowing breast conservation and 
avoiding mastectomies (Makris 1999), in assessing the response to treatment and adjusting it 
as needed (not possible in adjuvant setting) as well as providing prognostic information. It is 
also an excellent setting to perform biomarker analysis of the tumor, as tumor may be sampled 
at diagnosis, after few weeks of treatment and at final surgery (Makris 1999, Petit 2004). Its 
increasing role in breast cancer therapy has been recognized recently in a publication by FDA 
of a guidance for industry on “the use of neoadjuvant treatment of high-risk early stage breast 
cancer as an endpoint to support accelerated approval” (FDA 2012) for HER2-positive and 
triple negative breast cancers.
Use of endocrine neoadjuvant therapy was initially restricted to elderly ER+ BC patients 
based on the fact that hormone receptor positive tumors were responding less to 
chemotherapy as compared to other breast cancer types (Gianni 2005, Berry 2006, EBCTCG 
2005). More recent trials have shown the lack of interaction between neoadjuvant endocrine 
therapy outcome and age (Olson 2009), and comparable outcome between chemotherapy and 
endocrine neoadjuvant therapy in ER+ BC patients (Semiglazov 2007). Neoadjuvant 
endocrine treatment can thus now be proposed to postmenopausal women as neoadjuvant 
treatment regardless of their age (NCCN guidelines 2013).
In neoadjuvant trials, a variety of endpoints have been used like, pathological response rate, 
clinical response rate, breast conserving surgery rate, preoperative endocrine prognostic index
(PEPI) score and Ki67 variation (.clinicaltrials.gov ongoing endocrine neoadjuvant clinical 
trials).


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Pathological response rate is generally expected to be low with endocrine therapy alone and 
not predictive of clinical benefit (FDA 2012, Bottini 2005). However, it has been identified as 
an acceptable end-point for combination trials, in particular with PI3K inhibitors (Miller 
2011a), and presents the advantage that it can be validated and is a reproducible endpoint.
Ki67 is a marker of proliferation and its high level of expression in breast tumors after two 
weeks of endocrine therapy has been shown to be predictive of lower recurrence free survival 
(Dowsett 2007).
PEPI score is related to relapse risk and is a prognostic model that incorporates standard 
pathological staging variables and “on-treatment” biomarker values. This model was 
developed using data from the P024 neoadjuvant endocrine therapy trial that compared 4 
months of letrozole and tamoxifen before surgery, with follow-up data (median >60 months) 
to address the relationships between post-neoadjuvant endocrine therapy tumor characteristics 
and risk of early relapse. The model was validated using data from the IMPACT trial, an 
independent neoadjuvant endocrine therapy study that compared anastrozole, tamoxifen, or 
the combination for 3 months before surgery. The total PEPI score assigned to each patient is 
the sum of the risk points derived from the pT stage, pN stage, Ki67 level, and ER status of 
the surgical specimen (see Appendix 3 for more details). The total risk point score for each 
patient is the sum of all the risk points accumulated from the four factors in the model (Ellis 
2008).
1.1.2
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).
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). Moreover, preliminary data suggest that activation of the PI3K 
pathway may be a predictor of poor prognostic outcome in many cancers.
The dysregulation of the PI3K signaling pathway is implicated in many human cancers 
(Samuels 2004, Hennessy 2005, Markman 2010, Wong 2010, Yuan 2008) and includes the 
inactivation of the PTEN tumor suppressor 
gene (Sansal and Sellers 2004), 
amplification/overexpression or activating mutations of some receptor tyrosine kinases (e.g.: 
erbB3, erbB2, EGFR), and amplification of genomic regions containing AKT or PIK3CA 
genes (Cheng 1992, Cheng 1996, Shayesteh 1999, Markman 2010).
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
1.1.3
PI3K pathway activation in HR+ Breast Cancer
Over the past few years, progress has been made in understanding the molecular biology and 
genetics of BC which are central to the development of novel therapies.
PI3K is frequently altered in breast cancer. Gain-of-function mutations in oncogenes such as 
PIK3CA (encoding the catalytic subunit p110α) have been observed in about 10% to 40% of 
BC patients and are commonly observed in HR+ tumors. Inactivation of the tu mor suppressor 
gene PTEN via loss-of-function mutations, gene deletion or transcriptional down-regulation 
also leads to PI3K pathway activation and has been reported in up to 13% of HR+breast 
cancer patients, see Table 1-1.
Table 1-1
PI3K signaling pathway mutations and alterations in breast cancer
PIK3CA Mutation
PTEN mutation/loss
All breast tumors
36%
NR
HR+ HER2-
45%
13%
Triple Negative
9%
35%
HER2+
39%
4%
(Cancer Genome Atlas Network 2012)
It is anticipated that, on average, 36% of patients with HR+ breast cancer will be PIK3CA 
mutated. The overlap between PIK3CA and either PTEN or INPP4B alteration appears 
however relatively rare (Cancer Genome Atlas Network 2012 and Figure 1-2)


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Figure 1-2
Frequency of PIK3CA, PTEN and INPP4B alterations in breast cancer
Extracted from TCGA publication in Nature 2012. Left portion of the graph (dark blue and 
pale blue bars) represent luminal A and B patients (Cancer Genome Atlas Network 2012).
Furthermore, pre-clinical data have shown that the ER pathway interacts with the PI3K 
pathway. Extensive crosstalk has been shown between ER and growth factor pathway (Miller 
et al 2011a; Osborne and Schiff 2011). For example estrogen deprivation leads to 
hyperactivation of the PI3K/mTOR pathway, which induces in turn an increase in cell 
proliferation and survival (Bjornsti 2004; Crespo 2002; Huang 2004; Mita 2003; Wullschleger 
2006). This mechanism is linked to de novo or acquired resistance to endocrine the rapy 
(Campbell 2001), including AI resistance (Shoman 2005; Crowder et al 2009; Miller 2011a). 
Treatment with PI3K inhibitors in absence of estrogen can inhibit proliferation of long term 
estrogen deprived cell lines supporting the concept of using combination of a PI3K inhibitor 
with an endocrine therapy in breast cancer.
More specifically, inhibition of the PI3K pathway (including both alpha and beta subunits) 
has been shown to induce a unique synthetic lethality in the context of estrogen deprivation 
(Crowder et al 2009).
Hence, the combination of endocrine treatment and PI3K-inhibitors, which have shown to 
lead to increased cell death in vitro, could also lead to an increased pathologic response in 
clinics by eliciting tumor apoptosis.
Together these observations suggest that PI3K pathway could constitute an important 
therapeutic target for the treatment of patients with HR+ breast cancer in a neoadjuvant setting.
The combination offers potential for tumor cell death and delayed resistance to AI prolonging 
response to treatment.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of BYL719
BYL719 is an oral class I α-specific PI3K inhibitor belonging to the 2-aminothiazole class of 
compounds. Targeting the alpha isoform of PI3K is expected to reduce the potential for 
inducing treatment related toxicity and improve the therapeutic window over inhibitors with 
less isoform specificity. BYL719 strongly inhibits the PI3Kα isoform (both p110α wild-type 
and p110α mutated) and much less strongly the β, δ and γ isoforms. It is inactive against the 
majority of other kinases.


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BYL719 has demonstrated anti-tumor activity in preclinical in vitro and in vivo tumor models.
In vitro, BYL719 has been shown to inhibit the proliferation of cell lines harboring PIK3CA 
mutations. The combination of BYL719 and letrozole was studied in an in vitro model of 
MCF7 breast cancer cells engineered to express aromatase (MCF7-Aro). The extent of growth 
inhibition of the MCF7-Aro cell line was assessed in dose matrices across escalating doses of 
BYL719, letrozole and both drugs in combination. From this data, significant synergy was 
observed.
In vivo, BYL719 has demonstrated dose-dependent tumor growth inhibition in various 
subcutaneous tumor transplant models. Both in vitro and in vivo cross indication models 
(other than breast cancer) provided evidence that PTEN driven model might display a lesser 
sensitivity to BYL719, in particular if the pTEN alteration is concomitant with PIK3CA 
mutation. This feature however might not be relevant in HR+ breast cancer patients (see 
Section 1.2.4). BYL719 is currently being investigated in Phase I dose escalation trials and in 
Phase Ib combination trials. Doses up to 450 mg once daily (QD) have been administered to 
cancer patients. The MTD of single-agent oral BYL719 has been declared at 400 mg QD.
For further details on clinical and non-clinical experience, please refer to the latest version of 
[BYL719 Investigators Brochure].
1.2.1.1
Non-clinical experience
1.2.1.1.1 Pharmacodynamics of BYL719
In biochemical assays, BYL719 inhibits specifically p110α (IC50 = 5nM,) much more potently 
than the p110δ and γ isoforms. BYL719 is equipotent against the most common somatic 
mutations of p110α (H1047R, E545K) compared to wild type p110α. The BYL719 biological 
activity correlates with inhibition of various PI3K/AKT downstream signaling pathway 
components commonly used as indicators of pharmacodynamics. Please refer to the [BYL719 
Investigators Brochure] for further details.
In vivo, BYL719 shows dose and time-dependent inhibition of the PI3K/AKT pathway in 
relevant tumor xenograft models (p110α-mechanistic model and p110α-mutant xenograft 
models) in nude mice and rats. In vivo analyses of tumor tissues, upon acute dose or after 
multiple treatments, show a good correlation between compound exposure and PI3K pathway 
blockade. Furthermore in lung cancer models, tumor samples from the animals treated at 20 or 
40 mg/kg show that NVP-BYL719 inhibits partially S473P-AKT levels up to 2 h post 20 
mg/kg treatment, but fully inhibits S473P-AKT levels up to 12 h post 40 mg/kg treatment 
(Figure 1-3).


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Figure 1-3
Pharmacodynamic profile of NVP-BYL719 after multiple treatments in 
NCI-H596 tumor bearing nude rats
*Female athymic rat bearing subcutaneous xenotransplants of NCI -H596 tumors were treated with 20 
mg/kg or 40 mg/kg of NVP-BYL719, p.o. At the indicated time points post last treatment, the groups of 
rats (n=3) were sacrificed, blood and tissues removed. Each tumor tissue was flash-frozen then 
pulverized and analyzed by Western blot to determine S473P-AKT levels. (Novartis internal data)
Finally, in breast cancer xenografts models, treatment with BYL719 led to significant 
decrease in AKT phosphorylation (brown represent positivity for the antigen of interest, blue 
is hematoxylin used to label all nuclei). Please see Figure 1-4.
Figure 1-4
Supporting evidence for pathway inhibition in preclinical model of 
breast carcinoma (T47D) by NVP-BYL719 at 50 mg/kg
(Novartis internal data)
1.2.1.1.2 Nonclinical PK and metabolism of BYL719
BYL719 demonstrates low plasma clearance, a moderate volume of distribution 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%). BYL719 showed a 
rapid distribution to almost all rat tissues, except the brain (rat ADME study).
BYL719 is a substrate of Breast Cancer Resistance protein (BCRP) and has low affinity for P-
glycoprotein (P-gp/MDR1). BYL719 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 BYL719 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).


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BYL719 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), CYP2C9 (Ki 22 µM) and CYP2C19 
(IC50 75 µM) was also observed. BYL719 may inhibit metabolic clearance of co-medications 
metabolized by CYP3A4, CYP2C8, CYP2C9 and CYP2C19, if sufficiently high 
concentrations are achieved in vivo but given observed clinical peak plasma concentrations 
are unlikely to translate to a clinical effect.While clinically significant pregnane X receptor-
(PXR)-mediated induction of CYP3A4 or aromatic hydrocarbon receptor-mediated induction
of CYP1A2 by BYL719 has not been expected based on in vitro nuclear activation assays, 
there has been recent growing evidence from a hepatocyte induction assay that BYL719 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 a combination with everolimus, which showed no increase of everolimus 
exposure after concomitant administration with BYL719 at steady state, as well as PBPK 
modelling using SimCyp, time-dependent inhibition and induction of CYP3A4 by BYL719 
seem to balance each other out at clinical relevant doses.
Results from 4-week 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.
The overall biotransformation of BYL719 in hepatocytes and microsomes across all tested 
species was low. The main biotransformation pathway that was observed was hydrolysis. 
CYP450 dependent oxidative metabolism is expected to be minor. No covalent drug protein 
adduct formation was noted in human microsomes or hepatocytes.
Disposition of BYL719
In vitro elimination of BYL719 - at the current stage of knowledge - appears to be a three-
parted pathway consisting of CYP450-mediated oxidative metabolism, hydrolysis (enzymatic 
or chemical, currently unknown) and biliary elimination, but the extent of each of them 
remain uncertain and may be species-dependent.
Metabolism studies in both human and animal liver preparations (microsomes, hepatocytes) 
showed a low metabolism of BYL719 by phase I and phase II metabolic enzymes. 
Phenotyping studies in human liver microsomes and with recombinant CYPs confirmed that 
biotransformation mainly takes place via CYP3A4 (minor involvement of CYP2J2), with no 
major participation of UGTs. An in vivo rat ADME study with [14C]-BYL719 displayed, 
however, two monohydroxylation products (M2 and M3) in both plasma (≤ 5% total AUC) 
and feces (~5-15% of dose each), indicating some contribution of oxidative metabolism, at 
least in the rat. This is also be supported by the presence of two further metabolites yet to be 
identified (accounting for ≤ 7% total AUC in plasma).
Another metabolite, the carboxylic acid M4 (BZG791) formed by hydrolysis (a 
pharmacologically inactive amide hydrolysis product), was found to a comparable degree in 
plasma (≤ 5% total AUC) and feces (~15% of dose) in this study showing also a non-
oxidative metabolism pathway.


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A separate rat excretion study in bile-duct annulated rat demonstrated that 25% of the dose of 
[14C]-BYL719 was excreted in feces with 40% of the dose being found unchanged in bile. As 
BYL719 is a substrate for human BCRP in vitro there is strong evidence for a hepatobiliary 
excretion and potential for hepatic recirculation (active transport into the bile and intestinal 
reabsorption), at least in the rat, that is also supported by rat sandwich-cultured hepatocyte 
experiments.
In general, excretion in feces (via bile and direct secretion into the intestine) was the major 
route of excretion in rats with 77% of the dose rapidly eliminated as metabolites within 7 days. 
Contribution of renal excretion based on the results can be considered minor.
In humans, metabolite identification has been performed so far based on patient plasma of 
study [CBYL719X2101] that seems to confirm the implication of oxidative metabolism in 
human, though its extent is still unknown. An ongoing human ADME trial will provide more 
insight on the human situation which currently cannot be fully assessed based on the available 
in vitro data.
1.2.1.1.3 Safety pharmacology and toxicology of BYL719
Routine safety pharmacology and toxicology studies were conducted in rats and dogs. In 
addition, for exploratory studies, such as insulin/glucose tolerance tests, mice were also used.
BYL719 was relatively well tolerated in the repeated-dose toxicity studies (daily dosing of up 
to 4 weeks of duration) at dosages at which tumor growth control was achieved in mouse or 
rat tumor models. BYL719 affected rapidly dividing tissues which only resulted in 
pharmacologically relevant observations in the animals exposed to a BYL719 dose close to or 
at MTD. The most frequently affected organs were the bone marrow and lymphoid tissue 
(spleen, thymus), the epithelia of the alimentary tract, while other tissues like the vagina and 
uterus in rats, or prostate in dogs were also affected at higher doses. Bone/cartilage and tooth-
forming structures were only affected in rats. In dogs, epithelial effects were seen in the 
cornea; however, the dose-dependency of this cornea observation was not evident. No other 
ophthalmologic abnormalities, associated with BYL719 treatment, were observed in rats or in 
dogs.
Abnormal clinical chemistry and histopathology (pancreatic islets) findings indicated an 
altered glucose metabolism, correlating with a clear effect towards insulin insensitivity. In 
both rats and dogs, histopathology and clinical pathology findings were generally observed at 
higher doses that were also associated with reduced body weight development (in the growing 
animals) and reduced food intake. All toxic events were reversible or showed a tendency to 
reversibility after a 4-week treatment-free recovery period.
Cardiac safety studies, conducted in vitro and in vivo, did not indicate an electrophysiological 
risk. Furthermore, BYL719 in the rat safety pharmacology studies showed no effect on 
neuronal or pulmonary function, and no evidence of a phototoxic potential was found in a 3T3 
neutral red uptake test in vitro.
In conclusion, the majority of the observed toxicological effects of BYL719 were related to 
the pharmacological activity of BYL719 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 


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to or at MTD with the bone marrow and lymphoid tissue, pancreas, and some reproductive 
organs of both genders being the main target organs of the toxic effects (refer to the [BYL719 
Investigators Brochure] for further details).
Genotoxicity status of BYL719
BYL719 is not genotoxic in vitro, based on the results of an Ames test and a chromosome 
aberration test.
1.2.1.2
Clinical experience
There are six ongoing studies assessing the safety and tolerability of BYL719 in solid tumors: 
[CBYL719X2101], 
[CBYL719X1101], 
[CBYL719X2104], 
[CBYL719X2105J], 
[CMEK162X2109] and [CSTI571X2103]. These trials are briefly described below with a 
focus on safety and efficacy data for the first-in-human dose escalation study [CBYL719X2101].
[CBYL719X2101]: is a first-in-human phase 1 study of oral BYL719 in adult patients with 
advanced solid malignancies whose tumors have an alteration of the PIK3CA gene. This study 
also includes the investigation of BYL719 in combination with fulvestrant in patients with 
HR-positive advanced or metastatic BC.
Clinical safety of BYL719
As of 20th May 2014, 134 patients had been enrolled into the single dose arm of the study
[CBYL719X2101]. Nine patients were still on treatment, and 124 had discontinued; of those, 
99 patients (73.9%) discontinued due to disease progression, 19 patients (14.2%) due to AEs, 
3 patients (2.2%) due to withdrawn consent, and 3 patients (2.2%) due to death. The median 
age of patients was 58.5 years (range 21 to 82), with the majority of patients (70.9%) below 
65 years of age. The majority (92.5%) of patients were Caucasian. The male/female ratio was 
36/98, and baseline ECOG performance status was 0 or 1 in all patients (33.3% and 66.7%, 
respectively). Nine dose levels have been tested using a QD dosing regimen: 30 mg (N=1),60 
mg (N=3), 90 mg (N=6), 180 mg (N=6), 270 mg (N=4),300 mg (N=8), 350 mg (N=6), 400 
mg (N=65), and 450 mg (N=9).Three dose levels have been tested using a BID dosing 
regimen: 120 mg (N=5), 150 mg (N=15), and 200 mg (N=6). In the single agent arm of this 
study, the maximum tolerated dose (MTD) of BYL719 was determined to be 400mg QD. The 
median duration of exposure across all dose levels was 11.9 weeks (range 0.4 to 105.6).
A total of 127 patients (94.8%) experienced AEs suspected of being drug related, the most 
frequent of which were hyperglycemia (65 patients, 48.5%), nausea (64 patients, 47.8%), 
diarrhea (53 patients, 39.6%), decreased appetite (50 patients, 37.3%), vomiting (39 patients, 
29.1%) and fatigue (37 patients, 27.6%). Grade 3 or 4 AEs were experienced by 100 patients 
(74.6%), of which 57 patients (42.5%) experienced Grade 3 or 4 AEs suspected of being drug 
related. The most common treatment-related Grade 3 or 4 event was hyperglycemia (32 
patients, 23.9%); all other Grade 3 to 4 AEs occurred in ≤ three patients. For further details, 
refer to current [BYL719 Investigators Brochure].
In the combination part of the study with fulvestrant, 74 patients had been enrolled as of 20th 
May 2014; thirty patients (40.5%) were still on treatment and forty four (59.5%) had 
discontinued: thirty patients (40.5%) due to disease progression, seven patients (9.5%) due to 


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AEs, five patients (6.8%) due to withdrawn consent, and one patient (1.4%) each for lost to 
follow up and administrative reasons.
Three dose levels have been tested in the combination part of the study using the QD regimen: 
300 mg (N=9), 350 mg (N=7) and 400 mg (N=58). The MTD was declared at 400mg QD 
BYL719 in combination with fulvestrant intramuscular (IM) at 500mg/q28 days. Sixty seven 
patients (90.5%) experienced at least one suspected treatment-related AE. The most frequent 
AEs suspected of being drug-related were hyperglycemia (33 patients, 44.6%), diarrhea (32 
patients, 43.2%), nausea (24 patients, 32.4%), decreased appetite (18 patients, 24.3%), 
vomiting (18 patients, 24.3) and fatigue (17 patients, 23.0%).
For further details, refer to the current [BYL719 Investigators Brochure].
In addition, the following Novartis-sponsored clinical studies are conducted with BYL719 
either as single agent or combination study:
[CBYL719X1101] is a phase I study of BYL719 in adult Japanese patients with advanced 
solid malignancies. The study was initiated in September 2011. As of the cutoff date of 20th 
May 2014, 27 patients had been enrolled, of which 2 were still on treatment and 25 had 
discontinued (5 due to AEs, 17 due to lack of efficacy, 2 due to patient/guardian decision, and 
1 due to death). The median age of patients was 55.0 years (range 24.0 to 76.0). Five dose 
levels have been tested in the dose escalation part, all using QD regimen: 90 mg (N=3), 180 
mg (N=4), 270 mg (N=5), 350 mg (N=6), and 400 mg (N=7). An expansion part is ongoing at 
the dose of 350 mg (N=2). Two patients in the 400 mg QD cohort experienced dose-limiting 
toxicities: (DLT) one patient Grade 3 maculopapular rash and one patient Grade 3 maculo-
papular rash with Grade 2 conjunctivitis. The recommended phase 2 dose (RP2D) was declared 
at 350 mg BYL719 QD. The median duration of exposure across all dose levels was 56.0 
weeks (range 17.0 to 440.0).
[CBYL719X2104]: BYL719 is being tested in combination with cetuximab in patients with 
head and neck squamous cell cancer (HNSCC) in a phase Ib dose escalation trial.
For Arm A, the RP2D was declared to be 300 mg QD BYL719 in combination with 
cetuximab. For Arm B, the RP2D which was declared after the cut-off date, was also 300 mg 
QD BYL719 in combination with cetuximab. The median duration of exposure to study 
treatment was 12 weeks for Arm A and 6 weeks for Arm B, respectively. For both Arm A and 
Arm B, the RP2D for BYL719 in combination with cetuximab has been declared at 300 mg 
QD. For further details, refer to current [BYL719 Investigators Brochure].
[CBYL719X2105J]: a Phase Ib/II open-label study of the combination of BYL719 plus AMG 
479 (ganitumab) in adult patients with selected advanced solid tumors.
 
 
 
 
 
 


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[CMEK162X2109]: a Phase Ib, open-label, multi-center, dose escalation and expansion study 
of an orally administered combination of BYL719 plus MEK162 (binimetinib) in adult 
patients with selected advanced solid tumors. 
 
[CSTI571X2103]: a Phase Ib multicenter study of imatinib in combination with BYL719 in 
patients with gastrointestinal stromal tumor (GIST) who failed prior therapy with imatinib and 
sunitinib. As of 20th May 2014, 38 patients have been enrolled to study treatment. For more 
information, refer to [Imatinib (Glivec) Investigators’ Brochure].
[CBYL719XUS03T] is an ongoing phase Ib study the evaluates the combination of BYL719 
and letrozole in metastatic HR-positive BC. The RP2D of BYL719 in combination with 
letrozole was declared at 300 mg. Rash was the DLT at 350 mg. The most common AEs 
were consistent with those observed with BYL719 single agent, i.e. rash, hyperglycemia, 
nausea, fatigue, and diarrhea.
Clinical efficacy in ER+ metastatic breast cancer (MBC) [CBYL719X2101]
In [CBYL719X2101], 133 patients were evaluable for efficacy as of 20 May 2014. Seven 
patients (5.3%) experienced a confirmed partial tumor response (PR); an additional eight 
patients (6.0%) achieved an unconfirmed PR; and 70 patients (52.6%) had SD; 21 patients 
(15.8%) could not be assessed for tumor response per RECIST. All tumor responses were 
observed following treatment with total daily dose of 270 mg BYL719 orhigher. The disease 
control rate (CR/PR/SD, including unconfirmed PR) was 57.9% (Juric 2014).
Eighty-four patients had been enrolled (50 with PIK3CA mut tumors, 31 wild-type, 3 
unknown). The MTD for BYL719 was declared at 400 mg, with DLTs in 4 patients (diarrhea, 
vomiting, decreased appetite, abdominal distension and fatigue). Preliminary efficacy results 
have been reported (Janku F, SABCS 2014). Best overall response achieved was confirmed 
PR for 12 (24%) patients and SD for 28 (56%) patients with PIK3CA mutated tumors vs SD 
in 14 (45%) patients with PIK3CA wild-type tumors. Disease control rate was 80% (95% CI: 
66.3–90.0) and 45% (95% CI: 27.3–64.0) in the PIK3CA mutated and PIK3CA wild-type 
groups, respectively. Estimated median PFS was longer in the PIK3CA mutated group vs 
PIK3CA wild-type group (8.3 months vs 4.7 months).
Preliminary efficacy data have also been reported for the phase Ib study [CBYL719XUS03T] 
that evaluates BYL719 in combination with letrozole in post-menopausal women with HR-
positive HER2-negative BC (n=26). Three patients (11%) achieved a PR and 14 (54%) had 
SD as their best response (clinical benefit rate [PR + SD ≥6 months] of 27% (Mayer 2014)
1.2.1.3
Clinical pharmacokinetics of BYL719
Preliminary pharmacokinetic data of study [CBYL719X2101] showed that BYL719 is well 
absorbed after oral administration. Median time to reach the peak plasma concentration 
(Tmax) at the MTD dose (400 mg once daily) was 2 hours. Tmax did not correlate with dose 
and the median values at different doses spanned a wide range (range 1 to 7 hours), both after 
single and repeated dose. Plasma concentrations of BYL719 generally declined in a mono-
exponential manner, suggesting rapid distribution towards the tissue (relative to absorption). 


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Median terminal elimination half-life (T1/2) after a 400 mg oral dose was 7 to 8 hours and 
generally appeared to be independent of dose and time. Steady-state BYL719 plasma levels 
can be expected to be reached at 2 to 3 days following onset of therapy in most patients.
At the MTD (400 mg QD), Cmax and drug exposure within a dosing interval (AUC0-24h) 
after one month of daily dosing (steady-state) were 3560 ng/mL (range 501; 7930), and 
~39600 hr*ng/mL (range 5210; 81700), respectively (Table 5-2). At clinical relevant doses 
(270-400 mg) between-subject variability in Cmax and AUCinf (CV%) was moderate to high 
with 40-60% at C1D8.
The median accumulation ratio (Racc) of BYL719 across all dose levels and regimens ranged 
between 1.0 and 2.0, which is in agreement with the short T1/2 of BYL719. At 400 mg QD 
the median Racc was 1.2 after 1 week. An apparent higher drug accumulation than expected 
based on the drug half-life was observed in some patients, with no clear relationship with dose. 
Also, an approximate dose proportional increase in both Cmax and AUC was found, 
indicating no relevant deviation from linear pharmacokinetics.
1.2.1.4
Potential drug-drug-interactions between BYL719 and letrozole
As BYL719 is a time dependent inhibitor of CYP3A4, and CYP3A4 is the main metabolism 
pathway for letrozole, there is likelihood for an increase of letrozole plasma exposure when 
combined with BYL719 at 350 mg QD. Based on the median Cmax observed for BYL719 in 
[CBYL719X2101] an increase in letrozole exposure of between 1.6 and 4-fold is predicted at 
steady-state when not accounting for induction of CYP3A4 (see below). Because the normal 
half-life of letrozole is long (about 2 days), reduction in clearance due to a drug-drug-
interaction with BYL719 could prolong the time to reach elevated steady state levels 
depending on the magnitude of the potential change in half-life. Dynamic DDI predictions by 
SimCYP based on PK models of BYL719 (400 mg QD dose) and letrozole, simulated over a 
time of 24 days, showed that the steady state was not yet reached at day 24 and predicted a 
median increase of > 1.8 fold. As a recent phase II trial (Dixon 2001) showed no safety 
concerns with an administration of 10 mg letrozole daily in the neoadjuvant setting over a 
period of three months, a safety margin of at least 4-fold can be expected if PK is linear to this 
dose. Thus, even if an interaction can be confirmed it is postulated that this margin will be 
sufficient to alleviate the safety risk. At 300mg QD BYL719 a lower increase in letrozole 
exposure is predicted in comparison to the dose at 350 mg, further reducing the safety risk for 
the combination of BYL719 and letrozole.
In addition, based on new in vitro findings that BYL719 is also a potential inducer of 
CYP3A4 and growing evidence that time-dependent inhibition and induction are balancing 
each other out (see Section 1.2.1.1.2), an interaction is considered to unlikely. This has also 
been supported by preliminary clinical PK data from study [LEE011X2107] showing that in 
combination of letrozole with BYL719 (doublet assessment, Arm 2) letrozole exposure was 
comparable or rather slightly lower relative to historical single agent data for letrozole on both 
Day 1 and Day 21 of the first cycle.
An interaction is not anticipated to have an impact on BYL719 exposure. Letrozole itself is a 
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(see Section 1.2.3). Since BYL719 is not metabolized by either of these cytochrome P450 
isoenzymes (see Section 1.2.1.1.2), a drug-drug-interaction based on metabolism is unlikely.
1.2.2
Overview of buparlisib (BKM120)
Buparlisib (BKM120) is a potent and highly specific oral pan-class I (PI3K) inhibitor that is a 
2, 6-dimorpholino pyrimidine derivative. This compound has been studied extensively in non-
clinical models and is currently being evaluated in clinical trials. Further information 
concerning the non-clinical and clinical properties of buparlisib may be found in the 
[Buparlisib Investigator’s Brochure].
1.2.2.1
Non-clinical experience of buparlisib
1.2.2.1.1 Pharmacodynamics of buparlisib
Buparlisib inhibits wild-type PI3K(IC50: 35 nM), with greater than 50-fold selectivity 
compared to activity against other protein kinases outside the PI3K family. The compound is 
equipotent against somatic PI3Kmutants (H1047R-, E542K- and E545K-p110) and is 
active against the other three PI3K paralogs (PI3Kβ, -γ, -δ; IC50 108 to 348 nM range). 
buparlisib does not significantly inhibit the related kinases mTOR or Vps34, nor does it 
inhibit (IC50 >10 µM) other receptors and ion channels profiled.
1.2.2.1.2 Non clinical pharmacokinetics and metabolism of buparlisib
Buparlisib showed favorable pharmacokinetic properties in all animal species tested. The 
absorption of [14C]-buparlisib- related radioactivity was > 84% in the rat. Oral bioavailability 
was moderate to high in rats, dogs and monkeys (42-100%). The estimated steady state 
plasma volume of distribution (Vss) was moderate in all species (3.0–3.5 L/kg). Buparlisib 
penetrated the blood brain barrier in rats with a tissue-to-plasma ratio about 2. Buparlisib was 
moderately bound to plasma protein across all species examined (free fraction ~15% and 
independent of concentration in humans).
Oxidative metabolism of buparlisib is predominantly mediated by cytochrome P450 (CYP) 
isoenzyme 3A4 in vitro. Recombinant human CYP1A1 also has the capacity to metabolize 
buparlisib; however, its endogenous expression in the human liver is negligible, and therefore 
it is not expected to have any impact on hepatic buparlisib metabolism. Direct Phase II 
metabolism (glucuronidation) via UGT1A4 is also observed in human liver microsomes 
supplemented with uridine diphosphate glucuronic acid (UDPGA). All Phase I metabolites 
identified in human hepatocytes and microsomes are not unique to humans and were also 
detected in animals. Buparlisib and identified metabolites have a low potential for covalent 
binding to protein.
At the concentrations observed in the clinic, buparlisib is a weak reversible inhibitor of 
CYP3A4 (IC50=8μM, Ki = 13.6 μM,). The [I]/Ki ratio was estimated around 0.3. It also 
weakly inhibits the CYP2C family (2C8, 2C9 and 2C19) with IC50 values ranging from 35–
65 μM. Buparlisib did not show time-dependent inhibition of CYP450 enzymes. With respect 
to transporter-based drug-drug interactions, buparlisib is not an inhibitor or substrate of 
Pglycoprotein (P-gp), multidrug resistance associated protein (MRP)-2, breast cancer 
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at concentrations above 10 μM. Based on the observed free concentrations of buparlisib in 
plasma, the impact in vivo of such inhibition is expected to be very limited. It is possible that 
buparlisib activates the pregnane X receptor (PXR) in vivo and induces CYP3A4 at 
concentrations ≥50 μM; however, the absence of any time-dependent changes in the 
pharmacokinetics of buparlisib in the relevant therapeutic dose range in humans suggests that 
this might not be relevant in vivo. Finally, experiments showed a potential for buparlisib to 
induce UGT1A1 at concentrations between 0.5 and 100 μM. The mean maximum free 
concentration calculated at steady state to date in the study [CBKM120X2101] was 0.671 μM 
(Cmax, tot=4.20 μM). Therefore a potential induction of UGT1A1 cannot be formally 
excluded, although the clinical relevance of observed activation of UGT1A1 activity is 
unclear.
1.2.2.1.3 Safety pharmacology and toxicology of buparlisib
Safety pharmacology and toxicology
Safety pharmacology studies in rats revealed no effects on neuronal (behavior) or respiratory 
functions. Cardiac safety studies, conducted in vitro and in vivo did not indicate a prominent 
electrophysiological risk. No relevant electrophysiological effect was seen in dogs. The only 
effect considered relevant was a trend towards an increase in systolic and diastolic blood 
pressure that was observed in two dog telemetry studies. In rats and dogs, clinical pathology 
and histopathology findings showed quantitative reductions of lymphoid and erythroid counts 
and lymphoid tissue hypoplasia.
The pancreas was seen to be affected by treatment with buparlisib, particularly in dogs, where 
acinar cell toxicity was seen in the exocrine part of this organ. In the 4 -week study in rats, no 
pancreatic toxicity was observed. However, at higher doses in the 2-week dose-range-finding 
study in rats, there were histopathological findings in both the endocrine as well as the 
exocrine pancreas.
Male sexual organs and associated tissues were found to be targets of toxicity in both rats and 
dogs. Changes included minimal to slight germ cell depletion, formation of spermatic giant 
cells and abnormal spermatids, and cellular debris in epididymal tubules. Testicular toxicity 
did not fully reverse after the 4-week treatment-free period in rats (highest dose), although a 
clear trend towards recovery was seen. In individual female rats, minimal to slight cyst 
formation occurred in the Graafian follicles. In dogs, there was no effect on female sexual 
organs.
Glucose homeostasis was affected in various species (mice, rats, dogs), as expected from the 
mode of action of buparlisib. However, these effects were minimal in both rats and dogs at the 
doses used in the 4-week studies.
Other safety considerations include:

No evidence for a direct DNA interaction was found in an Ames test and two chromosome 
aberration tests in vitro with buparlisib. However, evidence of a genotoxic potential with 
buparlisib has been seen in vitro and in vivo and is likely due to an aneugenic effect.

No phototoxic potential or any effect on wound healing has been identified with buparlisib
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In conclusion, the majority of the observed effects were related to the pharmacological 
activity of buparlisib as an inhibitor of PI3K, such as a potential influence on glucose 
homeostasis and the risk of increased blood pressure.
Genotoxicity status of buparlisib
In preclinical in vitro and in vivo studies, buparlisib elicited a genotoxic potential. Although 
no evidence for a direct DNA interaction was found in an Ames test and in two chromosome 
aberration tests in vitro, an aneugenic potential was observed in the latter. Because clinical 
studies with buparlisib enroll patients with advanced malignancies that often have no 
remaining standard treatment options, it is deemed justified to include adults (men and women 
of childbearing potential) with the clear recommendation to all patients that they must use 
appropriate contraception.
1.2.2.2
Clinical experience of buparlisib
As of September 8th, 2014, approximately 3000 patients and healthy volunteers have been 
enrolled into 35 Novartis sponsored clinical studies of buparlisib, including 5 blinded phase II 
or III studies (for further details please refer to the [Buparlisib Investigators’ Brochure]):
1. Phase I single agent studies [CBKM120X2101], [CBKM120X1101], [CBKM120Z2102], 
[CBKM120C2110], [CBKM120C2104], [CBKM120C2106], [CBKM120C2111], 
[CBKM120C2102], [CBKM120C2108], [CBKM120C2113] and [CBKM120C2114].
2. Phase I combination studies [CBKM120B2101], [CBKM120X2107], [CBKM120E2101], 
[CBKM120E2102], [CBEZ235A2118], [CLDE225X2114], [CSTI571X2101], 
[CMEK162X2101], [CINC424A2104], [CBEZ235D2101], [CBKM120D2204]
[CBKM120D2205], [CLEE011A2112C] and [CLEE011X2108].
3. Phase II single agent studies [CBKM120C2201], [CBKM120Z2402] and 
[CBKM120D2201].
4. Phase II combination studies, [CBKM120F2203], [CBKM120H2201], [CBYL719A2201]
[CBKM120F2202] and [CINC280X2204].
5. Phase III double-blind randomized combination studies [CBKM120F2302] and 
[CBKM120F2303]
1.2.2.2.1 Human safety, tolerability data, single agent buparlisib
Generally, single agent buparlisib is well tolerated with the majority of the reported adverse 
events (regardless of study drug relationship) being mild or moderate (Grade 1 or 2) and 
transient in nature.From current clinical experience, special attention needs to be paid to the 
following side effects: hyperglycemia, psychiatric disorders, liver toxicity, skin rash / 
hypersensitivity, lung toxicity and pneumonitis. Details on these AEs of special interest are 
briefly summarized below.Please refer to [Buparlisib Investigator’s Brochure] for more 
detailed information on specifics of clinical safety and tolerability of buparlisib.
Hyperglycemia
The PI3K/AKT pathway is important in regulating glucose metabolism, particularly by 
regulating glucose transport into adipocytes and muscle tissue. Therefore, hyperglycemia is 
considered to be an “on target” effect of buparlisib, and it has been commonly observed in 


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patients treated with buparlisib with an incidence of all-grade hyperglycemia ranging 
between 17.6% in [CBKM120B2101] and 63.6% in [CBKM120D2205] study, and Grade 3 
or 4 between 7.3 in [CBKM120X2101] and 36.4% in [CBKM120D2205]. The highest rate of 
hyperglycemia has been observed in trials conducted in patients with controlled diabetes 
mellitus such as [CBKM120C2201] and in [CBKM120D2205] study requiring corticosteroid 
as premedication for docetaxel (current version of Buparlisib IB).
In order to mitigate the potential risk of developing uncontrolled hyperglycemia, conservative 
inclusion/exclusion criteria are implemented in the protocol as well as detailed guidelines to 
monitor patients.
Psychiatric and mood disorders
There is evidence indicating that the modulation of AKT/GSK3 signaling pathway may play 
an important role in the behavior regulation (Beaulieu et al 2009). Psychiatric side effects 
events have been reported in patients treated with buparlisib and are currently under 
investigation. The current data does not allow the identification of any sign or symptom that
could predict patient susceptibility to buparlisib induced psychiatric disorders. At least one AE 
(regardless of study drug relationship) belonging to system organ class (SOC) “psychiatric 
disorders”, which include a broad range of AEs e.g. depression, anxiety, mood altered, confusional 
state, affective disorders, insomnia, hallucination, panic disorders, suicidality, have been reported. 
The overall frequency ranges between 23.5% [CBKM120B2101] to 66.7% [CBKM120X1101] of 
patients treated with buparlisib monotherapy and combination. Overall the incidence of grade 3 and 
4 psychiatric events ranged from 0 to 13.2%. The frequency of mood disorders, regardless of 
study drug relationship, ranged from 0% in [CBKM120B2101] and [CBKM120Z2402] 
studies to 44.4 % in [CBKM120X2101] study, the majority of events being of grade 1 or 2 
severity.
Conservative inclusion/exclusion criteria are implemented in the protocol as well as detailed 
guidelines to monitor patients, including the use of PHQ-9 and GAD-7 questionnaires, and 
psychiatric consultation. Psychiatric consultation should be performed by a qualified person 
able/entitled to make correct diagnosis and prescribe appropriate treatment, preferably by a 
psychiatrist.
Liver toxicity
Although transaminase increases are relatively common, only a few of the patients with liver 
function tests (LFTs) alterations had other simultaneous observations related to impair liver 
function (e.g. bilirubin increase or clinical symptoms). Based on these findings, conservative 
inclusion criteria and guidelines to monitor and to follow patients with LFT alterations 
(including dose and schedule modifications) are currently implemented in study protocols 
investigating buparlisib.
The rates of liver toxicity observed with buparlisib in combination with conventional
chemotherapy and/ or with targeted therapies are similar to those reported in single agent 
trials. Liver function test (LFT) alterations observed during ongoing and completed studies 
have been mostly transaminase enzyme increases (ALT and/or AST). The frequency of liver 
toxicity thus defined, regardless of study drug relationship, ranged from 4.2% from 
[CBKM120Z2402] to 44.4 % in [CBKM120X1101] study, the majority of events being of 


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grade 1 or 2. The highest rate of grade 3 and 4 LFT alterations have been observed in 
[CBKM120Z2102] study conducted as single agent in Chinese patients (64.7%) including a 
cohort of 17 patients treated at 100mg/d.
Between 25 to 45% of patients treated with single agent buparlisib reported liver toxicity (all 
grades, regardless of study drug relationship, 100 mg/d dose) based on a search of multiple 
MedDRA event terms (e.g. SMQ preferred terms). The incidence of grade 3 and 4 events was 
approximately 10 to 30%. Liver function test (LFT) alterations observed during ongoing and 
completed studies have been mostly transaminase enzyme increases (ALT and/or AST). Data 
suggest a slightly higher rate of grade 3 and 4 liver enzyme elevations in Japanese patients 
(44%) in the [CBKM120X1101] study, however, the number of patients treated at 100 mg in 
this study was limited (n=9). Transaminase elevations typically occur during the first 6 to 8 
weeks of treatment start.
Although transaminase increases are relatively common, only a few of the patients had other 
simultaneous observations related to impaired liver function (e.g. bilirubin increase or clinical 
symptoms).
Based on these findings, conservative inclusion criteria and guidelines to monitor and follow 
patients with LFT alterations (including dose and schedule modifications) have been 
implemented. Please refer to the respective inclusion/exclusion criteria and Section 5 in this 
protocol for more detailed guidelines.
A recent liver safety review across Novartis-sponsored trials with buparlisib identified several
potentially drug-induced liver toxicity (DILI) cases (e.g. AST/ALT >3.0 x ULN and 
TBL >2.0 x ULN at any time during the treatment, regardless of causality. Upon medical 
review, most of these cases occurred in the context of disease progression in terminally ill, 
advanced cancer patients and/or were confounded by other causes. However, six of these DILI 
candidates were consistent with Hy’s law criteria (e.g. AST/ALT >3.0x ULN and 
TBL >2.0xULN in the absence of cholestasis and other explanatory causes) with probable 
causal relationship to study treatment. Five of these cases were enrolled in the study 
[CBKM120F2302], a double-blind phase III randomized study that evaluates buparlisib or 
buparlisib/placebo in combination with fulvestrant in metastatic HR-positive breast cancer;
and one study evaluating buparlisib in combination with the investigational drug LDE225 
(sonidegib). All patients have recovered upon treatment discontinuation except one patient for 
whom no data is available since the patient refused to return for safety follow-up.
Skin rash and hypersensitivity
Skin rash is commonly observed in patients treated with buparlisib. The rate of skin rash and 
other related event terms MedDRA Version 16.0 and Novartis Medical Queries (NMQs) is 
ranged from 23.5% in [CBKM120Z2102] study conducted in Chinese patients to 85.3 % in 
[CBKM120B2101] study conducted in combination with MEK inhibitors in patients with 
advanced solid tumors
The frequency of skin rash reported in studies of buparlisib in combination with other agents 
might be slightly higher when buparlisib is combined with trastuzumab (45.3%) in 
[CBKM120X2107] study or with MEK inhibitor (85.3%) in [CBKM120B2101] study 
(Table 5-26).The skin rashes seen have no typical location or distribution pattern, are mainly 


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papulo-macular (only a minority acneiform) and are frequently associated with pruritus. 
Events have been reversible after treatment interruption and/ or dose reduction. Effective 
medications have included antihistamines, topical corticosteroids and/or low-dose systemic 
corticosteroids (the latter should be used with caution due to the increased risk of 
hyperglycemia). There have been few cases reported of allergic reactions and DRESS (drug 
rash with eosinophilia and system symptoms), but these have not been of acute onset or of a 
severe nature.
Complementary information collected suggests that sun exposure may exacerbate the 
condition and should be avoided; however, genuine photosensitivity reaction has not been 
confirmed and no phototoxic potential was seen pre-clinically. Patients are advised (e.g. in the
written patient information) to avoid sun exposure, or take measures to protect themselves 
from intense sunlight, during study treatment.
Lung Toxicity/Pneumonitis
Lung changes compatible with pneumonitis have not been observed in the preclinical setting. 
The safety database, as of 08-Sep-2014 contains in total 30 cases reporting 31 events 
including 23 events of pneumonitis occurring in buparlisib trials, and 8 events of interstitial 
lung disease (ILD). Twenty seven of these 30 cases were reported as suspected to treatment 
with buparlisib, and 5 of these had a fatal outcome. One fatal case was in a complex clinical 
context, combining progression of lung metastases and possible infection with pneumocystis 
carinii or cytomegalovirus. 
 
 
The third case was a patient with lung cancer who was reported to have non-infective 
inflammatory ILD and died. The investigator considered that the underlying malignancy was 
an alternative causal explanation. The fourth case occurred in a patient with metastatic breast 
cancer enrolled in a combination trial of buparlisib and fulvestrant and was not suspected to 
buparlisib but to the progression of the underlying disease. The last case was reported in 
subject who received abiraterone acetate plus buparlisib for prostate cancer. The CT scan 
features were consistent with pneumonitis rather than with an infection. The investigator 
reported that the pneumonitis was suspected to buparlisib. Ten of the non-fatal suspected 
cases were reported as resolved or improving. Others were unchanged or improving at the 
latest report, or the outcome not reported. The currently available data support preliminary 
assessment of causal relationship of pneumonitis with buparlisib treatment. Clinical activity of 
buparlisib in Breast Cancer
The main clinical safety and efficacy experience of buparlisib given for the treatment of breast 
cancer patients is based on the completed Phase I first-in-human study of single agent oral 
buparlisib [CBKM120X2101] and the completed phase Ib study [CBKM120XUS13T], where 
buparlisib was combined with letrozole (2.5 mg/day) (Mayer 2014).
The CBKM120X2101 study was designed as a Bayesian dose-escalation trial with an MTD 
dose-expansion arm enrolling patients with advanced solid tumors. Out of the total 83 patients 
treated in the study, twenty one had metastatic breast cancer (Rodon 2011). At the cut-off date 
of 4th July 2011 and for the MBC patients, the most common adverse events (AEs) (25%) (all 
Grades) included nausea and fatigue/asthenia, each in 9 patients (43%), anxiety and diarrhea, 
each in 8 patients (38%), hyperglycemia and rash, each in 7 patients (33%) and decreased 


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appetite, depression and pruritus in 6 patients each (29%). Fatigue/asthenia and transaminase 
increase were the most common Grade 3 AEs suspected to be related to the study drug, and 
were observed in 3 patients each. The only Grade 4 AE suspected to be related to buparlisib 
was hyperglycemia, which was observed in 1 patient at the 150 mg/day dose level. Overall, 
buparlisib was well tolerated with only a minority of patients experiencing grade 3 and 4 
toxicities. The safety profile for MBC patients is similar to the safety profile for the full 
population enrolled in the [CBKM120X2101] study.
At the cut-off date of 4th July 2011, twenty breast cancer patients were evaluable for objective 
tumor response by RECIST 1.0. Two breast cancer patients exhibited partial responses, which 
were confirmed in a triple-negative MBC patient, and unconfirmed in an ER-positive HER2-
negative MBC patient. For these 2 patients, the treatment duration was respectively 27 months 
(ongoing) and 5 months. An additional 8 breast cancer patients (40%) had stable disease 
(Rodon 2011).
An ongoing phase Ib study of buparlisib and fulvestrant in post-menopausal women with 
metastatic HR-positive HER2-negative BC (n=31) has been reported. A similar toxicity 
profile for buparlisib in combination with fulvestrant to that reported for buparlisib given as a 
single agent (Ma C et al 2013). The observed grade 3 and 4 events in continuos schedule (n=6) 
were grade 3 ALT increase in 2 cases, and grade 3 rash and hyperglycemia in one case each; in 
intermittent schedule (n=11), grade 3/4 ALT increase in 2 cases, grade 3 AST increase and 
hyperglycemia in one case each. The authors concluded that a slightly lower incidence of severe 
AEs were observed with the intermittent dosing schedule. In addition, in a recent update of this 
study a similar outcome in terms of tumor response and treatment duration has been reported with 
both the continuos and intermittent schedules (Ma et al 2014).
In the completed phase Ib study [CBKM120XUS13T], buparlisib was combined with 
letrozole (2.5mg/day) (Mayer 2014). Results are presented in Section 1.2.4.
1.2.2.2.2 Clinical Pharmacokinetics
Buparlisib has been administered from 25 mg to 150 mg daily, and the single agent RP2D is 
100 mg. When orally administered, buparlisib is rapidly and well absorbed, and the extent of 
absorption is estimated to be between 57 and 85%, with a median Tmax between 0.5 and 3 
hours after administration. Cmax and AUC appeared to be linear in the tested range, with an 
estimated slope close to 1, but the 90% CI for both AUC0-24, [0.75, 1.21], and Cmax, [0.72, 
1.16], was fairly wide, most likely due to low sample size at extreme doses. In plasma, 
buparlisib concentrations follow a bi-exponential decay, with a long terminal half-life that 
could not be well estimated given the initial sampling schedule used after daily dosing. It was 
however well estimated from the terminal half-life cohort and was found to be 48 hours.
After repeated dosing the effective half-life (T1/2, acc), was obtained from the observed drug 
accumulation (Racc). The median T1/2, acc (T1/2 accumulation) calculated from exposure 
data on Day 28 ranged between 36 and 58 hours across all dose levels. After repeated single 
dose, steady state is reached in 8 days with an accumulation ratio around 3.
The intermittent schedule QD 5 days on / 2 days off employed in this study was assessed based on 
a population pharmacokinetic model (Novartis Internal Data). This alternative regimen has the 
benefit of maintaining a weekly exposure slightly higher than an 80 mg QD regimen. The mean 


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exposure (AUCtau) was predicted to be around 114000 ng x h/mL with an estimate for oral 
plasma clearance (CL/F) of 4.38 L/h, while the weekly exposure under daily dosing of buparlisib 
would be 154000 ng.h/mL for 100 mg QD and 126000 ng.h/mL for 80 mg QD, respectively. In 
the [CBKM120X2101] study, the maximum concentration (Cmax) reached at steady-state whith a 
100 mg QD regimen was reported to be 1939 ng/mL while the Cmax achieved on the Day 5 of the 
alternative regimen was predicited to be only 1440 ng/mL. Therefore, this alternative regimen 
presents the benefit of decreasing Cmax, maintaining an efficacious level of exposure to 
ultimately propose a better safety profile for buparlisib.
Buparlisib is eliminated mainly through metabolism in a plethora of entities. After 
administration of a single dose of [14C]-buparlisib, 51% of the radioactivity was recovered in 
urine even though buparlisib only contributed to less than 2%. The remainder of the 
radioactivity was recovered in feces, with buparlisib representing 15%, all other metabolites 
being below 5%. CYP3A4 was found in vitro to be a major contributor to buparlisib 
metabolism together with direct glucuronidation, which contributes to less than 10%.
A drug-drug interaction study has recently been conducted with a strong CYP3A4 inhibitor 
(ritonavir) [CBKM120C2111], showing only a 1.73 fold increase of the exposure and 1.19 
fold of Cmax when buparlisib was co-administered with ritonavir. These findings support the 
involvement of the CYP3A4 in the metabolism of buparlisib but to a lower extend that 
anticipated from in vitro results. The increase of exposure was not considered as clinically 
relevant and moderate CYP3A4 inhibitors (and consequently inducers) can be used with 
caution on the basis of this trial. This is also in line with the results of a drug -drug interaction 
study with dexamethasone (a weak CYP3A4 inducer) [CBKM120C2106] which showed no 
significant change in buparlisib pharmacokinetics.
1.2.2.3
Potential drug-drug-interactions between buparlisib and letrozole
The chance of a clinically important drug-drug interaction between letrozole and buparlisib is 
low. Both drugs are metabolized primarily via CYP3A4. While in vitro tests have indicated 
burparlisib is a weak inhibitor of CYP3A4 (see Section 1.2.2.1.2), letrozole exposure could be 
increased.
In a phase Ib study [CBKM120XUS13T], buparlisib (100mg QD or 5 on/2 off days) was 
combined with letrozole (2.5mg QD) in ER+/HER2- postmenopausal breast cancer patients 
(see Section 1.2.4), and the combination was found to be both safe and well-tolerated.
1.2.3
Overview of letrozole
Letrozole is a non-steroidal 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 
estrogens, which is the primary source of estrogens in postmenopausal women. Letrozole is a 
highly selective inhibitor of aromatase that induces 75% to 95% decrease of estrogen levels 
after two weeks of treatment with daily doses of 0.1 to 5 mg, with no significant clinical and 
laboratory toxicities or changes in levels of other hormones of the endocrine system as shown 
in early phase I (Lipton 1995; Trunet 1996). It is 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. It is also indicated for the treatment of 


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advanced HR+ breast cancer, both in the first-line setting as well as in patients who have 
disease progression following anti-estrogen therapy. 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 v. 6.0 months) and median OS trended 
superior for letrozole (median, 34 v. 30 months) but this difference was not statistically 
significant (Mouridsen et al 2001).
Letrozole is administered orally 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 primarily 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. In addition, CYP2A6 
forms the carbinol metabolite as well as its ketone analog. In vitro metabolism studies 
performed to examine the inhibition of cytochrome P450 enzymes showed that letrozole is a 
reversible inhibitor of CYP2A6 (Ki = 0.12 µM, strong) and CYP2C19 (Ki = 9 µM, moderate). 
Based on its labeling, no further information is available on the induction and inhibition 
potential of letrozole on other metabolizing enzymes or transporters (Femara Prescribing 
Information).
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 
incidences of adverse events were similar for tamoxifen in this setting. In general, the 
observed adverse reactions are mild to moderate in nature. (Femara SmPC)
Refer to the package insert of the local supply of letrozole for more details.
1.2.4
Overview of BYL719/buparlisib plus letrozole
The relevant role of the PI3K pathway activation in breast carcinoma has been described in 
Section 1.1.3. BYL719 and buparlisib are potent and highly specific oral class I 
phosphatidylinositol-3-kinase (PI3K) inhibitors. Buparlisib is a pan-PI3K inhibitor while 
BYL719 is an alpha-specific PI3K inhibitor.
Preclinical data
Experiments in a panel of 18 luminal BC cell lines show that 7 out of 10 ER-positive and 
HER2-negative cell lines have displayed cell-death (average 44%) when treated with 
buparlisib (Novartis internal data). While cell line data suggest that PIK3CA mutation is 
correlated with BYL719 and buparlisib (although to a lesser extent) sensitivity in a broad 
panel of cancer cell lines, data specific to ER+ breast cancer models have shown comparable 
responses to BYL719 and buparlisib in PIK3CA mutated, PIK3CA wild-type and PTEN 
mutated xenografts models (O’Brien et al, 2014 ). Indeed, in each of these xenografts models, 
buparlisib and BYL719 have shown similar ability to regress tumor burden over several 
weeks of treatment (Figure 1-5).


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Figure 1-5
Single agent activity of BYL719 in ER+ breast cancer models
In vitro combination of letrozole with BYL719 in a PIK3CA mutated cell line of ER+ breast 
cancer (MCF7) displays synergy (Novartis internal data) in line with the concept of synthetic 
lethality seen previously when PI3K was inhibited in an estrogen deprived cell line (Crowder 
2009, Figure 1-6 – Sanchez 2011).
Similarly buparlisib was shown to induce cell death in a series of breast cancer cell lines in 
the context of ER deprivation using fulvestrant (Figure 1-7 - Miller 2011b; Sanchez 2011).
Figure 1-6
Apoptosis rate with BKM120 in MCF7, MCF7-long term oestrogen 
deprived (LTED) and MCF7-estrogen retreated LTED cell lines


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Figure 1-7
Activity of BKM120 as single agent in ER+ breast cancer model; HE 
staining and IHC for Ki67 and cleaved caspase-3/7 (analysis of tumor 
tissue from animals treated with either fulvestrant (2nd row), BKM120 
(3rd row) or a combination of both (bottom panel))
Together these data support the hypothesis that combination of letrozole with a PI3k inhibitor 
might induce tumor cell death in breast cancer.
Orally administered, letrozole is rapidly and almost completely absorbed. Its absorption was 
not substantially modified by food. Its apparent volume of distribution is moderate to high 
(130 L) and it exhibits a low systemic clearance. Letrozole has a long apparent terminal half-
life estimated at 82 hours in breast cancer patients. Steady-state was achieved in 2 to 6 weeks. 
The metabolism of letrozole is > 90% mediated by CYP3A4 through formation of the the 
major metabolite (4,4’-methanol-bisbenzonitrile). This metabolite is then glucuronidated and 
ninety percent of the dose is recovered as this glucuronide in the urine. The high dependence 
of letrozole for its systemic clearance on CYP3A4 together with the potential of BYL719 to 
inhibit CYP3A4 in a time-dependent manner suggests the potential for a drug-drug-interaction 
with letrozole as the victim and BYL719 as perpetrator. The predicted increase in letrozole 
exposure at steady state when combined with 400 mg QD of BYL719 is arou nd 4 fold. 
Additionally, because the clearance of letrozole may be very low when combined with 
BYL719, the effective half-life may be very long, so steady state for letrozole in combination 
could take several months to reach.
Clinical data
Buparlisib + Letrozole
In the completed phase Ib study [CBKM120XUS13T], buparlisib was combined with 
letrozole (2.5mg QD) in post-menopausal women with HR-positive HER2-negative 
metastatic BC (Mayer 2014). Fifty-one ER+/HER2- postmenopausal BC patients were 
accrued in two different arms: buparlisib (100 mg/day) was given continuously (Arm A, n=20) 
or intermittently (5 days on/2 days off; Arm B, n=31). Forty-nine out of these 51 patients had 
previously been treated with an AI for advanced or metastatic disease. Patients cha racteristics 
were different amongst the two arms, with a longer median time since diagnosis in arm A (76 
months versus 29 months), and more chemotherapy in the metastatic setting for patients in the 
arm B (42% versus 15%).


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Buparlisib’s maximum-tolerated dose (MTD) was 100 mg/d. Common drug-related adverse 
events included ≤ grade 2 hyperglycemia, nausea, fatigue, transaminitis, and mood disorders. 
The DLTs observed in Arm A and B were elevated transaminases and depression respectively; 
both at 100 mg. Overall all grade AEs were less frequent with the intermittent schedule as 
compared to the continuous schedule; main AE rates amongst the two arms were respectively 
45% versus 75% for transaminases increase, 48% and 70% for hyperglycemia, 42% and 70% 
for fatigue, 35% and 50% for diarrhea, 32% and 55% for depression, 26% and 65% for nausea 
42% and 45% for anxiety, 30% and 40% for rash maculopapular. The clinical benefit rate was 
similar for both treatment arms (30%). Eleven patients (55%) in the continuous arm had
SD; of those, six patients (30%) had SD≥6 months. None of the patients in the 
intermittent arm had a response, but 14 (45%) of them had SD; of those, 10 (32%) had 
SD ≥6 months.
BYL719 + Letrozole
[CBYL719ZUS03T] is a phase Ib dose-escalation study of BYL719 and letrozole in women 
with HR-positive HER2-negative metastatic BC (n=26). Preliminary safety and efficacy 
results have been reported (Mayer IA, ASCO 2014).
The RP2D was declared at 300 mg. The safety profile was consistent with that described for 
BYL719 as a single-agent, being the most common toxicities observed at 300 mg (n=20) as 
follows: diarrhea (81%), nausea (68%), hyperglycemia (50%), fatigue (37%), and rash (30%). 
There were 3 PRs (15%) documented at 300 mg. Seven patients stayed on treatment for more 
than 6 months, five of whom had a PIK3CA mutation.
2
Rationale
2.1
Study rationale and purpose
Letrozole is indicated for adjuvant and first line therapy for HR+ BC patients and is 
considered a valid therapeutic option for neoadjuvant treatment of postmenopausal HR+ BC 
patients (Charehbili A et al 2014). While the introduction of adjuvant treatment of ER+ 
postmenopausal breast cancer patients with hormonal therapy has led to improved long term 
outcomes, there remain a non-negligible percentage of patients relapsing after standard 
adjuvant treatment with 5 years of letrozole (16%) (Kennecke H et al 2007), justifying the 
need for more efficient treatments. Because efficacy of adjuvant treatment is based on long 
term outcomes, neoadjuvant testing offers a quick way to identify which combination may 
lead to a better outcome over a single agent endocrine treatment. Pathological complete 
response is one of the indicators of response to neoadjuvant treatment and it has been shown 
to be linked to long term outcomes for neoadjuvant chemotherapy treatment in certain breast 
cancer diseases (VonMinckwitz 2012). However, pCR rate remains low with endocrine single 
agent (Dixon 2001).
As a general concept, the inhibition of the PI3K-AKT-mTOR pathway has already been 
shown to lead to improved clinical outcomes when everolimus was added to letrozole in a 
randomized phase II trial in neoadjuvant treatment of postmenopausal women 
(Baselga 2009) or in a phase III trial in a metastatic setting in combination with exemestane 


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(Baselga 2012). Promising pre-clinical data showing potential for cell death in addition to 
decreased proliferation have been observed when PI3K inhibitors are given in combination 
with hormonal therapy (Sanchez 2011). Furthermore, clinical activity has been observed with
single agent BYL719 or buparlisib in heavily pre-treated ER+ BC patients (Juric 2012, Rodon 
2011) and when buparlisib was given in combination with letrozole to metastatic breast 
cancer patients (Mayer 2014a; Mayer 2014b).
As shown in Section 1.1, the PI3K pathway might be activated via different routes. Within the 
given ER+/PR+ subtype, activation can be seen via PIK3CA mutations (activation of the 
alpha subunit) or PTEN alterations (activate the pathway primarily via beta subunits). Hence,
the use of an alpha-specific PI3K inhibitor like BYL719 or a pan-PI3K inhibitor like 
buparlisib (equipotent against alpha and beta subunits) in combination with letrozole may 
improve letrozole single agent outcomes by increasing the rate of tumor cell apoptosis. It is 
hypothesized that inhibiting the PI3K pathway upfront in combination with estrogen 
deprivation might be sufficient to lead to an increase in pathologic response and might prove 
to be an effective treatment in neoadjuvant treatment for postmenopausal HR+ HER2- BC 
patients.
In addition, in theory, an alpha specific inhibitor would demonstrate superior efficacy in the 
PIK3CA-mutant cancer population, with a potentially improved safety profile as compared to 
pan class I PI3K inhibitors. On the other hand, a panPI3K inhibitor may offer benefit over an 
alpha- specific one by being possibly active in circumstances where PI3K is activated via 
other subunits (beta, delta or gamma) 
However, there is lack of sufficient preclinical data to predict respective impact of alpha 
versus pan-PI3K inhibition in ER positive breast cancer in the clinic and only a trial using 
both compounds in the same patient population could provide additional preliminary 
information to help differentiate the compounds in this context.
The purpose of the study is to determine whether treatment with a PI3K inhibitor (BYL719 or 
buparlisib) plus letrozole leads to an increase in pathologic response and in Objective 
Response Rate (ORR) compared to treatment with placebo plus letrozole in patients with 
hormone receptor-positive HER2-negative breast cancer for the following populations: i) in 
patients with tumors harboring a mutation in the PIK3CA gene ii) in patients with tumors
harboring a wild type PIK3CA gene.
2.2
Rationale for the study design
This study is a multicenter, randomized, double-blind, placebo-controlled phase II trial in 
neoadjuvant patients with ER+/HER2- breast cancer. The trial is double-blinded with respect 
to buparlisib or matching placebo and BYL719 or matching placebo, but not with respect to 
the type of treatment (i.e. buparlisib or BYL719 arm).
The primary purpose of this part would be to assess the treatment effect of BYL719 plus 
letrozole and buparlisib plus letrozole versus letrozole alone on pathological complete 
response (pCR) and Objective Response Rate (ORR), in neoadjuvant treatment of HR+ 
HER2-negative locally advanced breast cancer in each of the two cohorts, namely, i) PIK3CA 
mutated and ii) PIK3CA wild type.


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Breast conserving surgery rate, objective response rate, Ki67 changes as well as PEPI score
will be assessed. The safety, tolerability and pharmacokinetics of the combination of BYL719 
and letrozole and buparlisib plus letrozole will also be assessed.
2.2.1
Rationale for study design and inclusion of wild-type patients
Based on the mechanism of action understood to date, HR+ breast cancer patients with PI3K 
pathway activation seen through a mutation of the PIK3CA gene, may be particularly suited 
to treatment with the alpha specific PI3K inhibitor, BYL719; while HR+ BC patients with 
activation of the PI3K pathway via loss of the negative regulators 
 might 
gain more benefit from the pan PI3K inhibitor buparlisib. However, while initial preclinical 
experiments have shown some level of predictivity of PIK3CA mutation status on cell lines 
sensitivity to BYL719 treatment and to buparlisib treatment, this was not confirmed in 
xenograft models of ER+ breast cancer (Novartis internal data and Figure 1-4). HR+ breast 
cancer may display a dependency on the PI3K pathway independent of PIK3CA gene 
mutation status and hence confer sensitivity in a broader population.
Furthermore clinical data acquired to date with buparlisib has not yet revealed whether a PI3K 
pathway activated breast cancer patient would derive superior clinical benefit. However, 
differences in molecular features between primary tumor and metastasis, as well as recurrent 
tumor after previous chemotherapy have been described (Kuukasjärvi 1997, Jensen 2011, 
Gonzalez-Angulo AM 2011) and may explain the lack of predictivity of PIK3CA mutations 
on responses to buparlisib seen in early phase I trials in metastatic setting so far.
In addition, data from the TCGA demonstrate a lack of correlation between activation of the 
PI3K pathway via phosphorylation and the presence of mutation. Indeed tumors without 
PIK3CA mutations may still display PI3K pathway dependency due to other pathway 
interactions.
Thus, enrollment of patients with mutated as well as wild-type PIK3CA gene, based on tumor 
tissue assessment, is considered appropriate. In addition, to assess the treatment effect of each 
of the PI3K inhibitors specifically in patients with PIK3CA wild-type and PIK3CA mutated 
HR+ BC, patients will be separated into two different cohorts and within each of these cohorts, 
60 patients will be randomized in each of the three arms (i.e. BYL719+ letrozole, 
buparlisib+letrozole, or placebo+letrozole). Within the placebo+letrozole arm, half the 
patients will receive matching BYL719 or buparlisib placebo, respectively (See Figure 4-1).
In addition, all patients will receive standard of care treatment with letrozole at the standard 
approved dose (either in monotherapy or in combination), regardless of mutational status of 
the tumor.
2.2.2
Rationale for the stratification factors
There are two stratification factors in this study: Ki67 level (≥14% or <14%) and lymph node 
status (positive versus negative). Within each cohort (PIK3CA mutated tumors and PIK3CA 
wild type tumors), patients will be randomized into one of the three treatment arms stratified 
by the above factors.
Luminal A and luminal B are the two different subtypes of ER+ breast cancer, presenting with 
different prognosis. From a histopathological point of view, apart from ER and/or PR 


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positivity, luminal A and B differ by the level of expression of Ki67 (Goldhirsch 2011), the 
Ki67 index cutpoint being below 14% for luminal A and above or equal to 14% for luminal B 
(Cheang 2009). Using that cutpoint, 35% of patients are expected to be classified as luminal 
B-like, and 65% as luminal A-like. To ensure homogeneity, Ki67 assessment will be made 
centrally for stratification purposes.
A number of prognostic factors predict for future recurrence or death from breast cancer. 
Among these, the number of axillary lymph nodes involved is one of the strongest prognostic 
factors (Cianfrocca 2004). Clinical lymph node status (positive or negative) will be used for 
stratification purpose. It is expected that about 30% of patients will have clinically positive 
lymph nodes at study entry (Ellis 2011).
2.3
Rationale for dose and regimen selection
The recommended dose for letrozole is 2.5 mg once daily (Femara Prescribing Information
and Section 1.2.3).
BYL719 300 mg QD will be given in combination with letrozole 2.5 mg QD for 24 weeks. 
The rationale for the choice of BYL719 dose level (300 mg QD) together with letrozole 2.5 
mg is based on the following elements:
1. Ongoing FIH study [CBYL719X2101] showed 400 mg QD to be the MTD for BYL719 
given as single agent and 350 mg QD to be an acceptable starting dose for phase II trials. 
The recommended phase 2 dose (RP2D) for BYL719 given as a single-agent in the 
Japanese phase I dose escalation [CBYL719X1101] study was also established at 350 mg
(see Section 1.2.1.2).
2. Study [CBYL719ZUS03T] has determined 300 mg as the RP2D of BYL719 in 
combination with letrozole (see Section 1.2.1.2).
3. In addition, overlapping toxicities for BYL719 and letrozole are very limited and consist
mainly of asthenia: in the ongoing phase I trial (IIT; [CBYL719ZUS03T]) combining 
BYL719 and letrozole, no DLTs have been observed at 300 mg in five patients (with two 
confirmed partial responses out of three patients evaluable for efficacy). Six patients 
received BYL719 at 350 mg starting dose: dose reduction was required in four patients 
and after dose reduction two patients were able to resume and continue treatment in 3.
Other phase I dose escalation trials of BYL719 in combination with different compounds 
have also shown that the dose of BYL719 that can be used in combination lies between
270 mg and 400 mg (see Section 1.2.1.2). BYL719 will thus be given at the starting dose 
of 300 mg with standard dose of letrozole.
4. Letrozole doses of 0.1 to 5 mg QD have led to selective and almost complete decrease of 
the level of circulating estrogens with no significant clinical and laboratory toxicities nor 
impact on levels of other hormones. In a recent clinical study, doses of letrozole (10 mg 
per day) higher than the recommended one (2.5 mg per day) have been administered 
without safety concerns in a phase II trial (Dixon 2001) when the drug was given in the 
neoadjuvant setting over a period of three months. If the PK is linear in this dose range, 
this implies a wide margin of safety for letrozole of at least 4-fold. Thus, even if a drug-
drug interaction between BYL719 and letrozole is confirmed, leading to higher 
concentrations of letrozole (Section 1.2.4), it is postulated that this will not cause


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additional safety concerns compared to the standard dose of 2.5 mg QD 
(see Section 1.2.3).
Buparlisib will be administered at a dose of 100 mg QD 5 days on/2 days off in 
combination with letrozole 2.5 mg QD. For the rationale of this regimen please refer to 
Section 1.2.2.3.
Duration of treatment will be 24 weeks. While in initial trials of neoadjuvant endocrine 
therapies, treatment has been given for 16 weeks (Ellis 2001) more recent data have shown 
that a longer duration of treatment can yield greater benefits for patients (Dixon 2009, Dixon 
2011, Allevi 2013) and 24 weeks can be considered as an acceptable duration for therapy.
2.4
Rationale for choice of combination drugs
Promising pre-clinical data showing potential for leading to cell death instead of decreased 
proliferation have been observed when PI3K inhibitors are given in combination with 
hormonal therapy (see Section 1.1.3). In addition, mechanism of endocrine resistance thought 
to play a key role in ER+ breast cancer is that multiple receptor tyrosine kinases and 
intracellular signaling pathways are activated in the presence of endocrine therapy to 
compensate for the loss of estrogen signaling. Many of the receptor tyrosine kinases 
responsible for this mechanism signal via the PI3K/AKT/mTOR intracellular cascade. Hence, 
early treatment with PI3K inhibitors might delay resistance to endocrine therapy and prolong 
response to treatment.
The relevance of inhibiting the PI3K/AKT/mTOR pathway has been shown in the clinical 
setting already when everolimus (an allosteric inhibitor of TORC1 inducing cytostasis) was 
added to letrozole in neoadjuvant treatment of postmenopausal breast cancer patients and 
resulted in a significant increase in the clinical response rate (68.1% of the patients receiving 
the combination treatment vs 59.1% in the placebo arm; p=0.062) and significant decrease in 
Ki67 levels at day 15 (in 57% of the patients receiving the combination treatment versus 30% 
in the placebo arm; p<0.01) (Baselga 2009). Mechanistically, inhibiting the pathway at the 
p110 level is expected to induce cell death instead of cell stasis.
Therefore it is hypothesized that combining agents that target the PI3K and ER pathway 
simultaneously may be a way to improve letrozole single agent outcomes by increasing the 
rate of tumor cell apoptosis and thus the pCR rate.
2.5
Rationale for choice of comparators drugs
Letrozole is indicated for adjuvant and first line therapy for HR+ BC patients. Letrozole has 
been evaluated in several neoadjuvant trials (Eiermann 2001, Ellis 2001, Thomas 2007, Dixon 
2009, Ellis 2011, Dixon 2011) including three randomized trials against other endocrine 
agents. In two of these trials, letrozole was compared to tamoxifen and found to have superior 
activity in terms of response rate and breast conserving surgery; when used in a phase II study
comparing exemestane, letrozole and anastrozole (Ellis 2011), letrozole and anastrozole were 
selected for further clinical development based on clinical response rate.
Letrozole is thus considered as a valid therapeutic option for neoadjuvant treatment of 
postmenopausal HR+ BC patients (NCCN Guidelines 2013, Dixon 2009).


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2.6
Risks and Benefits
Potential benefits for clinical trial participants
Treatment with alpelisib in combination with letrozole as a neoadjuvant endocrine therapy for 
women with early-stage hormone receptor-positive breast cancer may result in an improved 
clinical and pathological response compared to letrozole alone in this patient population. All 
patients enrolled in this trial receive standard of care endocrine therapy (i.e. single agent 
letrozole) for their disease. Based on preclinical and clinical data, treatment with alpelisib in 
combination with letrozole is expected to be well tolerated and it is hypothesized to increase 
clinical efficacy (Mayer IA et al 2016). For further details on clinical safety, please refer to 
the latest version of the [Alpelisib (BYL719) Investigator’s Brochure].
Potential risks for clinical trial participants
Patients in this study will be closely monitored for key toxicities that have been observed with 
alpelisib, letrozole, or the combination of both. Some of the safety assessments include, but 
are not limited to, laboratory assessments of hematology, chemistry (including amylase and 
lipase), renal function, and ECGs. In addition, patients have a mandatory imaging efficacy 
evaluation at cycle 4 day 1 and before surgery (i.e. after cycle 6 day 28). Further efficacy 
evaluations can also be performed during the conduct of the study based on clinical judgement.
Risks will be further minimized by i) the adherence to the inclusion/exclusion selection 
criteria; ii) the avoidance of concomitant medication that may pose a drug-drug interaction 
risk; and iii) the observance to the detailed dose adjustment guidelines based on the toxicities 
that a patient may experience. 
In summary, Novartis considers that the benefit-risk assessment of the clinical trial 
CBYL719A2201 remains favorable. The newly added safety information in the latest version 
of the [Alpelisib (BYL719) Investigator’s Brochure] has been taken into consideration and 
CBYL719A2201 upcoming amendment and updated ICF will reflect such changes.
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 anti-tumor activity of BYL719 QD plus letrozole versus 
letrozole alone in increasing the pathologic complete response (pCR) 
rate during neo-adjuvant treatment among postmenopausal patients 
with HR+, HER2-negative breast cancer for each of the two cohorts: i) 
PIK3CA mutated and ii) PIK3CA wild tumor types based on tumor 
tissue. 
and 
To assess the anti-tumor activity of BYL719 QD plus letrozole versus 
letrozole alone in increasing the Objective Response Rate (ORR) 
during neo-adjuvant treatment among postmenopausal patients with 
HR+, HER2-negative breast cancer for each of the two cohorts: i) 
PIK3CA mutated and ii) PIK3CA wild tumor types based on tumor 
tissue. 
Pathologic complete response (pCR) per investigator assessment 
following completion of 24 weeks defined as of treatment absence 
of any residual invasive cancer on hematoxylin and eosin 
evaluation of the resected breast specimen and all sampled 
ipsilateral lymph nodes following completion of neoadjuvant 
systemic therapy
Objective response rate (complete + partial response) per 
investigator assessment according to RECIST 1.1 
Secondary
Refer to Section 10.5
To assess the anti-tumor activity of BYL719 QD plus letrozole versus 
letrozole alone in increasing the pCR rate and ORR for each of the two 
cohorts: i) PIK3CA mutated and ii) PIK3CA wild tumor types, based on 
ctDNA.
pCR and ORR (complete + partial response) according to 
RECIST 1.1 criteria, per investigator assessment 
To evaluate the safety and tolerability of the combinations 
Frequency/severity of AEs, laboratory abnormalities
To estimate the rate of breast conserving surgery for each of the two 
cohorts, namely, i) PIK3CA mutated and ii) PIK3CA wild type based on 
tumor tissue
Rate of breast conserving surgery is defined as the percentage of 
patients with no mastectomy following completion of 24 weeks of 
treatment
To evaluate the association between changes in Ki67 from baseline to 
day 15, and baseline to surgery, with pCR for each of the two cohorts, 
namely, i) PIK3CA mutated and ii) PIK3CA wild type based on tumor 
tissue
Correlation between pCR and change in Ki67 from baseline to 
day 15 and baseline to surgery
To assess centrally the Preoperative endocrine prognostic index (PEPI) 
score for each of the two cohorts, namely, i) PIK3CA mutated and ii) 
PIK3CA wild type based on tumor tissue
Response defined as central PEPI score of 0
To characterize the pharmacokinetics of BYL719/buparlisib and 
letrozole when given in combination
● Plasma concentration time profiles of BYL719/buparlisib and 
appropriate individual PK parameters (e.g. AUCtau, Cmax, Tmax 


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and other PK parameters if deemed appropriate)
●Plasma concentration time profiles of letrozole and appropriate
individual PK parameters (e.g. AUCtau, Cmax, Tmax and other 
PK parameters if deemed appropriate)
Exploratory
Refer to Section 10.6
To assess the anti-tumor activity of BYL719 QD plus letrozole and 
buparlisib (QD continuous or QD 5 days on/2 days off) plus letrozole 
versus letrozole alone in increasing the pathologic complete response 
(pCR) rate during neo-adjuvant treatment among postmenopausal 
patients with HR+, HER2-negative breast cancer regardless of 
PIK3CA mutational status (overall patient population).
Pathologic complete response (pCR) per investigator assessment 
following completion of 24 weeks of treatment defined as absence 
of any residual invasive cancer on hematoxylin and eosin 
evaluation of the resected breast specimen and all sampled 
ipsilateral lymph nodes following completion of neoadjuvant 
systemic therapy
To assess the anti-tumor activity of a PI3K inhibitor (BYL719 QD plus 
letrozole and buparlisib QD continuous or QD 5 days on/2 days off plus 
letrozole arms pooled together) versus letrozole alone in increasing the 
pathologic complete response (pCR) rate during neo-adjuvant treatment 
among postmenopausal patients with HR+, HER2-negative breast 
cancer for the overall patient population (regardless of PIK3CA 
mutational status).
Pathologic complete response (pCR) per investigator assessment 
following completion of 24 weeks of treatment defined as absence 
of any residual invasive cancer on hematoxylin and eosin 
evaluation of the resected breast specimen and all sampled 
ipsilateral lymph nodes following completion of neoadjuvant 
systemic therapy
To assess the anti-tumor activity of buparlisib (QD continuous or QD 5 
days on/2 days off) plus letrozole versus letrozole alone in increasing 
the pathologic complete response (pCR) rate during neo-adjuvant 
treatment among postmenopausal patients with HR+, HER2-negative 
breast cancer for each of the two cohorts: i) PIK3CA mutated and ii) 
PIK3CA wild tumor types based on tumor tissue and ctDNA. 
and 
To assess the anti-tumor activity of buparlisib (QD continuous or QD 5 
days on/2 days off) plus letrozole versus letrozole alone in increasing 
the Objective Response Rate (ORR) during neo-adjuvant treatment 
among postmenopausal patients with HR+, HER2-negative breast 
cancer for each of the two cohorts: i) PIK3CA mutated and ii) PIK3CA 
wild tumor types based on tumor tissue and ctDNA.
Pathologic complete response (pCR) per investigator assessment 
following completion of 24 weeks of treatment defined as absence 
of any residual invasive cancer on hematoxylin and eosin 
evaluation of the resected breast specimen and all sampled 
ipsilateral lymph nodes following completion of neoadjuvant 
systemic therapy
Objective response rate (complete + partial response) per 
investigator assessment according to RECIST 1.1
To explore the change in cell proliferation and cell death in the context 
of letrozole treatment alone versus letrozole treatment in combination 
Ki67 and markers of cell death 
 


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4
Study design
4.1
Description of study design
Figure 4-1
Description of study design
This is a multicenter phase II randomized, double-blind placebo controlled, study of letrozole 
2.5 mg with or without BYL719 300 mg or buparlisib 100 mg, for the neoadjuvant treatment 
of postmenopausal women with hormone receptor-positive HER2-negative breast cancer.


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A total of approximately 320 patients will be randomized. Patients will be assigned to one of
2 cohorts: PIK3CA mutated and PIK3CA wild-type. Following the permanent stop of the 
enrollment in the buparlisib arm, the target number of 60 patients per arm in each cohort 
remains unchanged for the BYL719 and placebo arms. However a lower number of patients 
will be randomized to buparlisib.
Within each of these 2 cohorts, randomization will be stratified according to Ki67% (<14% vs. 
≥14%, as measured by Novartis designated central lab) and lymph node status (positive or 
negative) (see Figure 4-1 for study design). Lymph node status should be assessed 
radiologically and/or histologically.
A sample from the diagnostic biopsy (referred thereafter as specimen 1) (slides or core) will 
be required for all patients for assessment of the PIK3CA status prior to randomization in 
order to evaluate the effect of the letrozole+BYL719 vs. letrozole+placebo according to 
PIK3CA mutation status.
PK profiles will be collected in at least 15 patients in the BYL719 and Placebo arms from 
selected centers. Final PK evaluations will only be conducted at the end of the trial.
Patients who discontinue letrozole for any other reason than documented disease progression 
(e.g. because of toxicity attributed to letrozole or at the discretion of the investigator) will be 
allowed to continue BYL719/placebo or buparlisib/placebo until treatment is completed or 
surgery, progression or unacceptable toxicity, and vice versa. Patients will be followed up to 
30 days post-treatment. The end of study is defined when the 30 day follow up is completed 
for all patients or all patients have discontinued treatment for any reason. No follow up other 
than safety follow up for 30 days after treatment discontinuation will be done.
After patients have completed 24 weeks of study treatment, surgery will be performed as early 
as possible but not more than 14 days after the last dose of BYL719/placebo or 
buparlisib/placebo. In the case that surgery is not immediately performed after the last dose of 
BYL719/placebo or buparlisib/placebo, letrozole will be continued until the day of surgery.
Surgery isn’t considered a study assessment.
Adjuvant treatment after surgery (endocrine therapy, chemotherapy or radiotherapy) is left to 
the judgment of the investigator and is outside the scope of this study.
Primary endpoints are based on local assessment.
Screening period
Upon signing the Study Informed Consent Form, patients will be evaluated for study inclusion 
and exclusion criteria. Eligible patients will be enrolled in the study within 28 days of the 
commencement of the screening assessments and evaluations (Table 7-1 and Section 7.1.2). A 
molecular prescreening assessment will be conducted and may occur in advance of the other 
assessments of the screening phase (any time after the site is initiated) or in parallel with the 
other assessments. Once the patient provides molecular pre-screening informed consent, 
demography will be collected and the diagnostic biopsy (7-9 sections or a full core, referred to 
as specimen 1) will be sent to a Novartis designated laboratory. If the diagnostic biopsy is not 
available a newly obtained tumor biopsy may be sent in its place. If a full core is not 
submitted at screening a second specimen (specimen 2) will be required for enrollment at 


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screening. The first specimen submitted at molecular pre-screening, (specimen 1), the 
diagnostic biopsy (full core (block) preferred but 7 to 9 pre-cut slides or punch are acceptable),
will be used primarily to establish the PIK3CA mutation status, and assess the Ki67 status. 
The laboratory will provide this information to the IRT for allocation of the patient to a given 
cohort (PIK3CA mutated or wild-type) and allow stratification (Ki67<14% or ≥14%) during 
the randomization process (see Section 7.1.1). Collection and shipment of Specimen 1 to a 
Novartis designated laboratory must occur as soon as possible and at least 14 days prior to the 
planned 
randomization 
date. 
The 
Novartis 
designated 
laboratory 
must 
provide 
acknowledgment of receipt of adequate tumor tissue quantity within 3 days of sample receipt.
If a full core block of sufficient size and tumor content is submitted as specimen 1, no 
additional material needs to be submitted to cover specimen 2 analyses (Figure 7-1). If a full 
core was not initially submitted, a second tumor specimen should be collected from all 
patients. In institutions where research cores are taken at diagnosis, one of these cores can be 
sent to Novartis. Alternatively specimen 2 can be prospectively collected from the patients. 
This specimen will be primarily used to assess ER, PR, HER2 status centrally (PEPI score) as 
well as molecular characterization using deep sequencing approaches and baseline 
phosphoproteins status (see Section 7.2.4). The second specimen can be collected and sent at 
any time before the first dose of treatment. The overall study informed consent must be signed 
by the patient prior to performing any other screening phase assessments.
Treatment phase
Once eligibility criteria have been confirmed, patients will be grouped into one the two 
cohorts (i.e. PIK3CA mutated and PIK3CA wild-type). Within each cohort, patients will be 
randomized into one of the arms (i.e. BYL719+letrozole or placebo+letrozole).Within the 
placebo+letrozole arm, the patients will now receive matching BYL719 placebo. Within each 
cohort, randomization will be stratified according to Ki67% (<14% vs. ≥14%, as measured by 
Novartis designated central lab) and lymph node status (positive or negative).
Study treatment should be started as soon as possible and no later than 3 days after the 
randomization of the patient.
Newly randomized patients will receive BYL719 300 mg QD or matching placebo given once 
daily continuously starting from Cycle 1 Day 1. In addition, letrozole 2.5 mg QD will be 
administered continuously starting at Cycle 1 Day 1.
Ongoing patients with buparlisib/buparlisib-placebo who are still benefiting from the 
treatment may continue the treatment based on the investigator’s clinical judgement. 
Buparlisib/placebo and BYL719/placebo dose modifications will be allowed (see Section 6.3). 
Safety will be monitored as outlined in Section 7.2.2.
In addition to the PK samples collected prior to the permanent stop of the enrollment in the 
buparlisib arm which will be kept for analysis, at least 15 patients in the treatment arms
BYL719+letrozole, and placebo+letrozole, whether in the PIK3CA mutated or wild-type 
cohort) will have PK sampling. This is performed in order to characterize the PK of buparlisib 
and BYL719 when given in combination with letrozole as well as the PK of letrozole. All 
letrozole samples will be analyzed for letrozole. Samples from buparlisib or BYL719 treated 
patients will be analyzed for either buparlisib or BYL719 (see Section 10.1.4).


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A core biopsy (14 to 16 gauge recommended) will be performed in all patients at the end of 
second week of treatment (C1D15 Biopsy) to assess Ki67 status and additional biomarkers as 
described in Section 7.2.4.
Patients will be treated for a maximum of 24 weeks or until surgery, or progression, or 
unacceptable toxicity or discontinuation from the study treatment for any other reason.
Tumor evaluations will be performed at baseline, at cycle 4 day 1 (with a window of +/- 7 
days) and at maximum 7 days before surgery. Disease progression should always be 
documented radiologically, if needed adding earlier than planned time point for tumor 
evaluation.
Surgical specimen will be assessed for Ki67 and molecular alterations as described in
Section 7.2.4.
30-day safety follow-up assessments
The End of Treatment visit occurs within 14 days after the last administration of study 
treatment (see Section 7.1.4). Safety follow-up assessments should be completed 30 days after 
the last dose of the study treatment.
4.2
Timing of interim analyses and design adaptations
There is no planned efficacy interim analysis. Safety data will be periodically reviewed by the 
internal DMC (Section 8.6).
4.3
Definition of end of the study
The study will end when the treatment phase and follow-up for safety period have ended for 
all patients. The study does not formally include the surgical procedure needed for 
pathological assessment as a study assessment. Appropriate safety follow-up will last for 
approximately 30 days after the last dose of study treatment.
4.4
Early study termination
The study may be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient will be contacted by the investigator or his/her designee. The patient should be 
seen as soon as possible for an End of Treatment (EOT) visit 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 IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
The patient population consists of postmenopausal women with hormone receptor-positive, 
HER2-negative, T1c-T3 operable breast cancer, whose disease has never been treated with 


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local nor systemic treatment, and are eligible for endocrine neoadjuvant treatment. Patients for 
whom immeadiate chemotherapy or immediate surgery is indicated are not eligible.
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.
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, female ≥ 18 years old at the time of informed consent.
2. Patient has a histologically and/or cytologically confirmed diagnosis of breast cancer.
3. Patient is postmenopausal at the time of breast cancer diagnosis. Postmenopausal status is 
defined either by:

Prior bilateral oophorectomy (in these cases, the oophorectomy must have been 
performed at least 6 months before the diagnosis of breast cancer in order to be 
considered post-menopausal for study entry)

Age ≥60

Age < 60 and amenorrhea for 12 or more months (in the absence of chemotherapy, 
tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the 
postmenopausal range for the local laboratory (if local ranges not available: FSH 
should be >40mIU/mL and estradiol <20 pg/mL)

For women with therapy-induced amenorrhea, oophorectomy or serial measurements 
of FSH and/or estradiol are needed to ensure postmenopausal status.

Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone 
(LH-RH) agonist (goserelin acetate or leuprolide acetate) is not permitted for 
induction of ovarian suppression.
4. Patient has T1c-T3, any N, M0 operable breast cancer. Multifocal and/or multicentric 
disease is allowed. Synchronous bilateral breast cancer patients are allowed provided 
ONLY ONE of the tumors in one of the breasts is considered for study purposes. Patients 
with cM0 (i+) disease are allowed to participate only if a documented radiographic test 
showing no signs of metastatic disease exists.
5. Patients must have measurable disease. Measurable disease will be defined as any mass 
that can be reproducibly measured by MRI and/or ultrasound in at least one dimension
6. Patient has diagnostic biopsy available for the analysis of PIK3CA mutation and Ki67 
level. One tumor block (preferred) or a minimum of 7to 9 unstained slides is 
recommended. For details on collection, handling and shipment please refer to the 
[CBYL719A2201 Laboratory Manual].
7. Patient has estrogen-receptor and/or progesterone positive breast cancer as per local 
laboratory testing
8. Patient has HER2 negative breast cancer defined as a negative in situ hybridization test or 
an IHC status of 0 or 1+ as per local laboratory testing.


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9. Patient has PIK3CA mutation status known (PIK3CA mutated or wild-type) as defined by 
a Novartis designated laboratory. (Patients with unknown PIK3CA mutation status will 
not be enrolled)
10. Patient has Ki67 level status determined centrally
11. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 
which the investigator believes is stable at the time of screening
12. Patient is able to swallow and retain oral medication
13. Patient has adequate bone marrow and organ function as defined by the following 
laboratory values:
a. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
b. Platelets (plt) ≥ 100 x 109/L
c. Hemoglobin (Hgb) ≥ 9 g/dL
d. Calcium (corrected for serum albumin) and magnesium within normal limits or ≤ 
grade 1 according to NCI-CTCAE version 4.03 if judged clinically not significant by 
the investigator.
e. Potassium within normal limits, or corrected with supplements.
f.
INR ≤ 1.5
g. Serum creatinine ≤ 1.5 x Upper Limit of Normal (ULN)
h. Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) ≤ 1.5 ULN
i.
Total serum bilirubin below ULN; or total bilirubin ≤ 3.0 x ULN with direct bilirubin 
within normal range in patients with well documented Gilbert’s Syndrome, which is 
defined as presence of several episodes of unconjugated hyperbilirubinemia with 
normal results from CBC count (including normal reticulocyte count and blood 
smear), normal liver function test results, and absence of other contributing disease 
processes at the time of diagnosis
j.
Fasting plasma glucose ≤ 140 mg/dL or 7.7 mmol/L HbA1c ≤ 6.5 %
Serum amylase ≤ 2 × ULN
Serum lipase within normal limits
14. Patient has signed informed consent before any screening procedures and according to 
local guidelines
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patient has locally recurrent or metastatic disease
2. Patient has inflammatory breast cancer
3. Patient has a known hypersensitivity to any of the excipients of BYL719 or letrozole
4. Patient has a concurrent malignancy or malignancy within 3 years of study enrollment 
(with the exception of adequately treated, basal or squamous cell carcinoma, non-
melanomatous skin cancer or curatively resected cervical cancer).
5. Patient has received any systemic therapy (e.g. chemotherapy, targeted therapy, and 
immunotherapy) or radiotherapy for current breast cancer disease before study entry.


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Patients receiving hormone-replacement therapy must have discontinued such therapy 28 
days before randomization.
6. Patient with type 1 diabetes mellitus or not adequately controlled type 2 diabetes mellitus 
(according to FPG and HbA1c values as outlined in inclusion criterion #13)
7. 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)
8. Patient classified into Child-Pugh class C
9. Patient has a known history of HIV infection (testing not mandatory)
10. Patient has any other concurrent severe and/or uncontrolled medical condition that would, 
in the investigator’s judgment contraindicate patient participation in the clinical study 
11. Patient has a score ≥ 12 on the PHQ-9 questionnaire. This criterion will only apply to 
buparlisib/buparlisib placebo arms (patients meeting this exclusion criterion will be 
randomized to BYL719/BYL719 placebo). This exclusion criterion is retired as of 
Amendment #5.
12. Patient selects a response of “1, 2 or 3” to question number 9 on the PHQ-9 questionnaire 
regarding potential for suicidal thoughts or ideation (independent of the total score of the 
PHQ-9). This criterion will only apply to buparlisib/buparlisib placebo arms (patients 
meeting this exclusion criterion will be randomized to BYL719/BYL719 placebo). This 
exclusion criterion is retired as of Amendment #5.
13. Patient has a GAD-7 mood scale score≥ 15. This criterion will only apply to 
buparlisib/buparlisib placebo arms (patients meeting this exclusion criterion will be 
randomized to BYL719/BYL719 placebo)
14. Patient has a medically documented history of or active major depressive episode, bipolar 
disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal 
attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others), or 
with an active severe personality disorder (defined according to DSM- IV). Note: for 
patients with psychotropic treatments ongoing at baseline, the dose and the schedule 
should not be modified within the previous 6 weeks prior to start of study drug. This 
exclusion criterion is retired as of Amendment #5.
15. Patient has ≥ CTCAE grade 3 anxiety This exclusion criterion is retired as of Amendment 
#5.
16. Patient has active cardiac disease or a history of cardiac dysfunction including any of the 
following:
a. Unstable angina pectoris within 6 months prior to study entry
b. Symptomatic pericarditis
c. Documented myocardial infarction within 6 months prior to study entry
d. History of documented congestive heart failure (New York Heart Association 
functional classification III-IV)
e. Documented cardiomyopathy
17. Patient has a Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple 
Gated acquisition (MUGA) scan or echocardiogram (ECHO)
18. Patient has any of the following cardiac conduction abnormalities


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a. Ventricular arrhythmias except for benign premature ventricular contractions
b. Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with 
medication
19. Conduction abnormality requiring a pacemaker
a. Other cardiac arrhythmia not controlled with medication
20. Patient has a QTcF > 480 msec on the screening ECG (using the QTcF formula)
21. Patients with congenital long QT syndrome or family history of unexpected sudden 
cardiac death.
22. Patient is currently receiving treatment with medication that has a known risk to prolong 
the QT interval or inducing Torsades de Pointes, and the treatment cannot be discontinued 
or switched to a different medication prior to randomization.
23. Patient has had major surgery within 14 days prior to starting study drug or has not 
recovered from major side effects
24. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to 
starting study drug, or has not fully recovered from side effects of such treatment. The 
following uses of corticosteroids are permitted: single dose, topical applications (e.g., 
rash), inhaled sprays (e.g., obstructive airways diseases), eye drops or local injections (e.g. 
intra-articular)
25. Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for 
treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin 
(LMWH), or fondaparinux is allowed. This exclusion criterion is retired as of 
Amendment #2.
26. Patient is currently receiving treatment with drugs known to be strong inhibitors or 
inducers of isoenzyme CYP3A. The patient must have discontinued strong inducers for at 
least one week and must have discontinued strong inhibitors before the start of treatment. 
Switching to a different medication prior to randomization is allowed.
27. Patient has a history of non-compliance to medical regimen or inability to grant consent.
28. Patient is concurrently using other approved or investigational antineoplastic agent.
29. Patient has acute viral hepatitis or a history of chronic or active HBV or HCV infection, 
(typically defined by elevated AST/ALT (persistent or intermittent), high HBV DNA level, 
HBsAg positive, or high HCV RNA
level (testing not mandatory, refer to
Section 7.2.2.5.6 Viral hepatitis serology and other tests for hepatotoxicity follow-up). 
This exclusion criterion is retired as of Amendment #5.
30. History of acute pancreatitis within 1 year of study entry or past medical history of chronic 
of pancreatitis
31. 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.


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6
Treatment
6.1
Study treatment
For this study, the term “investigational or study drugs” refers to Novartis study drug BYL719
and Novartis study drug buparlisib, which will be supplied by Novartis. The other drug to be 
used in this study is letrozole, which will be procured locally. “Study treatment” in this study 
refers to the combination of drugs in each of the study arms and includes investigational drugs 
(BYL719 and buparlisib) as well as the approved drug letrozole.
A control will be a BYL719 or buparlisib matching placebo (placebo). As this is a multi-
center randomized, double-blind study, the investigator and patient will be blinded (i.e. will 
not know if the patient is receiving active buparlisib/BYL719 or placebo of either drugs). In 
addition, all patients will receive open label letrozole as part of study treatment.
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF.
In December 22, 2015, the buparlisib/buparlisib-placebo arm was permanently stopped for 
enrolment. For those patients enrolled in the buparlisib/buparlisib placebo arms before 
December 22, 2015, treatment with buparlisib/buparlisib placebo and letrozole may continue 
based on the investigator’s clinical judgement.
6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule
Study treatments
Pharmaceutical form and 
route of administration
Dose2
Frequency and/or Regimen 
(28 day cycles)
BYL719
tablet for oral use
300 mg
(e.g. 2 x 50 mg tablets+ 1
x 200 mg tablet1)
Daily (continuous)
Letrozole
tablet for oral use
2.5 mg
Daily (continuous)
Buparlisib (BKM120)
capsule for oral use
100 mg
(2 x 50 mg capsules1)
5 days on/2 days off
1 In case of patient supply difficulties, any combination of BYL719/buparlisib/placebo (according to patient 
assignment) may be taken to consume the total dose.
2 Dose reduction levels for BYL719/buparlisib/placebo will be administered accordingly. For example, 
buparlisib/placebo 80 mg should preferentially be administered as 1x 50 mg size capsule, and 3x10 mg size 
capsule, and BYL719/placebo 250mg should preferentially be administered as 1 X 50 mg tablets + 1 x 200 mg 
tablet.
The study drugs will be administered orally, and dosed on a flat-fixed dose (see Table 6-1), 
and not by body weight or body surface area.
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.


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6.1.2
Instructions for administration
6.1.2.1
Study Drug Administration instructions for all patients

Patients should be instructed to take the study treatment of one or more tablets of 
BYL719/placebo daily or one or more capsules of buparlisib/placebo days 1-5 out of 7 
days, and letrozole daily together with a glass of water (~250 mL or ~8 fluid ounces) at 
approximately the same time each day (preferably in the morning after breakfast), except 
on the days blood collection is scheduled at the clinic, at which time the patients should 
take their doses at the clinic at any later point of time. Patients should be instructed to 
swallow the capsules and tablets whole and not to chew, crush or open them.

Patients should record if the dose was taken or not in the patient diary.

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 and/or 
diarrhea (or increase stool frequency) during a treatment cycle must be noted in the 
adverse events section of the eCRF. In addition, on the days of full pharmacokinetic 
sampling, the exact onset time of any episodes of vomiting and diarrhea (or increase stool 
frequency) within the first 24 hours post-dosing on that day must be noted in a separate 
section of the eCRF.

Patients must avoid consumption of Seville orange (and juice), grapefruit or grapefruit 
juice, grapefruit hybrids, pummelos, starfruits and cranberry juice from 7 days prior to the 
first dose of study drug and during the entire study treatment period due to potential 
CYP3A interaction. Regular orange (Citrus X sinensis) juice is allowed.
The following general guidelines should be followed for BYL719/placebo administration:

Patients should be instructed to take the dose of BYL719/placebo once daily at 
approximately the same time each day after a meal (preferably in the morning after 
breakfast) except on the days blood collection is scheduled at the clinic, at which time the 
patients should take their doses at the clinic at any later point of time.

BYL719/placebo 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 this happens 
on days of PK sampling, it should be documented in the CRF.

If the patient forgets to take study treatment during the daytime it should be taken in the 
evening (at approximately 6 pm) at the latest within 1 hour after a meal. If not taken by 
this time, the dose should be withheld that day. Missed doses should not be made up the 
next day. 
6.1.3
Guidelines for continuation of treatment
For guidelines for continuation of treatment, refer to Section 6.3 Dose modifications.
Patients who permanently discontinue one of the study drugs for any reason other than disease 
progression may continue the other study drug as part of the trial therapy at the investigators 
discretion for 24 weeks of treatment until disease progression, surgery, unacceptable toxicity, 
death or discontinuation from study treatment due to any other reason and should follow the 
protocol safety and efficacy assessments as scheduled (see the criteria for patient withdrawal 


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in Section 7.1.4). After discontinuing study treatment, further treatment is left to the 
physician’s discretion. No cross over to another treatment arm (from placebo to either 
buparlisib or BYL719 or from buparlisib to BYL719 and vice versa) will be allowed.
6.1.4
Treatment duration
Patients will be treated for 24 weeks. Patients may be discontinued from study treatment 
earlier than 24 weeks due to unacceptable toxicity, disease progression (radiologically 
documented according to RECIST 1.1), and/or if treatment is discontinued at the discretion of 
the investigator or the patient, or withdrawal of consent. For further details refer to 
Section 7.1.4.
After patients have completed 24 weeks of study treatment (BYL719/placebo or 
buparlisib/placebo, or letrozole), surgery will be performed as early as possible but not more 
than 14 days after the last dose of study treatment . In the case that surgery is not immediately 
performed after the last dose of BYL719/placebo or buparlisib/placebo, letrozole will be 
continued until the day of surgery. Surgery is not considered a study assessment.
Definition of treatment cycle
A complete treatment cycle is defined as 28 calendar days (± 3 days) during which 
BYL719/placebo with letrozole are given once a day, in a continuous daily regimen 
(BYL719/placebo treatment arms); and buparlisib/placebo is 5 days on/2 days off; and 
letrozole is given once a day, in a continuous daily regimen(letrozole arm).
6.2
Dose escalation guidelines
Not applicable
6.3
Dose modifications
6.3.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. Any changes in 
BYL719/placebo, buparlisib/placebo, or letrozole administration must be recorded on the 
eCRF.
BYL719/buparlisib/placebo dose modification guidelines are described in Section 6.3.1.1. 
Toxicities attributed to letrozole should be managed in a manner consistent with the 
investigator’s usual clinical practice and the package insert for letrozole, and should be 
reported in the eCRF. Refer to the package insert of the local supply of letrozole for more 
details. 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.
All dose modifications, interruptions or discontinuations must be based on the worst 
preceding toxicity as graded by the NCI Clinical Toxicity Criteria (NCI-CTCAE version 4.03). 
Once a dose has been reduced during a treatment cycle, re-escalation will not be permitted 
during any subsequent cycle.


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If the administration of BYL719/placebo or buparlisib/placebo is interrupted for reasons other 
than toxicity, then treatment with the respective study drug may be resumed at the same dose. 
The same provision applies if the patient experienced an unacceptable toxicity not specifically 
described in Table 6-4 provided that this toxicity resolved to ≤ CTCAE grade 1, unless 
otherwise specified.
If one or both study drugs are being held due to toxicity, scheduled visits and all assessments 
should continue to be performed (with the exception of the dosing of the held study drug), as 
described in Table 7-1.
If administration of BYL719/buparlisib or matched placebo dosing is held for more than 28 
days, then BYL719/buparlisib must be permanently discontinued. If letrozole is held for more 
than 28 days then letrozole mustbe permanently discontinued. Patients who permanently 
discontinue one of the study drugs for any reason other than disease progression may continue 
letrozole as part of the trial therapy at the investigators discretion, and vice versa.
Patients should have weekly follow-up for 30 days after discontinuation of all study treatment 
or resolution of the AE to ≤ grade 1, whichever occurs first, that includes all study 
assessments appropriate to monitor the event.
6.3.1.1
Criteria for BYL719/placebo and buparlisib/placebo dose modification
A BYL719/placebo dose reduction will be administered as shown in Table 6-2 below. A 
maximum of 2 dose reductions will be allowed, after which the patient will be discontinued 
from treatment with BYL719/placebo. Dose reduction should be based on the worst preceding 
toxicity. Dose reduction below BYL719 200 mg QD is not allowed. If a dose reduction below 
200 mg
QD is required, the patient should be permanently discontinued from 
BYL719/placebo.
Table 6-2
Dose reduction sequential steps for BYL719/placebo
BYL719 / placebo dose level
Dose and schedule
Starting dose
300 mg/ day continuously
Dose level -1
250 mg/ day continuously
Dose level -2
200 mg/ day continuously
A buparlisib/placebo dose reduction will be administered as shown in the Table 6-3 below. A 
maximum of 2 dose reductions will be allowed, after which the patient will be discontinued 
from treatment with buparlisib/placebo. Dose reduction should be based on the worst 
preceding toxicity. Dose reduction below buparlisib 60 mg/day 5 days on/ 2 days off is not 
allowed. If a dose reduction below 60 mg/day 5 days on/ 2 days off is required, the patient 
must be permanently discontinued from buparlisib/placebo. In the event of a study treatment 
interruption
in patients randomized to buparlisib/placebo, 
the reintroduction of 
buparlisib/placebo treatment should not start on either Day 6 or Day 7 of the intermittent 
dosing schedule.
Table 6-3
Dose reduction sequential steps for buparlisib/placebo
Buparlisib/placebo dose level
Dose and schedule
Starting dose
100 mg/ day 5 days on/2 days off


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Buparlisib/placebo dose level
Dose and schedule
Dose level -1
80 mg/ day 5 days on/2 days off
Dose level -2
60 mg/ day 5 days on/2 days off
Guidelines for dose modification and dose interruption for toxicities suspected to be related to 
BYL719/placebo or buparlisib/placebo are described in Table 6-4.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.
If a patient requires a dose delay of > 28 days from the intended day of the next scheduled 
dose of BYL719/placebo or buparlisib/placebo, then the patient must be discontinued from 
BYL719/placebo or buparlisib/placebo, but can continue on letrozole at the discretion of the 
investigator until study completion (i.e. 24 weeks), in which case all scheduled assessments
will continue to be performed. Patients who discontinue from the study for a study-related AE
or an abnormal laboratory value must be followed at least once a week for 4 weeks and 
subsequently at 4-week intervals, until resolution or stabilization of the event, whichever 
comes first.
Table 6-4
Criteria for interruption and re-initiation of BYL719/placebo or 
buparlisib/placebo
These changes must be recorded on the Dosage Administration Record eCRF. Letrozole may 
be continued while BYL719/placebo or buparlisib/placebo dose is being held, at the 
investigators discretion. Letrozole administration until surgery should be recorded on the 
Dosage Administration Record eCRF page.
Adverse drug 
reaction
Severity
Dose adjustment and management recommendations
Hematology
ANC <0.5 x 109/L 
without fever and/or 
platelets < 25 x 109/L
Omit buparlisib/placebo or BYL719/placebo until ANC is ≥ 
baseline value and the platelet count is ≥ 75 x 109/L.then
reduce 1 dose level
ANC <1.0 x 109/L with 
fever (≥38.5°C)
Omit buparlisib/placebo or BYL719/placebo until ANC is ≥ 
baseline value and no fever, then reduce 1 dose level
Cardiac – QTc 
prolongation
QTcF > 500 ms (≥ 
Grade 3) 
or > 60 ms change from 
baseline 
on at least two separate 
ECGs
- First Occurrence:
Omit buparlisib/placebo or BYL719/placebo
Perform a repeat ECG within one hour of the first QTcF of > 
500 ms or >60ms from baseline: if QTcF remains > 500 ms 
or >60ms from baseline, repeat ECG as clinically indicated, 
but at least once a day until the QTcF returns to < 480 ms.
Seek cardiologist input; address electrolytes, calcium and 
magnesium abnormalities; concomitant medication must be 
reviewed.
Once QTcF prolongation has resolved, buparlisib/placebo or 
BYL719/placebo may be restarted at one lower dose level
- Second Occurrence:
Permanently discontinue patient from buparlisib/placebo or 
BYL719/placebo
Cardiac – Left 
Ventricular systolic 
dysfunction
Asymptomatic, resting 
ejection fraction 40-
50%; or 10-20% drop 
from baseline
Maintain dose level, and continue buparlisib/placebo or 
BYL719/placebo with caution
Repeat LVEF within 4 weeks or as clinically appropriate
Symptomatic, 
responsive to 
intervention, ejection 
Permanently discontinue patient from buparlisib/placebo or 
BYL719/placebo


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fraction 20-39% or > 
20% drop from baseline
Refractory or poorly 
controlled, ejection 
fraction < 20%
Permanently discontinue patient from buparlisib/placebo or 
BYL719/placebo
Cardiac Events (other 
than QTc prolongation 
or left ventricular 
systolic dysfunction)
Grade 1 or 2
Maintain dose level
Grade 3
Omit dose until resolved to ≤ Grade 1, then reduce
buparlisib/placebo or BYL719/placebo 1 dose level
Grade 4
Permanently discontinue patient from buparlisib/placebo or 
BYL719/placebo
Diarrhea
Please see Appendix 
5 for guidelines for 
study drug-induced 
diarrhea management.
Grade 1
Maintain dose level
Grade 2
Omit dose until resolved to ≤ Grade 1, then restart at same 
dose
≥ Grade 3
Omit dose until resolved to ≤ Grade 1, then reduce 
buparlisib/placebo or BYL719/placebo 1 dose level
Eye disorders
≥ Grade 3 ocular/vision 
symptoms interfering 
with activities of daily 
life or requiring medical 
intervention
Discontinue patient from buparlisib/placebo or 
BYL719/placebo
Hepatic – Bilirubin
(*for patients with 
Gilbert Syndrome 
these dose 
modifications apply to 
changes in direct 
bilirubin only)
Grade 1 (> ULN – 1.5 x 
ULN)
Maintain dose level with liver function tests (LFTs)* 
monitored as per protocol
Grade 2 (> 1.5 – 3.0 x 
ULN) with ALT or AST 
≤ 3.0 x ULN
Omit dose until resolved to ≤ Grade 1, then:
If treatment delay is ≤ 7 days, restart at same dose
If resolved in > 7 days, reduce buparlisib/placebo or 
BYL719/placebo 1 dose level
Grade 3 (> 3.0 – 10.0 x 
ULN) with ALT or AST 
≤ 3.0 x ULN
Omit dose until resolved to ≤ Grade 1, then:
● If resolved in < 7 days, reduce buparlisib/placebo or 
BYL719/placebo 1 dose level
● If resolved in > 7 days, then discontinue patient from 
buparlisib/placebo or BYL719/placebo
Grade 4 (> 10.0 x ULN)
Permanently discontinue patient from buparlisib/placebo or 
BYL719/placebo 
Hepatic – AST or 
ALT
AST or ALT without bilirubin elevation > 2ULN
Note: confounding factors and/or alternative causes for increased transaminases like 
concomitant medications, infection, hepato-biliary disorder, obstruction, liver metastasis, 
etc. should be excluded before dose interruption/reduction
Same grade as 
baseline (i.e. Grade 0 
or Grade 1 
Maintain dose level AND monitor LFTs* weekly until 
AST/ALT is ≤ baseline
Increase from baseline 
Grade 0 to > 1.5 ULN 
or from baseline Grade 
1 to Grade 2
Can continue treatment with reduce buparlisib/placebo or 
BYL719/placebo 1 dose level
Increase of two grades 
from baseline (from 
baseline Grade 0 to 
Grade 2 or from 
baseline Grade 1 to 
Grade 3)
Omit dose until resolved to Grade 1 or less, then 1 dose 
level**
If no recovery in ≤ 28 days, discontinue permanently 
buparlisib/placebo or BYL719/placebo
Grade 4 (> 20.0 x ULN) 
Discontinue patient from buparlisib/placebo or 
BYL719/placebo


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Hepatic – AST or 
ALT and concurrent 
Bilirubin
AST or ALT > 3.0 x 
ULN and total
bilirubin > 2.0 x ULN
Permanently discontinue buparlisib/placebo or 
BYL719/placebo***
Hepatic toxicity monitoring (for patients with Gilbert Syndrome: total and direct 
bilirubin must be monitored, intensified monitoring applies to changes in direct bilirubin 
only). The monitoring includes the following LFTs: albumin, ALT, AST, total bilirubin 
(fractionated if total bilirubin > 2.0 x ULN), alkaline phosphatase (fractionated if alkaline 
phosphatase is grade 2 or higher) and GGT:
●
Cycle 1 and 2: every other week (if visit schedule allows a more frequent 
monitoring this should be considered) or more frequently if clinically indicated especially 
for patients with borderline acceptable AST/ ALT/ bilirubin values
●
Cycle 3 and onward: monthly or more frequently if clinically indicated
In case of any occurrence of ALT/AST/ bilirubin increase ≥ grade 2 the liver function 
tests must be monitored weekly or more frequently if clinically indicated until resolved 
to ≤ grade 1
In case of any occurrence of ALT/ AST/ bilirubin increase ≥ grade 3 the liver function 
tests must be monitored weekly or more frequently if clinically indicated until resolved 
to ≤grade 1; hereafter the moknitoring should be continued every other week or more 
frequently if clinically indicated until the end of treatment with study medication
Patients who discontinued study treatment should be monitored weekly, including LFTs* 
or more frequently if clinically indicated until resolved to ≤ grade 1 or stabilization (no 
CTCAE grade change over 4 weeks).
*LFTs include albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x 
ULN), alkaline phosphatase (fractionated if alkaline phosphatase is grade 2 or higher) 
and GGT
** In case of recurring Grade 3 or higher toxicity after re-challenge, patients should be 
permanently discontinued
*** All patients with ALT or AST >3.0x ULN and total bilirubin > 2.0x ULN in the absence 
of cholestasis must immediately be withdrawn from buparlisib/placebo or 
BYL719/placebo and every attempt should be made to carry out the liver event follow-up 
assessments as described below in Section 6.3.2.1.5 Management of hepatotoxicity 
(ALT and/or AST >3.0x ULN and total bilirubin >2.0x ULN) in patients receiving 
BYL719/placebo or buparlisib/placebo and viral hepatitis serology and other tests for 
hepatotoxicity follow-up).
Hyperglycemia
Hyperglycemia (see also Section 6.3.2.3.2)
Always consider consultation with a diabetologist and recommend/reinforce on lifestyle 
changes as per ADA, i.e. exercise and dietary advice (e.g. small frequent meals, low 
carb, high fiber, balancing carbs over the course of the day.  Three small meals and 2 
small snacks rather than one large meal).
Note: this table provides dose management recommendations. The preferred option for 
treating alpelisib-induced hyperglycemia is metformin, given its wide availability and well 
characterized safety profile. However, in case of intolerance to or unavailability of
metformin, investigator’s judgment should be exercised and other insulin 
sensitizers such as thiazolidinediones or dipeptidyl peptidase-4 Inhibitors can be used.
Hyperglycemia
Grade 1 (> ULN - 160 
mg/dL) [> ULN - 8.9 
mmol/L]
For patients with 
baseline values 
between >ULN – 140 
mg/dL (ULN – 7.7 
mmol/L) this apply only 
Maintain dose level, and remind patient on lifestyle 
changes*. 
● If FPG < 140 mg/dl, consider adding metformin as per 
guidance below or in cooperation with diabetologist
● If FPG 140-160 mg/dl, start/intensify metformin as per 
guidance below or in cooperation with diabetologist
Metformin 500 mg once daily with dinner. If no 
gastrointestinal (GI) intolerance after several days, increase 


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for values > 140 mg/dL 
(7.7 mmol/L)
to 500 mg bid, with breakfast and dinner. If tolerated, 
increase to 500 mg with breakfast, and 1000 mg with dinner. 
If tolerated, 1000 mg bid with breakfast and dinner. If not 
tolerated, reduce to prior tolerated dose.
Monitor FPG as clinically indicated and at least weekly for 8 
weeks, then continue checking at least every two weeks until 
FPG is within baseline values.
Grade 2 (>160 – 250 
mg/dL) [> 8.9 – 13.9 
mmol/L]
Maintain dose level and remind patient on lifestyle 
changes*, exclude confounding factors like e.g. urinary tract 
infection, consider consultation with a diabetologist and start 
oral-antidiabetic treatment, e.g. metformin 500 mg bid with 
breakfast and dinner. If no GI intolerance, increase to 500 mg 
with breakfast, 1000 mg with dinner. If tolerated, 1000 mg bid 
with breakfast and dinner. If not tolerated, reduce to prior 
tolerated dose. Titrate to the maximum tolerated dose over a 
period of 3 weeks.
● If FPG is still rising on maximum tolerated dose of 
metformin or persistently >160mg/dl (>8.9 mmol/L), add an 
insulin-sensitizer, e.g. pioglitazone 30 mg (max. dose).
● Monitor FPG as clinically indicated and at least weekly until 
FPG resolves to ≤ Grade 1.
● If FPG does not resolve to ≤ Grade 1 within 21 days after 
institution of appropriate anti-diabetic treatment, reduce 
alpelisib/placebo by 1 dose level.
● Continue with anti-diabetic treatment and check FPG at 
least weekly for 8 weeks, then continue checking at least 
every 2 weeks, alert treating physician if FPG>250mg/dl.
Hyperglycemia
Grade 3 (> 250 – 500 
mg/dL) [> 13.9 – 27.8 
mmol/L]
Omit alpelisib/placebo and confirm fasting status of the 
assessment. If non-fasting, re-check within 24 hours. 
Exclude confounding factors like e.g. urinary tract infection 
and consider consultation with a diabetologist.
Administer intravenous hydration and intervention for 
electrolyte/ketoacidosis/hyperosmolar disturbances as 
clinically appropriate. Start metformin and titrate as outlined 
for Grade 2, add pioglitazone as outlined for Grade 2.  Insulin 
may be used for 1-2 days until hyperglycemia resolves,
however this may not be necessary in the majority of 
alpelisib-induced hyperglycemia given the short half-life of 
alpelisib.
Monitor FPG as clinically indicated and at least twice weekly 
until FPG resolves to ≤ Grade 1.
● If FPG resolves to ≤ Grade1 within 3-5 days, while off study 
treatment and on metformin,  re-start alpelisib/placebo and 
reduce 1 dose level, continue with anti-diabetic treatment and 
check FPG at least weekly for 8 weeks, then continue 
checking at least every 2 weeks, alert treating physician if 
FPG>250mg/dl.
● If FPG does not resolve to Grade1 within 3-5 days while off 
study treatment and on metformin, consult a diabetologist for 
management of diabetes is strongly recommended. 
● If FPG does not resolve to ≤ Grade 1 within 21 days after
institution of appropriate anti-diabetic treatment in 
cooperation with diabetologist and exclusion of confounding 
factors e.g. urinary tract infection, permanently discontinue 
patient from alpelisib/placebo treatment.
Grade 4 (> 500 mg/dL) 
[≥ 27.8 mmol/L]
Omit alpelisib/placebo, confirm fasting status of the 
assessment. If non-fasting, re-check within 24 hours.


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Exclude confounding factors like e.g. urinary tract infection.
Consider cooperation with diabetologist, initiate or intensify 
medication with appropriate anti-diabetic treatment (see 
Grade 3), re-check within 24 hours.
● If grade improves then follow specific grade 
recommendations.
● If FPG is confirmed at Grade 4 and confounding factors 
could be excluded, permanently discontinue patient from 
alpelisib/placebo.
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
*specific recommendations please see Section 6.3.2.3.2.
Investigations 
(Metabolic)
Asymptomatic amylase and/or lipase elevation (see also Section 6.3.2.2)
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 reduce 1 dose level. 
Note: In cases of isolated amylase elevations only, dosing 
may be maintained provided amylase fractionation 
demonstrates that pancreatic amylase is ≤ Grade 1. Monitor 
total amylase (and continue to assess fractionated amylase) 
as specified in Section 6.3.2.2
Grade ≥ 3
Discontinue buparlisib/placebo or BYL719/placebo treatmentNote: Omit both 
buparlisib/placebo or BYL719/placebo and letrozole 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.
Pancreatitis
Grade 2 (enzymatic 
elevation or radiologic 
findings only)  
Omit dose until resolved to Grade ≤ 1, then resume treatment 
at decrease 1 dose level. If toxicity recurs, discontinue 
patient from study treatment
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 
decrease 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, discontinue patient from study 
treatment
● Permanently discontinue patient from study treatment
Grade 4
Permanently discontinue buparlisib/placebo or 
BYL719/placebo treatment
Pneumonitis
please see Section 6.3.2.3.1
Skin and subcutaneous tissue disorders
Consultation with a dermatologist is highly recommended for better assessment and management of alpelisib-
induced skin toxicity. (see also Section 6.3.2.3.5)


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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
● For patients with symptoms like burning and/or pruritus add 
non-sedating anti-histamine, consider adding a sedating anti-
histamine at night
● If active rash is not resolved within 28 days of appropriate 
treatment, consider adding low dose systemic corticosteroid 
(20-40 mg/d)
Grade 2 (10-30%  BSA 
with active skin 
toxicity*)
Maintain dose level.
● Initiate topical corticosteroids 3-4x daily, preferred 
compounds to use are Triamcinolone or Betamethasone as 
long as skin toxicity is active, during max. 28 days
● Consider adding systemic corticosteroids 20-40mg/d  
If rash resolves to ≤ G1 within 10 days systemic 
corticosteroid may be discontinued
● For patients with symptoms like burning, stinging and/or 
pruritus add non-sedating anti-histamine, consider adding a 
sedating anti-histamine at night
Grade 3 (>30% BSA 
with active skin 
toxicity*)
Omit alpelisib/placebo dose until rash /skin toxicity is no 
longer active but fading (G1), consider exploratory skin 
biopsy for central assessment
● Initiate topical corticosteroids 3-4x daily, preferred 
compounds to use are Triamcinolone or Betamethasone for 
at least 28 days.
● Add systemic corticosteroids 20-40mg/d 
If rash resolves to ≤ G1 within 10 days systemic 
corticosteroid may be discontinued.
For patients with symptoms like burning, stinging and/or 
pruritus add non-sedating anti-histamine during day time, 
consider adding a sedating anti-histamine at night
Re-start alpelisib/placebo dose once rash /skin toxicity is no 
longer active but  fading (G1):
- at same dose in case of first occurrence, at reduced dose 
level in case of second occurrence.
- If rash/skin toxicity still active in up to 10% BSA after more 
than 14 days, continue oral corticosteroid for at least 48 
hours upon re-challenge with alpelisib/placebo; if rash and/or 
pruritus do not reoccur within 48 hours after re-challenge with 
alpelisib, systemic corticosteroid may be discontinued.
For patients with symptoms like burning, stinging and/or 
pruritus antihistamine regimen should be continued for a 
minimum of 28 days after re-challenge with alpelisib/placebo.
Grade 4
(any % BSA associated 
with extensive 
superinfection, with IV 
antibiotics indicated; 
life-threatening 
consequences)
Permanently discontinue patient from alpelisib/placebo and 
consider a dermatology consult.
Treatment of rash should follow guidelines for Grade 3 above 
with the exception of rechallenge and with any additional 
measures needed.
Consider exploratory skin biopsy for central assessment.
*“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.
Serum creatinine
Grade 1 (< 2 x ULN)
Maintain dose level 


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Grade 2 (2 – 3 x ULN)
Omit dose until resolved to ≤ grade 1, then:
If treatment delay is ≤ 7 days, restart at same dose
If resolved in > 7 days, then reduce buparlisib/placebo or 
BYL719/placebo 1 dose level
Grade 3 (> 3.0 – 6.0 x 
ULN) 
Permanently discontinue patient from buparlisib/placebo or 
BYL719/placebo
Grade 4 ( > 6.0 x ULN) 
Permanently discontinue patient from buparlisib/placebo or 
BYL719/placebo 
Stomatitis/Oral 
mucositis
Grade 1 / Tolerable 
Grade 2
Maintain dose level.
Non-alcoholic or salt water mouthwash
(see also Section 6.3.2.3.4).
Intolerable Grade 2 or 
Grade 3
First occurrence: omit until ≤ Grade 1 and reduce 
buparlisib/placebo or BYL719/placebo 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: omit until ≤ Grade 1 and reduce 
buparlisib/placebo or BYL719/placebo 1 dose level.
Grade 4
Permanently discontinue patient from buparlisib/placebo or 
BYL719/placebo.
All other adverse 
events
Grade 1 or 2
Maintain dose level
Grade 3
Omit dose until resolved to ≤ Grade 1, then reduce 
buparlisib/placebo or BYL719/placebo 1 dose level
Grade 4
Permanently discontinue patient from buparlisib/placebo or 
BYL719/placebo
Note: Omit dose for ≥ Grade 3 vomiting or Grade 3 nausea 
only if the vomiting or nausea cannot be controlled with 
optimal antiemetic
Buparlisib specific 
dose modifications 
for mood alterations
Grade 1*
Maintain dose level
Consider psychiatric consultation at the investigator’s 
discretion and introduce optimal management
Grade 2*
Omit dose until resolved to ≤ Grade 1 or baseline status
Consider psychiatric consultation at the investigator’s 
discretion and introduce optimal management
First event: if the condition resolved to Grade ≤ 1 or to 
baseline status, continue to co-medicate and then maintain 
the dose level
Second and further events: if the condition resolved to Grade 
≤ 1 or to baseline status, continue to co-medicate and then 
reduce buparlisib/placebo 1 dose level 
Grade 3*
Omit dose until resolved to ≤ Grade 1 or baseline status
Psychiatric consultation is required and introduce optimal 
management
If the condition resolved to Grade ≤ 1 or to baseline status, 
continue to co-medicate and then reduce buparlisib/placebo 
1 dose level
Grade 4*
Permanently discontinue patient from buparlisib/placebo
Psychiatric consultation is required and introduce optimal 
management
* Note: For all grades, if question 9 on the PHQ-9 has a positive response (as indicated 
by selecting “1”, “2”, or “3”), omit study drug and refer patient for psychiatric consult 
regardless of the total questionnaire score or CTCAE grading to confirm if study drug 
should be interrupted or permanently discontinued.


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6.3.2
Follow-up for toxicities
All patients must be followed up for adverse events and serious adverse events for 30 days 
following the last dose of study treatment (BYL719/placebo, buparlisib/placebo, and/or 
letrozole). Patients whose treatment is interrupted or permanently discontinued due to an 
adverse event, including abnormal laboratory value, must be followed until resolution or 
stabilization of the event, whichever comes first which includes all study assessments 
appropriate to monitor the event.
6.3.2.1
Follow-up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potential DILI, and should be considered as clinically important events. The 
threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL value. 
Patients meeting any of the following criteria will require further follow-up as outlined below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as alkaline phosphatase (ALP) elevation > 2.0 x ULN with R value ≤2 in patients without 
bone metastasis, or elevation of ALP liver fraction in patients with bone metastasis.
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes if the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury).
In the absence of cholestasis, these patients should be immediately discontinued from study 
treatment, and repeat liver function tests (LFT) as soon as possible, preferably within 48 hours 
from the awareness of the abnormal results. The evaluation should include laboratory tests, a 
detailed history and physical assessment, and consideration should be given for newly 
diagnosed liver metastasis or new liver lesions, hepato-biliary obstructions/compressions, etc. 
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)and/or INR, and alkaline phosphatase. 
2. A detailed history, including information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplements consumption, and history of any 
pre-existing liver conditions or risk factors, should be collected. 
3. Further testing for acute viral hepatitis A, B, C or E infection and liver imaging (e.g. 
biliary tract) may be warranted. 
4. Obtain PK sample, as close as possible to last dose of study drug.  In this case, an 
unscheduled PK will be done. 
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with a specialist (e.g. an hepatologist). 


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All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented.
6.3.2.2
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.
6.3.2.3
Additional follow-up for selected toxicities
6.3.2.3.1 Management of pneumonitis
All patients will be routinely asked about and observed for the occurrence of adverse events 
including new or changed pulmonary symptoms (consistent with lung abnormalities). Patients 
who are suspected to have developed pneumonitis should suspend (BYL719/placebo or 
buparlisib/placebo) immediately (but may continue letrozole if clinically indicated) and 
undergo appropriate imaging (high resolution CT scan) and broncho-alveolar lavage 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. BYL719/placebo or buparlisib/placebo should be permanently discontinued in all 
patients with confirmed pneumonitis.


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Table 6-5
Management of pneumonitis
Pneumonitis
(any grade)
Immediately interrupt BYL719/placebo or buparlisib/placebo for any case of suspected 
pneumonitis. Letrozole may be continued if clinically indicated. Obtain appropriate imaging 
(high resolution CT scan) and consider broncho-alveolar lavage (BAL) and biopsy if 
appropriate based on clinical judgment. See Section 6.3.2.3.1 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. BYL719/placebo or buparlisib/placebo should be 
permanently discontinued in all patients with confirmed pneumonitis
6.3.2.3.2 Guidelines for the treatment of BYL719 induced hyperglycemia
BYL719, like other PI3K inhibitors, may affect glucose homeostasis which could result in 
increases of plasma glucose and insulin resistance (Busaidy 2012). Alpelisib induced 
hyperglycemia is generally manageable with adequate antidiabetic treatment. Alpelisib 
induced hyperglycemia typically occurs within the first month of treatment. Patients with pre-
diabetes (i.e. FPG 100 – 125 mg/dl; 5.6 - 6.9 mmol/L) and those with an established diagnosis 
of type 2 diabetes mellitus should be monitored carefully, thus allowing an early detection and 
prompt management of increases in FPG while on alpelisib/placebo treatment. However all 
patients, even those with FPG within normal limits at screening, may develop alpelisib 
induced hyperglycemia. Patients should always be instructed to follow dietary guidelines 
provided by the American Diabetes Association, e.g. small frequent meals, low carbohydrate 
content, high fiber, balancing carbohydrates over the course of the day; three small meals and 
2 small snacks rather than one large meal and exercise, as appropriate.
Detailed guidelines for management of alpelisib induced hyperglycemia is provided in Table 
6-4 following discussion with an advisory board. This includes early administration of 
metformin. Metformin may be titrated to a daily dose of 1000 mg BID. Local protocols per 
standard clinical practice may be followed. Fasting plasma glucose may be performed both 
locally and/or centrally for rapid availability for safety evaluation and management guidance. 
Special attention should be paid to the risk of hypoglycemia in patients interrupting alpelisib 
treatment and concomitantly receiving insulin and/or sulfonylureas.
Consultation with a diabetologist is highly recommended for better assessment and 
management of alpelisib-induced hyperglycemia.
6.3.2.3.3 Guidelines for the treatment of study drug induced psychiatric disorders in 
patients receiving buparlisib/placebo
Psychiatric adverse events will be closely monitored and evaluated at each planned visit until 
recovery to Grade ≤ 1 or baseline status. The grading of psychiatric adverse events/mood 
alterations must be based on the clinical interpretation of severity according to the NCI-
CTCAE (v 4.03) guidelines.
For patients who experience new or worsening of existing psychiatric Aes of Grade ≥1, 
psychiatric consultation should be considered as described in Table 6-4.
Patient self-reported mood questionnaires (GAD-7 and PHQ-9) will be used for screening and 
during the study treatment phase to aid the investigator in identifying new or worsening of 


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events. For additional information regarding safety assessments based on patient self-reported 
mood questionnaires, please refer to Section 7.2.2.6.
If question 9 in the PHQ-9 has a positive response (as indicated by selecting “1”, “2”, or “3”), 
omit treatment with study drug and refer the patient for psychiatric consultation for optimal 
management regardless of the total questionnaire score or CTCAE grading to confirm if study 
drug should be interrupted or permanently discontinued. In this specific case, the psychiatric 
advice can overrule the patient’s PHQ-9 self-assessment. During the study, subjects will be 
monitored at regularly scheduled visits (i.e. Day 15 of Cycle 1, Day 1 and Day 15 of Cycles 2 
and 3, Day 1 of each subsequent cycle, and at the End of Treatment visit) by the 
investigator/site staff through personal interaction and the two self-reported questionnaires.
Additional assessments may be done according to the clinical judgment of the investigator.
6.3.2.3.4 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 BYL719 and buparlisib metabolism (see Section 6.4).
6.3.2.3.5 Guidelines for the treatment of study drug induced skin toxicity
Skin toxicity is a class-effect adverse event observed with PI3Ki/mTORi agents. Close 
monitoring of potential skin reactions will be performed at each planned visit and will be 
reported as AE. The most frequent skin AEs reported are: maculopapular rash (only a 
minority present acneiform rash) pruritus and dry skin. The onset is typically within the first 2 
months of treatment start and is reversible with adequate comedication and treatment 
interruption if needed. Skin reactions may fade slowly over 10 days or more and may not 
require ongoing concomitant therapy. 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, i.e. not considered active any longer. Consultation with a 
dermatologist is highly recommended for better assessment and management of alpelisib-


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induced skin toxicity. Photographs of skin rashes events as well as skin biopsy, if possible,
are recommended. According to the investigator discretion, a paired skin biopsy could be 
obtained (from both affected and an unaffected skin area for local histopathology assessment) 
to further assess rash if clinically appropriate.
In case of Grade 3/4 skin toxicity, Novartis requests that a skin biopsy is performed and sent 
to Novartis Central laboratory for further research purpose on the pathology and mechanism 
of PI3K inhibitor treatment induced skin toxicity. At the Investigator’s discretion, non-
sedating antihistamines (e.g. cetirizine (Zyrtec©) once daily) may be used as prophylactic 
treatment to reduce severity of rash, especially for patients with a history of hypersensitivity 
reactions like seasonal allergies, hay fever, allergic asthma or drug induced exanthema.
Consultation with a dermatologist is highly recommended for better assessment and 
management of alpelisib-induced skin toxicity. 
Recommended therapies for skin toxicity events include: 

Topical steroids Triamcinolone or Betamethasone 3-4x daily for at least 28 days. Consider 
spray preparation for ease of application on trunk. For scalp involvement, consider a foam 
preparation

In case of burning, stinging, pruritus: oral antihistamines (sedating, evening): 
diphenhydramine 25-50mg t.i.d.; hydroxizine 25mg t.i.d. or q.i.d

Oral antihistamines (non-sedating, day time): fexofenadine 180mg q.d. or 60mg TID 
(monitor the use of this class of drugs since skin toxicity has also been reported)

Low dose oral corticosteroids, e.g. 20-40mg q.d. prednisone or equivalent up to 10 days of 
treatment. 

If lesions are still not controlled with all of the above, consideration can be given to the 
use of:

Topical antibiotics: clindamycin 1 - 2%; erythromycin 1% -2% (gel or solution 
formulation can be used, ointments cannot be used); metronidazole 1%; silver 
sulphadiazine

Oral antibiotics: doxycycline 100mg b.i.d.; minocycline 100mg b.i.d.; oxytetracycline 
500mg b.i.d

Topical antipruritics (pramoxine 1%, doxepin 5% cream) applied twice daily

GABA Agonists: Gabapentin 300mg every 8 hours, Pregabalin 50-75 mg every 8 
hours (to adjust of renal impairment). Depending on patient’s clinical condition be 
aware of potential and common side effects observed with GABA agonists such as: 
somnolence, dizziness (both drugs) and peripheral edema (Gabapentin) among others 
adverse events.
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%.
Although preclinical experiments demonstrated that buparlisib and alpelisib have no potential 
phototoxic effect, it is recommended to caution patients to avoid sun exposure during 
treatment with buparlisib or alpelisib, especially when they already have experienced rash or 


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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.
6.3.2.3.6 Management of hepatotoxicity (ALT and/or AST >3.0x ULN and total 
bilirubin >2.0x ULN) in patients receiving buparlisib/placebo and 
BYL719/placebo
Criteria for interruption and re-initiation of buparlisib/placebo or BYL719/placebo treatment 
in case of the occurrence of AST, ALT or bilirubin increase are detailed in Section 6.3.1, 
Dose Modification (Table 6-4).
Patients with clinically significant liver test abnormalities should perform liver-directed 
medical history, physical examination and other tests as medically indicated to assess 
potential relationship with study treatment and rule out other underlying causes (e.g. disease
progression/obstruction, infection/hepatitis or other liver diseases, sepsis, metabolic diseases 
including diabetes, concomitant medications including herbals, alcohol, drug-drug interaction, 
cardiovascular disease/ischemia, other organ injuries, etc.). Any pre-existing liver conditions 
or risk factors should be reported in the respective medical history and concomitant 
medication CRF pages (if not done already).
All patients with ALT or AST >3.0 x ULN and total bilirubin > 2.0 x ULN in the absence of 
cholestasis (elevation of ALP in patients without bone metastasis or if bone metastasis are 
present elevation of 5’-nucleotidase and ALP liver fraction) must be immediately withdrawn 
from buparlisib/placebo or BYL719/placebo, and every attempt should be made to carry out 
locally the liver event follow-up assessments as described below:

Inform the sponsor about the event immediately after its occurrence by reporting the event 
immediately in the clinical database if it meets the criteria for an AE or SAE.

Evaluate if associated with the appearance or worsening of clinical symptoms of hepatitis 
or hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia, or other organ involvement.

Obtain fractionated bilirubin, serum Alkaline Phosphatase (ALP), creatine phosphokinase 
(CPK), lactate dehydrogenase (LDH), and blood count with differential to assess 
eosinophilia.

Perform liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease including metastasis or new lesions, obstruction/compression, etc.

Perform viral hepatitis and other serology tests:

Hepatitis C (HCV) serology and viral DNA, Hepatitis B (HBV) serology and viral 
DNA, Hepatitis A (HAV) Immunoglobulin M (IgM) and HAV total

Hepatitis E (HEV) serology: IgM and IgG, viral DNA

Herpes Simplex Virus (HSV), Cytomegalovirus (CMV), Epstein-Barr viral (EBV) 
serology


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
Obtain PK sample, as close as possible to last dose of study drug . Record the date/time of
the PK blood sample draw and the date/time of the last dose of buparlisib /placebo prior to
blood sample draw on the eCRF

Verify and record the use of concomitant medications, acetaminophen, herbal remedies, 
and other over the counter medications, or putative hepatotoxins, on the concomitant 
medications report form.

Consultation with a specialist(s) or a hepatologist(s) is recommended.

Liver biopsy as clinically indicated to assess pathological change and degree of potential 
liver injury

LFTs should be followed-up weekly until resolve to ≤ grade 1, baseline or stabilization 
(no CTCAE grade change over 4 weeks) and outcome documented on the respective AE 
and lab chemistry pages.
6.4
Concomitant medications
All medications (other than the study drugs) taken within 4 weeks of study treatment initiation 
and all concomitant therapy and significant non-drug therapies (including physical therapy 
and blood transfusions) administered during the study, with reasons for use, will be recorded 
in the “Concomitant medications/Significant non-drug therapies” section of the eCRF. 
Medications include not only physician prescribed medications, but also all over-the counter 
medications, and nutritional or vitamin supplements.
The diagnostic biopsy of the primary breast cancer will be recorded as prior antineoplastic 
surgery in the “Prior antineoplastic therapy” section of the eCRF.
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after starting study drug.
Patients taking medication chronically should be maintained on the same dose and schedule 
throughout the study period, as medically feasible. The days of full PK blood sampling should 
be representative of the other study days with regard to the use of the chronically administered 
concomitant medications. However, if a concomitant medication is used intermittently during 
the study, this medication should be avoided on the days of full PK sampling, if medically 
feasible.
6.4.1
Permitted concomitant therapy
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the patient is permitted, except as specifically prohibited in Section 6.4.2 and Table 14-3 and 
Table 14-4 in Appendix 1. Please refer to the BYL719 and buparlisib Ibs.
6.4.1.1
Antiemetics
Use of anti-emetics is allowed. Prophylactic anti-emetics should be started only once the 
patient experiences nausea or vomiting, at the discretion of the investigator. It is 
recommended that patients use drugs that do not cause QT prolongation. Please note that 
some anti-emetics have a known risk for TdP and are prohibited (refer to Section 6.4.2 and 
Table 14-4 in Appendix 1).


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6.4.1.2
Bisphosphonates
The use of bisphosphonates is allowed provided patients have been on stable doses for at least 
2 weeks prior to study entry. Stable dose should be maintained during the treatment period. 
Patients requiring initiation of bisphosphonates for the treatment of metastatic breast cancer 
during the course of the study should be discontinued due to progressive disease.
6.4.1.3
Oral anti-diabetics
Patients who develop diabetes mellitus during the study should be treated according to the 
ADA (American Diabetes Association) guidance. It is recommended to start treatment with 
metformin. Patients receiving oral antidiabetics which are predominantly metabolized by 
CYP2C9 and CYP2C8, including but not limited to, repaglinide, rosiglitazone, glipizide and 
tolbutamide, should be monitored for hypoglycemia as BYL719 was found to be weak 
reversible inhibitor of these enzymes (refer to Table 14-1 in Appendix 1) in vitro.
6.4.1.4
Hematopoietic growth factors
Hematopoietic growth factors (e.g. erythropoietins, G-colony stimulating factor (CSF) and 
GM-CSF) are not to be administered prophylactically. Use of these drugs should be reserved 
to patients with severe neutropenia and anemia as per the labeling of these agents or as 
dictated by local practice (see also the guidelines established by the American Society of 
Clinical Oncology (ASCO)).
6.4.1.5
Anticoagulation
All anticoagulants or anti-aggregation agents may be administered under the discretion of the 
investigator.
Therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative 
anticoagulants should be used with caution because of its known interaction with many 
commonly used medications and certain foods. As warfarin has a narrow therapeutic range 
and both buparlisib and BYL719 are possible inhibitors of CYP2C9, the major metabolizing 
enzyme of S-warfarin (R-warfarin is metabolized by multiple CYP enzymes), it should be 
carefully monitored whenever used.
Caution is also advised when BYL719 and buparlisib is co-administered with anti-platelet 
pro-drugs such as clopidogrel, ticlopidine and prasugrel, which require metabolic activation 
by CYP3A4, CYP2C9 and CYP2C19. While the weak reversible in vitro inhibition potential 
of BYL719 and buparlisib towards CYP2C-family enzymes is unlikely to translate into 
clinical significance as the steady-state plasma concentrations at the maximum therapeutic 
doses are significantly lower than the experimentally determined inhibition constants, patients 
using anti-platetet pro-drugs should still be carefully monitored.
Direct Thrombin inhibitors (DTIs) and Factor Xa inhibitors are allowed as anticoagulants. 
Individual medications from each of the classes should be checked if they are not prohibited 
due to other drug-drug-interactions with BYL719. Please see Section 6.4.2 for Prohibited 
concomitant therapy and Appendix 14.1 for a list of prohibited drugs.Alternatively, 
therapeutic anticoagulation may be accomplished using low-molecular weight heparin.


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6.4.1.6
CYP450 substrates
BYL719
In vitro studies demonstrate that BYL719 is both a time-dependent inhibitor (TDI) and 
inducer of CYP3A4. While BYL719 may increase exposure to drugs strongly metabolized by 
CYP3A4 (e.g. midazolam) by more than 6.5-fold or reduce exposure by ~10-fold when 
applying either only time-dependent inhibition (enzyme inactivation) or induction (de novo 
protein synthesis) effects in an BYL719 PBPK model (SimCYP) at a 400 mg dose at steady 
state, both opposing effects seem to balance each other out, leading to a net exposure increase 
of 1.2-fold when applying both effects simultaneously during a simulation. This result has 
been supported by preliminary clinical PK results from a combination trial with everolimus (a 
sensitive CYP3A4 substrate) which showed no change in Everolimus PK upon co-
administration with BYL719.
Still, as time-dependent inhibition and induction of CYP3A4 may not be fully in balance after 
the first doses of BYL719, when equilibrium of CYP3A4 protein levels may have not yet 
been reached, caution is still advised when BYL719 is co-administered with CYP3A4 
sensitive or narrow therapeutic index drugs such as opioid analgesics. Inhibition of opioid 
metabolism by CYP3A4 can lead to opioid toxicity, including fatal respiratory depression, or 
an enhanced risk for QTc prolongation. Patients receiving BYL719 and opioid analgesics 
should therefore be carefully monitored. Synthetic opioids with clinically relevant interactions 
with CYP3A4 inhibitors include, but are not limited to, propoxyphene, fentanyl, alfentanyl 
and sufentanil. Use of alfentanyl, a sensitive CYP3A4 substrate with narrow therapeutic 
window, should be fully avoided whenever possible. The use of methadone and levomethadyl 
is prohibited (refer to Table 14-4 in Appendix 1).
While the weak reversible in vitro inhibition potential of BYL719 towards CYP2C-family 
enzymes is unlikely to translate into clinical significance based on normal clinical exposure, 
BYL719 may inhibit the metabolic clearance of co-medications metabolized by CYP2C8, 
CYP2C9, CYP2C19, if sufficiently high BYL719 concentrations are achieved in vivo.
Investigators, at their discretion, may administer concomitant medications known to be 
metabolized by CYP3A4/5, CYP2C8, CYP2C9 and CYP2C19 (refer to Table 14-2 in 
Appendix 1). Patients receiving such medications must be carefully monitored for potential 
toxicity due to any individual concomitant medications. Particularly, caution is advised when 
BYL719 is co-administered with drugs that are sensitive substrates for CYP3A4, CYP2C8, 
CYP2C9 or CYP2C19 and which have a narrow therapeutic index (Table 14-1 in Appendix 1).
Buparlisib
In vitro metabolism studies performed to examine the reversible and metabolism-dependent 
inhibition of cytochrome P450 enzymes showed that buparlisib is a weak, reversible inhibitor 
of CYP3A4/5, CYP2C8, CYP2C9 and CPY2C19. Buparlisib may therefore inhibit the 
metabolic clearance of co-medications metabolized by CYP3A4, CYP2C8, CYP2C9, 
CYP2C19, if sufficiently high concentrations are achieved in vivo. Investigators, at their 
discretion, may administer concomitant medications known to be metabolized by CYP3A4/5, 
CYP2C8, CYP2C9 and CYP2C19 (refer to Table 14-1 in Appendix 1).


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Thus, caution should in principle be used in administering concomitantly drugs whose 
disposition is mainly dependent on these cytochrome P450 isoenzymes and whose therapeutic 
index is narrow. Patients receiving such medications must be monitored for potentiation of 
toxicity due to any individual concomitant medications, and may require dose titration or 
reduction of the drug substrate.
6.4.1.7
Moderate CYP3A4 inhibitors and inducers (Buparlisib only)
As in vitro and in vivo metabolism studies suggest that oxidative metabolism of buparlisib is 
at least partially mediated by CYP3A4, moderate CYP3A4 inhibitors and inducers are 
permitted but should be used with caution (see Table 14-2 in Appendix 1 for a list of 
moderate CYP3A4 inhibitors and inducers). Please note that this list may not be 
comprehensive.
6.4.1.8
Drugs with a conditional or possible risk to induce Torsade de Pointes
If a patient, enrolled in the study, requires the concomitant use of any medication with a 
possible or conditional risk for TdP (see Table 14-5 in Appendix 1 for a list of such 
medications), then investigators, at their discretion, may co-administer such medications. 
Patients receiving such medications must however be monitored. Note: please refer also to 
Table 14-4 in Appendix 1 for a list of prohibited QT prolonging medication.
6.4.1.9
Gastric protection agents
BYL719 and buparlisib are characterized by a pH-dependent solubility. Therefore acid 
reducing agents (ARAs, e.g. proton-pump inhibitors, H2-antagonists and antacids) may alter 
the solubility of alpelisib and buparlisib and hence their bioavailability. A drug-drug 
interaction study in human healthy volunteers confirmed that co-administration of alpelisib 
with the H2-antagonist ranitidine after a meal lead to a decrease in exposure by only ~20%, 
considered to be not clinically relevant. For buparlisib a DDI study showed that co-
administration with the proton-pump-inhibitor rabeprazole did not significantly change the 
exposure of buparlisib, independent of the food condition. Hence both buparlisib and alpelisib 
can be co-administered with any ARAs.
6.4.1.10 BCRP inhibitors (BYL719 treatment only)
BYL719 was identified as a substrate for the human BCRP. Co-administration of BYL719 
with BCRP inhibitors may increase systemic exposure and/or alter tissue uptake of oral 
BYL719 and should therefore be used with caution. See Table 14-6 in Appendix 1 for a list of 
BCRP inhibitors.
6.4.1.11 Corticosteroids
Chronic dosing of high levels of corticosteroids such as dexamethasone and prednisone are 
known to induce CYP3A enzymes, thereby increasing the risk of reducing buparlisib. Based 
on experience from a study which was carried out to assess the impact of a repeated dose of 4 
mg dexamethasone on the PK of buparlisib [CBKM120C2106], an equivalent dose of 
dexamethasone up to 4 mg q.d. can be considered safe in patients receiving buparlisib.


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Since corticosteroids may prolong or aggravate hyperglycemia (steroid-induced diabetes), 
which is a common adverse event for PI3K inhibitors, they should be used with caution and 
closely monitored.
6.4.2
Prohibited concomitant therapy
6.4.2.1
Strong CYP3A4 inhibitors and inducers (Buparlisib only)
In vitro and in vivo metabolism studies suggest that oxidative metabolism of buparlisib is 
partially mediated by CYP3A4. Coadministration of buparlisib/placebo with strong CYP3A4 
inhibitors and inducers is therefore prohibited. Please refer to Table 14-3 in Appendix 1 for a 
list of prohibited drugs. Please note that this list may not be comprehensive.
6.4.2.2
Other investigational and antineoplastic therapies
Other investigational therapies must not be used while the patient is on the study. Anticancer 
therapy (chemotherapy, biologic or radiation therapy, and surgery) other than the study 
treatments must not be given to patients while the patient is on the study medication. If such 
agents are required for a patient then the patient must be discontinued from the study.
6.4.2.3
Drugs with a known risk for QT prolongation or of causing Torsades 
de Pointes
If a patient, enrolled in the study, requires the concomitant use of any medication included in 
Table 14-4 of Appendix 1 entitled “List of Prohibited QT prolonging drugs” (i.e., drugs that 
are generally accepted by the Advisory Board of the Arizona CERT to have a known risk of 
causing TdP), BYL719 or buparlisib administration must be interrupted as long as the patient 
requires therapy with the QT prolonging agent.
If the patient requires long term therapy with such a QT prolonging agent, leading to study 
treatment interruption of > 28 days, the patient must be permanently discontinued from 
BYL719 or buparlisib.
Co-administering QT prolonging drugs (or any other drug with the potential to increase the 
risk of drug-related QT prolongation e.g. via a potential drug-drug interaction increasing the 
exposure of the study drugs or the exposure of the QT prolonging drug) should be avoided. If 
during the course of the study, concomitant administration of drugs with a known potential to 
cause Torsades de Pointes is required and cannot be avoided, study drug must be interrupted 
until an assessment of the potential safety risk has been performed. A definitive list of drugs 
associated with QT prolongation and/or TdP is available online at www.qtdrugs.org. If, based 
on the investigator assessment and clinical need study treatment is resumed, close ECG 
monitoring is advised.
6.4.2.4
Herbal medications
Herbal preparations/medications are not allowed throughout the study. These herbal 
medications include, but are not limited to: St. John’s wort, Kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. 
Patients should stop using these herbal medications 14 days prior to first dose of study drug.


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6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned 
when the patient is first enrolled for screening and is retained as the primary identifier for the 
patient throughout his/her entire participation in the trial. The Subject No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a 
sequential patient number suffixed to it, so that each subject is numbered uniquely across the 
entire database. Upon signing the informed consent form, the patient is assigned to the next 
sequential Subject No. available to the investigator through IRT.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Subject No. must 
not be reused for any other subject and the Subject No. for that individual must not be 
changed, even if the patient is re-screened. If the patient fails to be randomized or start 
treatment for any reason, the reason will be entered into the Screening Disposition page.
IRT must be notified within 2 days that the patient was not randomized.
6.5.2
Treatment assignment or randomization
Once eligibility criteria have been confirmed, patients will be assigned to one of the two 
cohorts (i.e. PIK3CA mutated and PIK3CA wild-type). Within each cohort, patients will be 
randomized to one of the two arms (i.e. BYL719+letrozole or placebo+letrozole) in a 1:1 ratio. 
Within the placebo+letrozole arm, newly randomized patients will receive matching BYL719
placebo (see Section 4.1 and Section 6.1). Randomization will be stratified according to 
centrally measured Ki67 level (<14% or ≥14%) and lymph node status (positive or negative).
The PIK3CA mutation status and Ki67 results will not be communicated at time of the 
randomization in order to avoid any potential bias.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the Interactive Response Technology (IRT) provider 
using a validated system that automates the random assignment of patient numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers. A separate medication randomization 
list will be produced by or under the responsibility of Novartis Drug Supply Management 
using a validated system that automates the random assignment of medication numbers to 
medication packs containing each of the study treatments.
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The investigator or his/her delegate will call or log on to the 
IRT and confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT will 
assign a randomization number to the patient, which will be used to link the patient to a 
treatment arm and will specify a unique medication number for the first package of BYL719
or matching placebo to be dispensed to the patient. The randomization number will not be 
communicated to the caller.


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6.5.3
Treatment blinding
This is a multi-center randomized, double-blind study. Due to the different appearances of 
BYL719 and buparlisib the active treatment arms A and B are only blinded against placebo 
arm C but not against each other (see Figure 4-1 for more details on study design). The 
identity of the investigational drugs (BYL719 and buparlisib) vs. matching placebos will be 
concealed by identical packaging, labeling and schedule of administration. Randomization 
data are kept strictly confidential from patients, investigators, local radiologists, study team, 
or anyone involved in the study conduct until database lock.Treatment group information will 
be accessible to the DMC if required during their periodic safety reviews. The independent 
statistician and programmers producing outputs for the DMC will remain semi-blinded to the 
treatment groups. Details are presented in the DMC charter [DMC Charter].
Unblinding of study drug assignment by the IRT will only occur in the case of patient 
emergencies, for regulatory reporting purposes and at the conclusion of the study (Section 
8.3).
6.6
Study drug preparation and dispensation
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.
6.6.1
Study drug packaging and labeling
The study medication packaging has a 2-part label. A unique medication number is printed on 
each part of this label which corresponds to one of the treatments. Responsible site personnel 
will identify the study treatment package(s) to dispense to the patient by using the IRT and
obtaining the medication number(s). Site personnel will add the patient number on the label. 
Immediately before dispensing the package to the patient, site personnel will detach the outer 
part of the label from the packaging and affix it to the source document (Drug Label Form) 
for that patient’s unique patient number.
Medication labels will be in the local language and comply with the legal requirements of 
each country.
Table 6-6
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
BYL719 or BYL719 
matching placebo
Tablets in bottle
50 mg 
200 mg
Labeled as BYL719 50mg/ placebo and 
BYL719 200mg/placebo
Once daily dosing
buparlisib or buparlisib 
matching placebo
Capsules in bottle
10 mg 
50 mg
Labeled as BKM120 10mg/placebo and 
BKM120 50mg/placebo
5 days on/2 days off dosing
letrozole
Refer to local product information
Refer to local product information
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 


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designated site personnel have access. Upon receipt, the study treatment should be stored 
according to the instructions specified on the drug labels and in the BYL719 or buparlisib 
Investigator’s Brochures.
Table 6-7
Supply and storage of study treatments
Study treatments
Supply
Storage
BYL719 or BYL719 matching placebo
Centrally supplied by Novartis
Refer to study drug label
buparlisib or buparlisib matching placebo
Centrally supplied by Novartis
Refer to study drug label
letrozole
Locally
Refer to local product information
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
6.6.3.3
Handling of other study treatment
Not applicable.
6.6.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. Study drug destruction at the investigational site will only be 
permitted if authorized by Novartis in a prior agreement and if permitted by local regulations.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 


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documentation. Visit windows of +/- 3 days are allowed (except at cycle 1 Day 1 and where 
specified in Table 7-1).
The table indicates which assessments produce data to be entered into the database (D) or 
remain in source documents only (S) (“Category” column).


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Table 7-1
Visit evaluation schedule
Category
Protocol 
Section
Screening phase
Treatment phase
Post-
Treatmen
t Follow 
up phase
Cycle
Molecular Pre-
Screening
Screening
Cycle 1
Cycle 
2
Cycle 
3
Cycle 
4 to 
Cycle 
6
End of 
study 
treatment 
(EoT) –
before 
surgery
Days
Any time after the 
site initiation to -1
-28 
to -1
-7 to-1
1
8
15
22
1
15
1
1
N/A
N/A
Obtain molecular pre-
screening Informed Consent
D
7.1.1
X
Collection of tumor sample 
from diagnosis biopsy
D
7.1.1
X ( ≥ 14 days 
before 
randomization)
Acknowledgment of Receipt of 
adequate tumor tissue quantity 
from Novartis designated 
laboratory 
S
7.1.1
X (≥3 days after 
tumor receipt
PIK3CA mutation and Ki67 
status results entered in IRT
S
7.1.1
X (before 
randomization)
Obtain main study Informed 
Consent
D
7.1.2
X
IRT registration
S
6.5.1
X
X
X
X
X
X
X
IRT randomization
D
6.5.2
X
End of phase disposition
D
7.1.4
X
X
Demography
D
7.1.2.3
X
Inclusion/exclusion criteria
D
5.2/5.3
X


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Category
Protocol 
Section
Screening phase
Treatment phase
Post-
Treatmen
t Follow 
up phase
Cycle
Molecular Pre-
Screening
Screening
Cycle 1
Cycle 
2
Cycle 
3
Cycle 
4 to 
Cycle 
6
End of 
study 
treatment 
(EoT) –
before 
surgery
Days
Any time after the 
site initiation to -1
-28 
to -1
-7 to-1
1
8
15
22
1
15
1
1
N/A
N/A
Relevant medical 
history/current medical 
conditions 
D
7.1.2.3
X
Diagnosis and extent of cancer
D
7.1.2.3
X
Intended breast surgery type
D
7.1.2.3
X
Prior antineoplastic therapy 
(Surgery)
D
7.1.2.3
X
Physical Examination
S
7.2.2.1
X
X
X
X
X
X
X
X
ECOG Performance status
D
7.2.2.4
X
X
X
X
X
X
Height
D
7.2.2.3
X
Weight
D
7.2.2.3
X
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X
X
X
X
Pulmonary function tests
D
6.3.2.1
As clinically indicated
Hematology
D
7.2.2.5.1
X
X*
X
X
X
X
X
X
Biochemistry (partial)
D
7.2.2.5.2
X*
*
X
X**
X**
Fasting Biochemistry (full)
D
7.2.2.5.2
X
X*
X
X
X
X
X
X
Hepatotoxicity follow-up 
testing/procedures
D
7.2.2.5.6
As clinically indicated


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Category
Protocol 
Section
Screening phase
Treatment phase
Post-
Treatmen
t Follow 
up phase
Cycle
Molecular Pre-
Screening
Screening
Cycle 1
Cycle 
2
Cycle 
3
Cycle 
4 to 
Cycle 
6
End of 
study 
treatment 
(EoT) –
before 
surgery
Days
Any time after the 
site initiation to -1
-28 
to -1
-7 to-1
1
8
15
22
1
15
1
1
N/A
N/A
Coagulation
D
7.2.2.5.4
X
X
X
X
X
Fasting plasma glucose
D
7.2.2.5.3
X
X
X
X
X
X
X
X
X
Fasting C-peptide, Insulin
D
7.2.2.5.3
X
X
X
X
X
X
X
X
X
HbA1c 
D
7.2.2.5.3
X
X
X
Fasting Lipase
D
7.2.2.5
X
X
X
X
X
Fasting Amylase
D
7.2.2.5
X
X
X
X
X
Fasting Lipid profile
D
7.2.2.5.2
X
As clinically indicated
Urinalysis
D
7.2.2.5.5
X
As clinically indicated
Tumor evaluation
D
7.2.1
X
See Table 7-2
Pathological Response
D
7.2.1
X
*Hematology and Fasting Biochemistry (full) should be repeated on cycle 1 day 1 only if the screening assessment has been done more than 7 days before.
**Partial biochemistry will be performed at the local laboratory and is restricted to the parameters described in Section 7.2.2.5, Table 7-4.
ECG
D
7.2.2.6.
X
X
X
X
X
Cardiac imaging
D
7.2.2.6.1
X
As clinically indicated
X
Adverse events
D
8
Continuous
Up to 30 
days after 
last dose 
of 
treatment


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Category
Protocol 
Section
Screening phase
Treatment phase
Post-
Treatmen
t Follow 
up phase
Cycle
Molecular Pre-
Screening
Screening
Cycle 1
Cycle 
2
Cycle 
3
Cycle 
4 to 
Cycle 
6
End of 
study 
treatment 
(EoT) –
before 
surgery
Days
Any time after the 
site initiation to -1
-28 
to -1
-7 to-1
1
8
15
22
1
15
1
1
N/A
N/A
Surgical and Medical 
Procedure
D
7.1.2.3
Continuous
Up to 30 
days after 
last dose 
of 
treatment
Prior/concomitant medications
D
7.1.2.3 /
6.4
Continuous
Up to 30 
days after 
last dose 
of 
treatment
New Antineoplastic Therapies  
since discontinuation of study 
treatment
D
7.1.6
To be collected, if applicable, until surgery is performed.
N/A 
Patient self-reported 
questionnaires : PHQ-9 / GAD-
7
(buparlisib/placebo)
D
7.2.2.7
See Table 7-6
Biomarkers Assessment
D
7.2.4
See Table 7-9 and Table 7-10
Tumor Biopsy
X
X
X
PK sampling (for PK subset)
D
7.2.3
See Table 7-8
Meal record (PK subset)
D
7.2.3
X
X 
(C4D1 
only)


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Category
Protocol 
Section
Screening phase
Treatment phase
Post-
Treatmen
t Follow 
up phase
Cycle
Molecular Pre-
Screening
Screening
Cycle 1
Cycle 
2
Cycle 
3
Cycle 
4 to 
Cycle 
6
End of 
study 
treatment 
(EoT) –
before 
surgery
Days
Any time after the 
site initiation to -1
-28 
to -1
-7 to-1
1
8
15
22
1
15
1
1
N/A
N/A
Patient Diary
S
7.1.3
Daily Continuous
BYL719 / Placebo 
administration
D
6.1
Daily Continuous Dosing
Buparlisib /Placebo 
administration
D
6.1
5 days on/2 days off
Letrozole administration
D
6.1
Daily Continuous Dosing


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7.1.1
Molecular pre-screening
The molecular pre-screening may occur well in advance of the other screening phase 
assessments (any time after the site is initiated and provided the molecular pre-screening ICF 
has been signed) or can occur in parallel with the other screening assessments (provided that 
the main ICF has been signed).
Once the patient signs the molecular pre-screening ICF, demography should be collected and 
the tumor sample should be shipped to the Novartis designated laboratory as soon as possible 
but no later than 14 days before the planned randomization date. The PIK3CA mutation status
based on tumor tissue assessment, as well as Ki67 results, will need to be determined by the 
Novartis designated laboratory. These results will be entered directly to the IRT prior to 
randomization to confirm patient eligibility and allow stratification.
The IRT system will notify sites when Ki67 results and PIK3CA mutation status have been 
entered. Only patients meeting minimum criteria listed below will undergo the molecular pre-
screening:

Patient has a confirmed diagnosis of early breast cancer (non-metastatic)

Patient has estrogen-receptor and/or progesterone positive breast cancer as per local 
laboratory testing

Patient has HER2 negative breast cancer defined as a negative in situ hybridization test or 
an IHC status of 0 or 1+ as per local laboratory testing

Patient is postmenopausal at the time of breast cancer diagnosis

Patient has not previously received a treatment, either systemic or local for the current 
diagnosis of breast cancer
The PIK3CA mutation status and Ki67 status are assessed centrally; the steps required for 
patient enrollment are as follows:
1. Upon patient signature on the molecular pre-screening ICF, the tumor sample from 
diagnosis biopsy should be immediately collected and shipped to a Novartis designated 
laboratory. The sample should be shipped at least 14 days prior to the planned 
randomization date to allow proper time for the analysis.
2. The site should get confirmation of receiptby Novartis designated laboratory within 3 days 
of sample receipt. The site will also be informed if the sample quality is not appropriate.
3. The Novartis designated laboratory will generate the PIK3CA mutation status and Ki67 
results before the planned randomization date and enter them directly into the IRT system
4. The sites will be informed by the IRT system that the results have been entered.
7.1.2
Screening
Written molecular pre-screen and main informed consent must be obtained before any study 
specific assessments are performed.
The screening assessments must be performed within maximum 28 days to confirm patient’s 
eligibility and before the start of the first study treatment dose (BYL719/placebo in 
combination with letrozole).


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Patients who fail to be started on treatment may be re-screened one time, provided the patient 
was not registered previously in IRT as having entered the Treatment Period. In this situation, 
the Patient No. which was previously assigned to the patient will be re-applied to the same 
patient throughout her entire study participation.
Radiographic tumor assessments should be performed within 28 days prior to randomization.
Any imaging assessments already completed during the regular work-up of the patient within
28 days prior to randomization, including before signing the main study ICF can be 
considered as the baseline images for this 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.
For details of assessments, refer to Table 7-1.
7.1.2.1
Eligibility screening
While the investigator is responsible to ensure that each patient meets all inclusion/exclusion 
criteria prior to randomization, a subset of those criteria have been identified as key eligibility 
criteria and will also be verified by the sponsor through IRT prior to permitting the patient to 
be randomized. The eligibility checklist form must be completed in IRT by the investigator or 
designee at the following study timepoints:

at molecular pre-screening, for minimum criteria details refer to Section 7.1.1

at cycle 1 day 1 prior to starting the treatment phase and receiving the first dose of study 
drug (letrozole and BYL719/placebo). Verification of all eligibility criteria must be done 
prior to contacting IRT. After the eligibility has been checked in IRT and confirmed that 
the patient is eligible for the trial, then the patient can be enrolled into the treatment phase 
of the study.
Please refer and comply with detailed guidelines in the IRT manual.
7.1.2.2
Information to be collected on screen failures
Patients who sign the main informed consent, but fail to be started on treatment for any reason 
as well as patients who sign the molecular pre-screening informed consent but do not have a 
tumor sample which can be analyzed (insufficient amount of tumor tissue was present in the 
patient’s archival sample) will be considered screen failures.
The following data must be collected in the eCRF for any patient that signs any ICF

Informed Consent Dates,

Demography,

Screening Phase Disposition eCRF page (including reason for not being started on 
treatment),

Serious Adverse Events (see Section 8.2 for details around SAE collection and 
requirements),


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
Death, if applicable,

Biomarker assessment page – tumor biopsy,

Inclusion/Exclusion Criteria,

Withdrawal of consent, if applicable,

PIK3CA mutation status based on tumor tissue and Ki67 results (reported via data 
transfer), if applicable.
If a screen failure patient experiences an AE which does not meet the SAE criteria, details 
about the AE will be recorded only in the investigator’s source documents. In case of an SAE 
after signing of main study informed consent, data must be recorded on both the AE and SAE 
forms.
No other data is required to be entered into the clinical database for patients who are screen 
failures.
If the patient fails to start the study, then IRT must be notified within 2 days of the screen fail 
that the patient was not enrolled (Section 7.1.2.2).
7.1.2.3
Patient demographics and other baseline characteristics
Patient information to be collected at screening will include:

Demography (Date of Birth and Initials (where permitted), sex, race, ethnicity, source of 
patient referral).

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.

Diagnosis and Extent of Cancer (including staging, histology/cytology and sites of disease 
at study entry).

Intended breast surgery type (i.e. the type of surgery intended prior to treatment should be 
recorded for all patients.)

Prior antineoplastic surgical interventions prior to the administration of study drug.

All medications and significant non-drug therapies (including physical therapy, oxygen 
and blood transfusions) taken within 28 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 to assess the eligibility of the 
patient:

PIK3CA mutation status

Ki67 status

HER2 status

ER/PR status


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
Physical Examination (See Section 7.2.2.1)

Vital signs (See Section 7.2.2.2)

Height and weight (See Section 7.2.2.3)

ECOG performance status (See Section 7.2.2.4)

Laboratory evaluations (e.g., hematology, coagulation, chemistry, urinalysis) (See Section 
7.2.2.5)

ECG (See Section 7.2.2.6)

Cardiac imaging (See Section 7.2.2.6.1)
7.1.3
Treatment period
Within each of the two cohorts (PIK3CA mutated and PIK3CA wild-type), patients will be 
randomized using Ki67 results and lymph node status for stratification (see Section 4). Study 
treatment should be started as soon as possible and no later than 3 days after the 
randomization of the patient.
Patients will be assigned to one of the treatment arms to be treated at cycle 1 day 1 with 
letrozole plus BYL719 or letrozole plus placebo. Patients will receive treatment until week 24, 
surgery, disease progression, unacceptable toxicity, death, or discontinuation from the study 
treatment due to any other reason.
Patients will come to the site for assessments at a minimum of every 2 weeks for the first 2 
cycles of treatment, then every cycle thereafter. A biopsy will be taken at week 2 for Ki67 and 
other biomarkers assessment. A sample will also be collected at the time of surgery for Ki67 
and other biomarkers assessment.
Patients will be fasting at each site visit when fasting clinical laboratory parameters have to be 
assessed.
Patients will be instructed to complete a daily patient diary that will be reviewed at each site 
visit by site staff for study drug compliance at PK days and during the course of the study 
participation.
For details of assessments, refer to Table 7-1.
7.1.4
Discontinuation of Study Treatment
Patients may voluntarily discontinue from the buparlisib/Placebo plus Letrozole or 
BYL719/Placebo plus Letrozole treatment arm for any reason at any time. If a patient decides 
to discontinue from study treatment, the investigator must make a reasonable effort (e.g. 
telephone, e-mail, letter) to determine the primary reason for this decision and record this 
information in the patient’s chart and on the appropriate CRF pages. They may be considered 
withdrawn if they

state an intention to withdraw,

fail to return for visits,

become lost to follow-up for any other reason.


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The investigator should discontinue buparlisib/placebo plus letrozole or BYL719/placebo plus 
letrozole treatment arm for a given patient if he/she believes that continuation would be 
detrimental to the patient’s well-being.
Patients may be discontinued from the study treatment if any of the following occur:

Adverse Event

Non-compliance with study treatment

Progressive Disease

Study terminated by sponsor

Technical problems

Use of prohibited treatment and medications refer to Section 6.4.1 and Section 14.1

Any protocol deviation that results in a significant risk to the patient’s safety

Death
The appropriate personnel from the site and Novartis will assess whether buparlisib/placebo 
plus letrozole or BYL719/placebo plus Letrozole treatment should be discontinued for any 
patient whose treatment code has been broken inadvertently for any reason.
Patients who discontinue buparlisib/placebo or BYL719/placebo study treatment should NOT 
be considered withdrawn from the study. They should continue taking Letrozole as per 
investigators’ clinical judgment, in which case the patient must and return for the assessments 
indicated in Section 7.2.1. If they fail to return for these assessments for unknown reasons, 
every effort (e.g. telephone, email, letter) should be made to contact them as specified in 
Section 7.1.7.
If the decision to withdraw the patient occurs at a regularly scheduled visit, that visit may 
become the end of treatment (EOT) visit rather than having the patient return for an additional 
visit.
Patients 
who 
discontinue 
study 
treatment 
(e.g. 
letrozole, 
BYL719/placebo 
and 
buparlisib/placebo) should be scheduled for an EOT visit as soon as possible, and within 14 
days after the date study treatment is permanently discontinued, at which time all of the 
assessments listed for the EOT visit will be performed. Known information on intended 
surgery and pCR should be collected on the eCRF for these patients. Patients who discontinue 
but do NOT withdraw consent and have surgery within 30 days post-discontinuation should 
have pCR data collected at the time of surgery.
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations during the 30 days following 
the last dose of study treatment.
The investigator must contact IRT to register the patient’s treatment discontinuation.
7.1.5
Withdrawal of Consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not want any
further study related contact.


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Novartis will continue to retain and use all research results that have already been collected 
for the study evaluation. All biological samples that have already been collected may be 
retained and analyzed at a later date (or as required by local regulations).
If a patient withdraws consent, the investigator should make a reasonable effort (e.g. 
telephone, e-mail, letter) to understand the primary reason for this decision while respecting 
the subject’s rights and record this information.
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up
7.1.6
Follow up for Safety Evaluations
All patients must have safety evaluations for 30 days after the last dose of study treatment.
Patients lost to follow up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, the investigator 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.
All patients will be followed for AEs and serious adverse events for at least 30 days following 
the last dose of study treatment. At the end of this period, the investigator should assess and 
discuss with the patient any AE observed/concomitant medication taken since discontinuation 
of study treatment.
7.1.7
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
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 
End of treatment Disposition CRF.
7.1.8
Breast Cancer Surgery
Definitive breast surgery will be performed as early as possible, but no later than 14 days after 
the last dose of BYL719/placebo or buparlisib/placebo or letrozole. If a patient discontinues 
from BYL719/placebo or buparlisib/placebo, letrozole treatment will be maintained until the 
day of surgery.
Surgical management of the primary tumor and axilla is left at the discretion of the surgeon. 
Patients with involved or close surgical margins after breast conserving surgery may undergo 
additional surgery to obtain negative margins.
After the study treatment period (i.e. 24 weeks) or if the patient prematurely discontinues for 
any reason other than withdrawal of consent, the investigator will report if patient undergoes 
breast surgery, and the type of surgery performed. The investigator will receive the 
pathological response report generated by the local lab that assessed the tumor following the 
protocol mandated by Novartis. A separate tissue sample from the surgery will also be sent to 


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the Novartis designated laboratory for Ki67 and other biomarkers assessment (see Section 
7.2.4)
7.2
Assessment types
7.2.1
Efficacy assessments
Tumor evaluation will be determined locally according to the Novartis guideline 
(Appendix 2) on the Response Evaluation Criteria in Solid Tumors (RECIST), based on 
RECIST Version 1.1 unless otherwise specified below. The investigator’s assessment of ORR 
will be used for the primary efficacy analysis.
Any imaging assessments already completed during the regular work-up of the patient within 
28 days prior to start of treatment, including before signing the main study ICF, can be 
considered as the baseline images for this study.
Magnetic Resonance Imaging (MRI) or ultrasound (US) of breast will be performed at 
screening, cycle 4 day 1 (+/- 7 days) and prior to surgery (maximum 7 days before). The same 
technique should be used throughout the duration of the trial. Additional radiological 
assessments may be performed when needed as per investigator judgment e.g. at screening (to 
exclude metastasis) or during the course of the study (to rule out clinical progression).
All patients who discontinue from study treatment due to disease progression must have their 
progression clearly documented according to the criteria specified in Appendix 2 (RECIST 
v1.1). Further treatment is left up to the investigator’s discretion.
Table 7-2
Imaging collection plan
Procedure
Screening/Baseline
During Treatment/Follow-up
Ultrasound or MRI of Breast
Mandated
At C4D1; after C6D28, before surgery
CT or MRI
(Chest, Abdomen, Pelvis or other organ 
as indicated)
As clinically indicated
As clinically indicated
Bone Scan
As clinically indicated
As clinically indicated
Other Radiological Assessments
As clinically indicated
As clinically indicated
Pathological complete response assessment:
Pathological Complete Response (pCR) is one of the two primary endpoints and is based on 
local assessment. Surgical breast and axillary node resection specimens will be evaluated for 
pathologic tumor response within 2 weeks of surgery following the pCR guidelines distributed 
by Novartis. Patients will be considered pathological complete responders if there is no 
invasive cancer remaining in the breast and lymph nodes specimens (whether or not there is in 
remaining in situ component) according to the FDA definition of pCR: ypT0/Tis ypN0 
(AJCC staging system).
7.2.2
Safety and tolerability assessments
Safety will be monitored by physical examination, vital signs, weight, performance status 
evaluation, ECG, laboratory evaluations including glucose monitoring and the assessment of 


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patient rated mood scales, as well as collecting all serious and non-serious Adverse Events 
(AE).
Prior ECGs and/or echocardiogram/MUGA scan(s) performed as part of the regular work-up 
of the patient within 28 days prior to randomization can be considered as baseline safety 
assessments for this study.
For details on AE collection and reporting, please refer to Section 8.1.
If one of the study drug is being held due to toxicity, scheduled visits and assessments should 
still be performed (with the exception of the dosing of the held study drug) as described in 
Table 7-1, unless otherwise specified.
7.2.2.1
Physical examination
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 present in the source documentation at the study site.
Physical examination is to be performed according to the visit schedule as outlined in 
Table 7-1.
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 (pulse rate, blood pressure) will be monitored as per the visit schedule (see 
Table 7-1). Blood pressure (systolic and diastolic) and pulse should be measured after the 
patient has been sitting for five minutes.
Clinically 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 at Screening. Significant 
new findings that begin or worsen after informed consent and meet the definition of an AE 
must be recorded on the Adverse Event page of the patient’s eCRF.
7.2.2.3
Height and weight
Height and body weight will be measured as outlined in the visit schedule (see Table 7-1).
7.2.2.4
Performance status
The performance status will be assessed according to the ECOG performance status scale 
(Oken 1982). ECOG performance status will be assessed as per the visit schedule 
(see Table 7-1).


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Table 7-3
ECOG performance status
Grade
ECOG status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
7.2.2.5
Laboratory evaluations
As outlined in Table 7-4, fasting plasma glucose, AST, ALT, ALP, total bilirubin and 
creatinine, will be performed both centrally and locally for rapid availability for safety 
evaluation and dose adjustments. Clinical laboratory analyses (Hematology, Biochemistry, 
coagulation, HbA1C, C-Peptide, and Urinalysis) are to be performed by central laboratory 
according to the Visit Schedule outlined in Table 7-1. If a local laboratory is used for any 
unscheduled laboratory assessments, 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 (outside) 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.
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 
Adverse Events eCRF page. Laboratory data will be summarized using the Common 
Terminology Criteria for Adverse events (CTCAE) version 4.0.3. Additional analyses are left 
to the discretion of the investigator.
Hepatotoxicity follow-up testing will be performed when needed (refer to Section 6.3.2.1.
Management of hepatotoxicity (ALT and/or AST >3.0x ULN and total bilirubin >2.0x ULN) 
in patients receiving BYL719/placebo or buparlisib/placebo).


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Table 7-4
Central Clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hemoglobin, Platelets, Red blood cells, White blood cells, Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils)
Fasting Biochemistry
(full)
Albumin, Alkaline phosphatase (ALP), ALT (SGPT), AST (SGOT), GGT, Bicarbonate, 
Calcium, Chloride, Creatinine, Creatine kinase, potassium, sodium, magnesium, Total 
Bilirubin (direct must be collected only in case total bilirubin is elevated > ULN), Total 
Protein, Blood Urea Nitrogen (BUN) or Urea, Uric Acid
Biochemistry (partial)
Creatinine, ALT, AST, Total bilirubin, ALP, fasting plasma glucose
Urinalysis
Dipstick analysis (WBC, blood, protein and glucose)
Coagulation
Prothrombin Time (PT) or International normalized ratio [INR], Partial thromboplastin 
time (PTT) or activated Partial thromboplastin time (aPTT)
Additional tests 
Fasting Plasma Glucose, Fasting Lipase, Fasting Amylase, C-peptide, Insulin,
Glycosylated Hemoglobin (HbA1c)
Fasting Lipid profile 
Total Cholesterol, HDL, LDL, Triglycerides
*Viral hepatitis 
serologic tests and 
other tests for 
hepatotoxicity follow-
up 
HAAb, HBsAg, HBsAb HBcAb, HCV RNA or HDV RNA (where needed), HEAb, 
CMVAb, EBcAb, ALP, CPK, LDH, WBC (eosinophilia), and others.
All laboratory analysis will be performed centrally; however fasting plasma glucose, ALT, AST, ALP, total bilirubin, 
and Creatinine will be performed both locally and centrally (for rapid availability for safety evaluation and dose 
adjustments). 
Any unscheduled laboratory assessment can be done locally but should be sent to the central laboratory as well 
for central analysis. The central results will be electronically transferred to the database. All local laboratory 
parameters results should be entered on eCRF.
*Hepatotoxicity follow-up testing/procedures will be performed locally (refer to Section 6.3.2.1. Management of 
hepatotoxicity (ALT and/or AST >3.0x ULN and total bilirubin >2.0x ULN) in patients receiving BYL719/placebo or 
buparlisib /placebo and Section 7.2.2.5.6 Viral hepatitis serology and other tests for hepatotoxicity follow-up).
7.2.2.5.1 Hematology
Hematology tests are to be performed by the central laboratory according to the Visit 
Schedules outlined in Table 7-1. For details of the Hematology panel refer to Table 7-4.
7.2.2.5.2 Biochemistry
Biochemistry tests are to be performed by the central laboratory according to the Visit 
Schedule outlined in Table 7-1. For details on the Biochemistry panel refer to Table 7-4.
Lipid panel is to be performed according to the Visit Schedule outlined in Table 7-1. For 
details on the Lipid Profile panel refer to Table 7-4.
7.2.2.5.3 Monitoring FPG, C-peptide, and HbA1C
Fasting Plasma Glucose (FPG), C-peptide, and HbA1C will be assessed according to the visit 
schedule in Table 7-1. Patients must be fasting overnight for at least 10 hours prior to the 
blood draw. The study personnel will ask the patient whether he or she has been fasting, 
which will be captured in the eCRF as well.
HbA1c will be measured at screening, Cycle 3 Day 1 and at EOT.


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7.2.2.5.4 Coagulation
Prothrombin Time (PT) or International normalized ratio (INR), and partial thromboplastin 
time (PTT) or aPTT, will be measured according to the visit schedule in Table 7-1.
7.2.2.5.5 Urinalysis
Urinalysis includes dipstick analysis will be performed as outlined in Table 7-1.
7.2.2.5.6 Viral hepatitis serology and other tests for hepatotoxicity follow-up
During study treatment, viral hepatitis serologic and other tests will be performed as per the 
guidelines of management of hepatotoxicity (ALT or AST >3.0x ULN and total bilirubin > 
2.0x ULN) in patients receiving
BYL719/placebo or
buparlisib/placebo, refer to 
Section 6.3.2.3.6 Management of hepatotoxicity (ALT and/or AST >3.0x ULN and total 
bilirubin >2.0x ULN) in patients receiving BYL719/placebo or buparlisib/placebo for details.
Viral hepatitis serology includes the following:

Hepatitis A IgM antibody and hepatitis A serology total

Hepatitis B surface antigen, Hepatitis B Core Antibody (IgM) and viral DNA

Hepatitis C serology and viral RNA

Hepatitis D RNA (where needed)

Hepatitis E IgM and IgG antibody and viral RNA
Obtain fractionated bilirubin, serum Alkaline Phosphatase (ALP), creatine phosphokinase 
(CPK), lactate dehydrogenase (LDH), and blood count with differential to assess eosinophilia.
Additional viral serology tests may include:

Cytomegalovirus IgM antibody

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing)

Herpes Simplex Virus
7.2.2.6
Electrocardiogram (ECG)
A standard 12 lead ECG will be performed after the patient has been resting for 5-10 min 
prior to each time point indicated in Table 7-5.
The interpretation of the tracing must be made by a qualified physician and documented in the 
ECG section of the eCRF. Each ECG tracing should be labeled with the study number, patient 
initials (if permitted by local regulations), Subject No, date, and kept in the source documents 
at the study site. Clinically significant abnormalities present when the patient signed informed 
consent should be reported on the Medical History eCRF page. Clinically significant findings 
must be discussed with the Novartis Medical Monitor prior to enrolling the patient in the 
study. New or worsened clinically significant findings occurring after informed consent must 
be recorded on the Adverse Events CRF page.


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Table 7-5
Local ECG collection plan
Cycle
Day
Time
ECG Type
Screening
-28 to -1
Any time
12 Lead
1
1
Pre-dose
12 Lead
2
1
Pre-dose
12 Lead
3 – n*
1
Pre-dose
12 Lead
Unscheduled sample
Anytime
12 Lead
7.2.2.6.1 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram
The left ventricular heart function will be evaluated by ECHO or MUGA at Screening to 
confirm eligibility and either after C6D28 or study treatment discontinuation (whatever occurs 
first) if last assessment was done more than 6 weeks before. Additional cardiac imaging 
during treatment is to be performed if indicated by clinical signs or symptoms. The same 
imaging modality should be used.
7.2.2.7
Patient self-reported Mood Questionnaires
The Patient Health Questionnaire-9 (PHQ-9) and General Anxiety Disorder-7 (GAD-7) are 
validated (Kroenke 2001, Spitzer 2006, Spitzer 1999), patient self-administered 
questionnaires developed for use in clinical practices.
The PHQ-9 (Appendix 4, Figure 14-1) consists of 9 questions that assess anhedonia, 
depressed mood, sleep, energy, appetite, guilt and worthlessness, concentration, feeling 
slowed down or restlessness, and suicidal thoughts. For each of these questions, patients are 
asked to rate how much over the past 2 weeks they have been bothered by the symptom.
Scoring of the PHQ-9 is based on a Likert-type scale from 0 to 3 (0 indicates not at all; 1, 
several days; 2, more than half the days; 3, nearly every day). The sum of all nine questions is 
used to determine a total PHQ-9 score ranging from 0 to 27.
The GAD-7 (Appendix 4, Figure 14-2) is a one-dimensional questionnaire consisting of 7 
questions. Similarly to the PHQ-9, in the GAD-7, patients are asked to indicate how often, 
over the past 2 weeks, they have been bothered by each of the seven core symptoms of 
generalized anxiety disorder as referenced in the DSM IV. Response options are ‘‘not at all,’’ 
‘‘several days,’’ ‘‘more than half the days,’’ and ‘‘nearly every day,’’ scored as 0, 1, 2, and 3, 
respectively. The sum of all seven questions calculates the total GAD-7 score. Therefore, 
GAD-7 scores range from 0 to 21.
Questionnaires will only be completed by patients in the buparlisib+letrozole and buparlisib
matching placebo+letrozole arms at Cycle 1 Day 15, Cycle 2 Day 1 and Day 15, and Cycle 3
Day 1 and at Day 1 of each subsequent cycle in addition to the EOT visit. An additional 
assessment at Cycle 3 Day 15 is also required if any psychiatric disorder is present at Cycle 3 
Day 1 (See Table 7-6). Additional assessments may be done according to the clinical 
judgment of the investigator.
All questionnaires should be given by the site to the patient in the patient’s local language and 
reviewed for completeness and possible AEs.


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Table 7-6
Patient self-reported mood questionnaire collection plan 
(buparlisib/placebo+letrozole arms only)
Patient Questionnaires
Visit/ Cycle*
Day
Time
PHQ-9
GAD-7
Cycle 1
Day 15
Prior to any clinical 
assessments, study 
drug dosing or 
diagnostic testing.
Cycle 2
Day 1, Day 15
Cycle 3
Day 1
(Day 15 only if any psychiatric 
disorder at C3D1)
Every Cycle
Day 1
End of treatment
Day of end of treatment assessment
End of treatment
Day of end of treatment assessment
The severity classification table described in Table 7-7 for the PHQ-9 and GAD-7 will be 
used in this study to increase the sensitivity of identifying potential anxiety and/or depression 
disorders. During the study, questionnaire scores and corresponding severity classification can 
be used to aid the investigator in identifying new or worsening of events. However, grading 
must be based on the clinical interpretation of severity according to the NCI- CTCAE (v 4.03).
Table 7-7
Classification of severity based on depression and/or anxiety 
questionnaire scores
PHQ-9 (depression)
GAD-7 (anxiety)
Score
Severity
Score
Severity
0-4
None
0-4
None
5-9
Mild
5-9
Mild
10-19
Moderate
10-14
Moderate
20-27
Severe
≥ 15
Severe
During the treatment phase, patients randomized to buparlisib or buparlisib-matching placebo,
who indicate a positive response by selecting ‘1, 2, or 3’ to question number 9 in the PHQ-9,
must omit treatment with study drug (buparlisib or matching placebo) and must be referred for 
psychiatric consultation for optimal management regardless of the total questionnaire score or 
CTCAE grading to confirm if study drug should be interrupted or permanently discontinued.
In this specific case, the psychiatric advice can overrule the patient PHQ-9 self-assessment.
Investigators must not encourage the patients to change responses reported in questionnaires.
Guidelines on how to instruct the patient to complete the questionnaires as well as how to 
determine the scores will be provided with each instrument. Guidance on scoring 
questionnaires is also provided in Appendix 4. Dosing modification guidelines for 
buparlisib/placebo are provided in Table 6-4. For additional information on AE reporting, 
please refer to Section 8.1.
7.2.3
Pharmacokinetics
Blood samples for plasma concentrations measurements for BYL719 and letrozole will be 
collected from at least 15 patients in each treatment arm from selected centers. The blood 
sampling regimen for determining PK is given in Table 7-8. One sample of blood will be 
drawn for two potential analytes and plasma samples will be split for BYL719/placebo and 


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letrozole analysis depending on the treatment arm. Post dose PK-samples are calculated from 
the start of BYL719/placebo or letrozole administration (tablets or capsules).
Exact dates and clock times of drug administration and actual blood draw will be collected on 
the appropriate eCRF. The time of the breakfast prior to PK sampling, where post dose 
timepoints are collected, should be recorded in the appropriate eCRF page. If a patient treated 
with either combination of treatments experiences an AE that fits the criteria of a SAE as 
determined by the Investigator, every attempt should be made to take a blood sample for 
measurement of plasma concentrations of study treatment.
If vomiting occurs within 4 hrs following study-drug administration on the day of PK 
sampling, where post-dose time points are collected, the time (using the 24 hrs clock) of 
vomiting should be recorded in a separate section of the eCRF and on the transmittal forms, 
which accompany the sample. No additional study medication should be taken in an effort to 
replace the material that has been vomited. If gastric protection agents were taken, this should 
be recorded in a separate section of the eCRF and on the transmittal forms, which accompany 
the sample.
If a patient withdraws prematurely from the study, a PK blood sample must be obtained 
whenever possible. This will be considered as an unscheduled. PK sample should be collected 
at any time, preferably within 2 weeks post-last BYL719 dose, and the date and time of the 
last dose recorded.
Whenever an ECG with a QTcF change from baseline > 60 msec or a new absolute QTcF ≥
501 msec result is obtained for patients treated with the drugs combination, a blood sample to
assess concentrations of BYL719, buparlisib and letrozole should be obtained and the time of 
sample collection noted.
7.2.3.1
Pharmacokinetic blood sample collection and handling
All blood samples will be taken by either direct venipuncture or an indwelling cannula 
inserted in a forearm vein. Blood should be collected in accordance with institutional 
guidelines. On days and time points when pharmacokinetics, biochemistry, hematology or 
other blood samples are to be performed, the pharmacokinetic sample must be drawn first. 
Complete instructions for sample processing, handling and shipment will be provided in the 
[CBYL719A2201 Laboratory Manual]. No time window for full PK sampling on Cycle 1 Day 
1 is allowed (other than specified in Table 7-8), while, other PK samples may be obtained ± 1 
day from the scheduled date. Dosing information of the last 3 or 7 days before the PK 
sampling may be recorded, if feasible at every PK visit (except at Cycle 1 Day 1) for PK 
analysis. Any sampling problems should be noted on the eCRF and on appropriate source 
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Table 7-8
Pharmacokinetic blood collection log
BYL719 / placebo
buparlisib / placebo
Letrozole
Cycle
Day
Time
Dose 
Reference ID
PK Sample 
Number
Dose 
Reference ID
PK Sample 
Number
Dose 
Reference ID
PK Sample 
Number
Blood 
Volume 
(mL)
1
1
Pre-dose*
301
301
401
401
501
501
2
1
1
0.5 hour post dose ± 10 min
301
302
401
402
501
502
2
1
1
1 hour post dose ± 10 min
301
303
401
403
501
503
2
1
1
3 hour post dose ± 15 min
301
304
401
404
501
504
2
1
1
6 hour post dose ± 30 min
301
305
401
405
501
505
2
1
1
9 hour post dose ± 30 min**
301
306
401
406
501
506
2
1
2
24 hour post dose* ± 120 min
301
3012
307
401
4012
407
501
5012
507
2
1
8
Pre-dose*
302
3021
308
402
4021
408
502
5021
508
2
1
15
Pre-dose*
303
3031
309
403
4031
409
503
5031
509
2
1
22
Pre-dose*
304
3041
310
404
4041
410
504
5041
510
2
2
1
Pre-dose*
305
3051
311
405
4051
411
505
5051
511
2
3
1
Pre-dose*
306
3061
312
406
4061
412
506
5061
512
2
4
1
Pre-dose*
307
3071
313
407
4071
413
507
5071
513
2
4
1
0.5 hour post dose ± 10 min
307
314
407
414
507
514
2
4
1
1 hour post dose ± 10 min
307
315
407
415
507
515
2
4
1
3 hour post dose ± 15 min
307
316
407
416
507
516
2
4
1
6 hour post dose ± 30 min
307
317
407
417
507
517
2
4
1
9 hour post dose ± 30 min**
307
318
407
418
507
518
2
4
2
24 hour post dose* ± 120 min
307
3072
319
407
4072
419
507
5072
519
2
5 to n
1
Pre-dose*
308+ 
3081+
320+
408+ 
4082+
420+
508+
5081+
520+
2
Unscheduled 
sample
---
---
---
3001+
---
4001+
---
---
5001+
2
* Take sample immediately prior to study treatment dose
** Optional sampling time
+ Refer to Lab manual for naming conventions


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7.2.3.2
Analytical method
Refer to the [CBYL719A2201 Laboratory Manual] for detailed instructions for the collection,
handling and shipping of samples.
Plasma concentrations of BYL719, buparlisib and letrozole will be measured at Novartis or 
designated CRO using validated liquid
chromatography-tandem mass spectrometry 
(LC/MS/MS) assays. The lower limits of quantitation (LLOQ) are currently 5.0 ng/mL, 
1.0 ng/ml and 2.0 ng/ml.
Residual plasma samples used for PK analysis may also be used for exploratory analysis.
 
 
7.2.4
Biomarkers
7.2.4.1
Biomarker assessments and biomarker sample collection plan
A summary of biomarker assessments and biomarker sample collection plan has been 
provided in Table 7-9.
For all biomarker samples, the sample collection information must be captured on the relevant 
eCRF page(s) and laboratory requisition form(s). Biomarker data will be sent electronically to 
Novartis. See laboratory manual for detailed sample collection, storage and shipment 
information
Table 7-9
Biomarker sample collection plan
Sample Type
Volume
Visit
Time point
Mandatory collections
Tumor samples
Tumor Tissue (referred as Specimen 
1, specimen 2, C1D15 biopsy and 
surgical specimen)
N/A
Screening, C1D15, 
and post treatment 
follow up
Screening (day -28 to day-1), C1D15
and /surgical specimen/ tumor 
progression
Blood Samples
Blood for circulating tumor DNA
2x10 mL
Screening
Screening
(day -28 to day-1)
10ml
Treatment
C1D15, C3D1, C4D1, C5D1, C6D1
10ml
End of treatment
after last dose of study treatment
Blood for germline DNA
6 mL
Treatment
Any time before first dose of study 
treatment
Optional collections
Skin Biopsy 
N/A
Anytime
At time of rash


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7.2.4.2
Biomarker assessment for randomization
7.2.4.2.1 Tumor tissue
The biopsy collected for initial diagnosis of breast cancer will be used to assess PIK3CA 
mutation and Ki67. Diagnostic biopsy or a minimum of 7 to 9 slides need to be provided at 
the earliest possible time. However, if initial diagnostic biopsy is insufficient, a new biopsy 
can be collected if feasible and acceptable to the patient (see [Laboratory Manual] and
Table 7-10 for details on tissue collection).
Assessment of PIK3CA mutation status will be performed to allow proper allocation of 
patients to a given cohort (PIK3CA mutated or wild-type). Ki67 will be used for stratification 
purpose (to differentiate luminal A – Ki67<14% - and luminal B – Ki67 ≥14% - breast cancer 
patients).
7.2.4.3
Biomarkers assessment for pathway inhibition and efficacy
7.2.4.3.1 Assessments at baseline
Tumor tissue:
Collection and shipment of specimen 1 (i.e. the tumor tissue acquired at the initial diagnosis 
of breast cancer) to a Novartis designated laboratory must occur as soon as possible and at 
least 14 days prior to the planned randomization date. The Novartis designated laboratory 
must provide acknowledgment of receipt of adequate tumor tissue quantity within 3 days of 
receipt of sample receipt. The PIK3CA mutation status as well as Ki67 status must be 
determined by the Novartis designated laboratory and entered into the IRT system prior to 
randomization (see Section 7.1.1).
Specimen 2 will be obtained from either the diagnostic material submitted at molecular pre-
screening (i.e. part of Specimen 1 if material had sufficient quantity and quality) (see Section 
4.1) or prospectively collected (i.e. a newly collected biopsy) from the patients, if Specimen 1 
material had sufficient quantity and/or quality, prior to initiation of treatment. This specimen 
will be primarily used to assess ER and Ki67status centrally; as these parameters are needed 
for calculating the PEPI score (secondary endpoint of the study). It will also be used to assess 
molecular alterations of many genes associated with the PI3K pathway in Breast Cancer 
(Cancer Genome Atlas Network 2012). In the event of a previously unidentified mutation, 
germline DNA will be used to confirm the tumor origin of the given mutation.
Blood:
Circulating tumor DNA: This will be utilized to test for mutations in genes that are relevant 
for PI3K signaling (e.g. PIK3CA). The mutation profile obtained from the circulating tumor 
DNA will be compared with the mutation profile obtained from the diagnostic biopsy 
collected at entry on trial. This is a required assessment which will provide a validation on the 
use of circulating tumor DNA mutation analysis in neoadjuvant context. The blood sample 
(2x10 mL) will be collected during screening or at cycle 1 day 1 (when patient is eligible and 
before first dose of treatment).


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7.2.4.3.2 Assesments during treatment
Tumor Tissue:
A new biopsy will be taken at C1D15, following 2 weeks of treatment: “C1D15 Biopsy” (see 
[Laboratory Manual] and Table 7-10 for details on tissue collection).
Ki67 will be measured to evaluate the dynamics of its variation under treatment 
(Dowsett 2007). Markers of cell death 
 will be measure to assess 
the percentage of cell death in response to treatment.
Finally, PI3K-driven intracellular signaling is typically driven by binding of ligand to a 
tyrosine kinase receptor followed by phosphorylation of several intracellular components 
ultimately activating of the PI3K function such as cell survival. The day-15 biopsy (Biopsy 3)
will be analyzed for markers shown to be closely associated with the PI3K pathway using a 
phosphoprotein multiplex approach to assess tumor response to the treatment and compared to 
baseline level assessed in specimen 2. 
 
Blood:
Circulating tumor DNA: In addition to a screening sample, blood samples (10 mL) for 
circulating tumor DNA will be collected at cycle 1 day 15, C3D1, C4D1, C5D1, C6D1 during 
treatment, . These samples will be utilized to test for mutations in genes that are relevant for 
PI3K signaling (e.g. PIK3CA and ESR1).
7.2.4.3.3 At the time of surgery
Tumor tissue (Surgical specimen): 
Tumor tissue (Surgical specimen): 4 samples from the surgical specimen (or tumor bed in 
cases of pathological complete response) will be sent within 4 weeks of surgery to the 
Novartis designated laboratory for central analysis of ER and Ki67 levels, together with other 
pathological features, in order to determine the PEPI score (Ellis 2008). Two of these samples 
should be formalin-fixed and shipped in ethanol; and the other two samples should be snap-
frozen and shipped on dry ice (for tissue preparation, please refer to the [CBYL719A2201 
Laboratory Manual]). 
In addition, tumor cell death marker analysis and molecular characterization of the tumor, by 
mutation and/or expression analysis, may be performed in order to assess the effect of 
treatment on the PI3kinase pathway and other cancer and cell signaling related pathways.
Blood:
Circulating tumor DNA: The mutation profile obtained from the circulating tumor DNA at 
the end of treatment will be assessed. 
For all tumor samples, the sample collection information must be captured on the relevant 
eCRF page(s) and laboratory requisition form(s).


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7.2.4.5
Optional additional biomarker studies
If the patient agrees, the tumor and blood samples remaining after analysis will be stored 
under the control of Novartis for up to 15 years for additional exploratory biomarker 
assessments 
and/or 
the 
development 
of 
biological/diagnostic 
test(s) 
related 
to 
BYL719/buparlisib/letrozole and/or Cancer. The decision to perform such analyses will 
depend on the outcome data, emerging internal or external data and sample availability.
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.
For patients whose PIK3CA mutation status is unknown and who sign the molecular pre-
screening ICF, AEs which occur after signature of this consent will only be captured if they 
meet the definition of serious as outlined in Section 8.2 and are reported to be causally related 
with study procedures (e.g. an invasive procedure such as biopsy). Once the main study ICF is 
signed, all AEs per the descriptions below will be captured in the Adverse Event eCRF.
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 (or 5 half-lives, whichever is longer) following the last dose 
of study treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event.
Adverse events will be assessed 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, corresponding to Grades 1 -
4, will be used. CTCAE Grade 5 (death) will not be used in this study; rather, information 
about any deaths (related to an Adverse Event or not) will also be collected through a Death 
form.


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The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine:
1. The severity grade (CTCAE Grade 1-4)
2. Its duration (Start and end dates)
3. Its relationship to the study treatment (Reasonable possibility that AE 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. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown)
7. 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
If the event worsens the event should be reported a second time in the CRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if 
improvement to a lower grade is determined a new entry for this event should be reported in 
the CRF noting the start date when the event improved from having been grade 3 or grade 4.  
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event 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 
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 


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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,

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


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8.2.2
Reporting
For patients with unknown PIK3CA mutation 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 mutation 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 main informed consent and until at least 30 days after the patient has 
stopped study treatment must be reported to Novartis within 24 hours of learning of its 
occurrence.
Any additional information for the SAE including complications, progression of the initial 
SAE, and recurrent episodes must be reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one 
should be reported separately as a new event.
Any 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 SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report.  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 Drug Safety and Epidemiology (DS&E) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 


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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
Emergency unblinding should only be undertaken when it is essential for effective treatment 
of the patient. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency code breaks are performed using the IRT. When the investigator 
contacts the IRT to unblind a patient, he/she must provide the requested patient identifying 
information and confirm the necessity to unblind the patient. The investigator will then 
receive details of the drug treatment for the specified patient and a fax confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
Study Lead that the code has been broken.
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The investigator will inform the patient how to contact 
his/her backup in cases of emergency when he/she is unavailable. The protocol number, study 
treatment name if available, patient number, and instructions for contacting the local Novartis 
CPO (or any entity to which it has delegated responsibility for emergency code breaks) will 
be provided to the patient in case emergency unblinding is required at a time when the 
investigator and backup are unavailable. However, if a mechanism is already in place to 
ensure that the investigator and/or back-up can always be reached in case of emergency then 
the procedure above is not required.
Study treatment must be discontinued once emergency unblinding has occurred.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
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.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochures. 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.


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8.6
Data Monitoring Committee
An internal Data Monitoring Committee (DMC) composed of Novartis personnel who are not 
directly involved with the BYL719 program will be constituted. The primary responsibility of 
the DMC will be to periodically review ongoing unblinded safety data from the study and 
advise whether the study should be stopped. Responsibilities of the DMC are included in the 
DMC charter.
8.7
Steering Committee
The steering committee (SC) will be established comprising investigators participating in the 
trial, and Novartis representatives from the Clinical Trial Team.
The SC will ensure transparent management of the study according to the protocol through 
recommending modifications as circumstances require. The SC will review protocol 
amendments as appropriate. Together with the clinical trial team, the SC will also develop 
recommendations for publications of study results. The details of the role of the Steering 
Committee will be defined in a Steering Committee charter. The SC will be blinded to the 
trial data.
Periodic review of safety data aggregated by blinded treatment group (BYL719+Letrozole 
and BYL719-placebo + Letrozoleor buparlisib/placebo) will be performed and results will be 
shared with study steering committee.
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.


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Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements 
and to enable appropriate age-related normal ranges to be used in assessing laboratory test 
results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan.
9.3
Data collection
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.
Pharmacokinetic (PK) and Biomarker (blood and tissue) samples drawn during the course of 
the study will be collected from the investigator sites and analyzed by a central lab contracted 
by Novartis. The site staff designated by the investigator will enter the information required 
by the protocol onto the PK and Biomarker Sample Collection eCRFs, as well as onto the 
designated CRO’s requisition form. One copy of the requisition form will be forwarded to the 


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central lab along with the corresponding samples with required information (including study 
number, subject ID, etc.) and one copy will be retained by the site.
9.4
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator and site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using 
the 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.
Pharmacokinetic and biomarker samples will be processed centrally and the results will be 
sent electronically to Novartis (or a designated CRO).
Laboratory samples for hematology, biochemistry, Urinalysis, coagulation, lipid profile and 
others assessments (HbA1c, fasting plasma glucose, fasting lipase and amylase, insulin and c-
peptide) will be performed by a Central Laboratory. However fasting plasma glucose, ALT, 
AST, ALP and Creatinine and total bilirubin will be performed both locally and centrally. 
Results of analysis tested centrally will be reconciled and sent electronically to Novartis (or a 
designated CRO). Unscheduled laboratory analysis performed locally will be collected 
directly in e-CRF by the sites.
Randomization codes and 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 vendor(s), who will also manage the database. The data will be 
sent electronically to Novartis personnel (or designated CRO).
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis 
personnel (or designated CRO). The occurrence of any protocol violations will be determined. 
After these actions have been completed and the data has been verified to be complete and 
accurate, the database will be declared locked and the treatment codes will be unblinded and 
made available for data analysis. Authorization is required prior to making any database 
changes to locked data, by joint written agreement between the Global Head of Biostatistics 
and Data Management and the Global Head of Clinical Development. 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
Data will be summarized by Novartis and/or designated CRO. Any data analysis carried out 
independently by the investigators must be submitted to Novartis before publication or 
presentation. It is planned that the data from the participating centers in this protocol will be 
combined so that an adequate number of patients will be available for analysis. Analysis will 


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be performed after all patients in each cohort (i.e. PIK3CA mutated and PIK3CA wild-type) 
have completed 24 weeks of treatment and have pCR evaluation available or have 
discontinued due to any reason.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises of all randomized patients in the study. Following the
intent to treat (ITT) principle, patients will be analyzed according to the treatment and strata 
they have been assigned to during the randomization procedure. 
The FAS will be the primary population for all the efficacy analyses.
10.1.2
Safety Set
The Safety Set will comprise all patients who received at least one dose of study treatment. 
Patients will be analyzed according to the study treatment received, where treatment received 
is defined as the randomized treatment if the patient took at least one dose of that treatment or 
the first treatment if the randomized treatment was never received.
10.1.3
Per-Protocol Set
The per-protocol set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the protocol. It will constitute of all randomized patients who receive at 
least one dose of study drug, have completed 24 weeks of therapy have undergone surgery
and have at least one tumor assessment. Other major protocol deviations may be considered 
for exclusion from the PPS and will be listed in the study reporting and analysis plan (RAP).
The PPS may be used to carry out sensitivity analyses of primary efficacy endpoint if the FAS 
and the PPS are different in the population the PoC is established.
10.1.4
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) consists of all patients who received at least one dose 
of BYL719, buparlisib or letrozole and have at least one evaluable post-treatment 
concentration measurement.
Due to the variability in the PK of BYL719, buparlisib and letrozole, at least 12 out of 15 
patients providing blood samples from each of the combinations are needed to be evaluable 
for a Full Sampling Pharmacokinetic Analysis Set to provide an estimate on the magnitude of 
the drug-drug interaction and assess PK parameters for BYL719 and buparlisib.
10.1.4.1 BYL719 Pharmacokinetic Analysis Set (BYL PAS)
The BYL PAS will include all patients who received at least one dose of study medication 
BYL719 and had at least one evaluable post-treatment BYL719 concentration measurement.
10.1.4.2 BYL719 Full Sampling Pharmacokinetic Analysis Set (BYL FPAS)
The BYL FPAS will include the subset of the patients in the BYL PAS who:


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
received all planned doses of BYL719 for the last consecutive 3 days preceding full PK 
profile assessment on Cycle 4 Day 1

did not vomit within 4 hours of BYL719 and/or letrozole dosing on the day of full PK 
profile assessment (Cycle 1 Day 1 and Cycle 4, Day 1)

received all planned doses of letrozole for the last consecutive 7 days and received ≥ 70% 
of all planned doses preceding full PK profile assessment Cycle 4, Day 1

had an evaluable full PK profile on the day of full PK assessment (C1D1 and C4D1)
10.1.4.3 Buparlisib Pharmacokinetic Analysis Set (BKM PAS)
The BKM PAS will include all patients who received at least one dose of study medication 
buparlisib and had at least one evaluable post-treatment buparlisib concentration measurement.
10.1.4.4 Buparlisib Full Sampling Pharmacokinetic Analysis Set (BKM FPAS)
The BKM FPAS will include the subset of the patients in the BKM PAS who:

received all planned doses of buparlisib on 10 days out of 14 days (including cycle 4 day 1) 
preceding full PK profile assessment on Cycle 4, Day 1

did not vomit within 4 hours of buparlisib and/or letrozole dosing on the day of full PK 
profile assessment (Cycle 1 Day 1 and Cycle 4, Day 1)

received all planned doses of letrozole for the last consecutive 7 days and received ≥ 70% 
of all planned doses preceding full PK profile assessment Cycle 4, Day 1.

had an evaluable full PK profile on the day of full PK assessment (C1D1 and C4D1).
10.1.4.5 Letrozole Pharmacokinetic Analysis Set (LZ PAS)
The LZ PAS will include all patients who received at least one dose of letrozole and had at 
least one evaluable post-treatment letrozole concentration measurement.
10.1.4.6 Letrozole Full Sampling Pharmacokinetic Analysis Set (LZ FPAS)
The LZ FPAS will include the subset of the patients in the LZ PAS who:

received all planned doses of letrozole for the last consecutive 7 days and received ≥90% 
of all planned doses preceding full PK profile assessment Cycle 4, Day 1.

did not vomit within 4 hours of letrozole dosing on the day of full PK profile assessment 
(Cycle 1 Day 1 and Cycle 4, Day 1)

had an evaluable full PK profile on the day of full PK assessment
10.1.5
Other analysis sets
Not applicable.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline disease characteristic/prognostic data will be summarized by 
cohort and treatment the patient was randomized to and pooled on cohorts for the FAS. 


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Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be summarized
separately by system organ class and preferred term, by cohort and treatment group.
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, 
minimum, and maximum will be presented.
The actual cumulative dose and duration of exposure to BYL719, buparlisib, placebo and 
letrozole treatment, as well as dose intensity (computed as the ratio of actual cumulative dose 
received to actual duration of exposure) and the relative dose intensity (computed as the ratio 
of dose intensity to planned dose intensity), will be listed and summarized using descriptive 
statistics. The summary data will be presented for each treatment, by cohort and pooled on 
cohorts. The duration of exposure will also be presented for the study treatment by arm and by 
cohort and pooled on cohorts. The total daily doses of BYL719, buparlisib, placebo and 
letrozole for each patient will be summarized using descriptive statistics (e.g. mean, median, 
and mode).
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by treatment arm and by cohort and 
pooled on cohorts. And all dosing data will be listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed by patient and summarized by ATC (Anatomical therapeutic 
chemical) classification system term for each treatment arm. These summaries will include 
medications starting on or after the start of study treatment or medications 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.
Compliance to the study drug will be assessed by the number of dose reductions and dose 
interruptions.
10.4
Primary objective
The primary objectives of the study are:

To assess the anti-tumor activity of BYL719 QD plus letrozole QD versus letrozole alone 
in increasing the pathologic complete response (pCR) rate as assessed locally by the 
investigator during neo-adjuvant treatment among postmenopausal patients with HR+, 
HER2-negative breast cancer for each of the two cohorts: i) PIK3CA mutated and ii) 
PIK3CA wild tumor types based on tumor tissue.
and

To assess the anti-tumor activity of BYL719 QD plus letrozole QD versus letrozole alone
in increasing the Objective Response rate (ORR) as assessed locally by the investigator 
during neo-adjuvant treatment among postmenopausal patients with HR+, HER2-negative 


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breast cancer for each of the two cohorts: i) PIK3CA mutated and ii) PIK3CA wild tumor 
types based on tumor tissue.
10.4.1
Variable
The primary efficacy endpoints are:

pathologic complete response (pCR) defined as absence of any residual invasive cancer on 
hematoxylin and eosin evaluation of the resected breast specimen and all sampled 
ipsilateral lymph nodes following completion of 24 weeks of treatment by local 
assessment (ypT0/Tis ypN0). Patients who experience progression of disease while 
undergoing neoadjuvant therapy, or who do not receive surgery for any reason, or receive 
antineoplastic treatment other than study drug(s) before surgery will be considered as non-
responders for the calculation of pCR rate.

Objective Response Rate (ORR) defined as the proportion of patients with a Best Overall 
Response (BOR) of Complete Response (CR) or Partial Response (PR) based on local 
investigator’s assessment according to RECIST 1.1 (Appendix 2). No confirmation of 
CR/PR is required.
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules:

CR = one determination of CR prior to progression 

PR = one determination of PR prior to progression (and not qualifying for a CR)

SD = at least one SD assessment (or better) > 5 weeks after randomization (and not 
qualifying for CR or PR).

PD = progression ≤26 weeks after randomization (and not qualifying for CR, PR or SD).

UNK = all other cases (i.e. not qualifying for CR or PR and without SD after more than 5
weeks or early progression within the first 26 weeks)
10.4.2
Statistical hypothesis, model, and method of analysis
The primary objectives of this study are to assess the anti-tumor activity of BYL719 plus 
letrozole vs. letrozole alone based on pCR rate or ORR in each of the following two cohorts 
of HR+, HER2-negative breast cancer patients: (i) PIK3CA mutated and (ii) PIK3CA wild 
type based on tumor tissue. 
There is no formal plan to compare the BYL719 and buparlisib combination arms. 
Since this study is double-blinded with respect to placebo but not whether a patient is on 
BYL719 or buparlisib, some patients in the control arm of letrozole will receive letrozole plus 
BYL719 placebo and some patients will receive letrozole plus buparlisib placebo. Letrozole 
plus BYL719 placebo and letrozole plus buparlisib placebo will be combined together within 
a cohort for all analyses.
Pathologic complete responseBased on published results, the pCR rate with letrozole is 
expected to be 5% or less. A 10% absolute improvement in the pCR rate to 15% is considered 
clinically meaningful among HR-positive patients. Therefore a Proof of Concept (PoC) about 
efficacy of treatment based on pCR will be declared if both of the following conditions are 
met for any cohort:


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
Posterior probability that the difference in the pCR rate is more than 0 is > 90% and

Estimated mean difference of the pCR rate between combination arm and letrozole is at 
least 10%
Overall Response Rate
Based on published results, the ORR with letrozole is expected to be around 45%. A 20% 
absolute improvement in the ORR is considered clinically meaningful among hormone 
receptor-positive patients. Therefore a PoC about efficacy of treatment based on ORR will be 
declared if both of the following conditions are met for any cohort:

Posterior probability that the difference in the ORR is more than 0 is > 90% and

Estimated mean difference in the ORR between combination arm and letrozole is at least 
20%
To determine the first criteria for PoC, the posterior distribution of the difference in the pCR 
rates (in the ORR respectively) between the combinations arm and letrozole will be estimated 
assuming binomial distribution of the pCR rates (of the ORR respectively) and using non-
informative beta priors. Details will be specified in the RAP.
Proof of concept will be declared in a given cohort if the PoC criteria are met for pCR or ORR.
The pCR rates and ORR in each of the treatment arms will be summarized by cohort using 
descriptive measures including 90% confidence intervals using Clopper and Pearson (1934) 
exact method. The pCR and ORR rates will also be summarized by each stratum.
10.4.3
Handling of missing values/censoring/discontinuations
Patients with no pCR evaluation will be considered non-responders. Patients who experience 
progression of disease while undergoing neoadjuvant therapy, or who do not receive surgery 
for any reason, or receive antineoplastic treatment other than study drug(s) before surgery will 
be considered as non-responders for the calculation of pCR rate.
Only tumor assessments performed on or before the start of antineoplastic treatment other 
than study drug(s) will be considered in the assessment of BOR. Patients with unknown best 
overall response will be considered as non-responders for the calculation of ORR.
10.4.4
Supportive and sensitivity analyses
As a sensitivity measure, primary efficacy analysis for pCR and ORR will be repeated using 
the PPS in a given cohort if the PoC is established and if the PPS and FAS are considered 
different in these population(s). 
Additional supportive analyses may be performed if appropriate and will be specified in the 
RAP.
Subgroup analyses in a given cohort may be performed based on age, race, and other 
demographic and disease characteristics (e.g. ER status, PR status, Ki67, Lymph node status) 
in an exploratory manner in the population(s) if the PoC is established. Details about other 
subgroups and additional subgroup analysis will be specified in the RAP.


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10.5
Secondary objectives
10.5.1
Key secondary objective(s)
None.
10.5.2
Other secondary efficacy objectives
The treatment effect of BYL719 plus letrozole vs. letrozole alone on pCR rate and ORR will 
be assessed in each of the following two cohorts: (i) PIK3CA mutated and (ii) PIK3CA wild 
type, based on ctDNA (assessed in hotspots from exons 9 and 20). The same statistical 
hypothesis, model, and method of analysis will be used as for PIK3CA cohorts based on 
tumor tissue. Patients with unknown mutation status based on ctDNA assessment will be 
excluded from the analysis.
Descriptive statistics (N, % and 90% confidence intervals using Clopper and Pearson (1934) 
method) will be used to summarize breast conserving surgery (BCS) rate. Summary statistics 
will also be presented for Ki67 changes under treatment (at day 15 and surgery) and PEPI 
score by treatment arm. The above analyses will be performed separately for the i) PIK3CA 
mutated and ii) PIK3CA wild type cohorts based on tumor tissue.
10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
All safety analyses will be carried out on the Safety set. All listings and tables will be 
presented by treatment arm irrespective of PIK3CA mutational status. 
The assessment of safety will be based mainly on the frequency of AEs 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.
The safety summary tables will include only assessments collected no later than 30 days after 
study treatment discontinuation. Those collected later than 30 days after study treatment 
discontinuation will be flagged in listings.
The safety data will be summarized and listed by treatment arm on pooled cohorts. Therefore, 
the safety assessment will be performed following the completion of both cohorts. Some 
safety analyses may be also performed separately for the continuous schedule and for the 5 
days-on / 2 days-off schedule of buparlisib. 
1. The overall observation period for all safety analyses will be divided into three mutually 
exclusive segments: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.
Periodic review of safety data aggregated by blinded treatment group (BYL719/placebo or 
buparlisib/placebo) will be performed and results will be shared with study steering 
committee.


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In addition, selected safety analyses will be performed by an independent statistician not 
involved with the conduct of the study. Details regarding the safety analysis review by DMC 
are provided in Section 8.6. Further details are described in the DMC charter.
10.5.3.2 Adverse events (AEs)
Summary tables for AEs will include only AEs that started or worsened during the on-
treatment period, the treatment-emergent AEs. However, 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.
The incidence of treatment-emergent AEs (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades 
version 4.03), type of AE, relation to study treatment.
Serious adverse events, non-serious adverse events and adverse events of special interest
(AESI) during the on-treatment period will be tabulated. 
All deaths (on-treatment and post-treatment) will be summarized. Deaths reportable as SAEs 
and non-fatal serious AEs will be listed by patient and tabulated by type of AE.
Specific safety event categories (SEC) will be considered. Such categories consist of one or 
more well-defined safety events which are similar in nature and for which there is a specific 
clinical interest in connection with the study treatment(s). SEC will be defined at project level 
and may be regularly updated. For each specified SEC, number and percentage of patients 
with at least one event part of the SEC will be reported.
10.5.3.3 Laboratory abnormalities
Laboratory data will be graded according to CTCAE version 4.03, if applicable. For 
laboratory tests covered by CTCAE, a Grade 0 will be assigned for all non-missing values not 
graded as 1 or higher.
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
The following summaries will be generated separately for hematology, biochemistry and 
urinary laboratory tests:
For laboratory tests where grades are defined by CTCAE v4.03

Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline.

shift tables using CTCAE grades v4.03 to compare baseline to the worst on-treatment 
value.
For laboratory tests where CTCAE v4.03 grades are not defined, 

shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on- treatment value

listing of all laboratory data with values flagged to show the corresponding CTCAE v4.03 
grades if applicable and the classifications relative to the laboratory normal ranges


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10.5.3.4 Other safety data
Other safety data collected will be listed and summarized using descriptive statistics as 
appropriate. Notable values may be flagged. Notable/abnormal values for safety data will be 
further specified in the statistical analysis plan.
ECG
The following summaries will be generated by parameter and treatment arm:

Notable ECG parameters change from baseline to worst on-treatment result

listing of ECG evaluations for all patients with at least one abnormality
Cardiac imaging
Summary for the change from baseline to worst post-baseline in LVEF values
Vital signs
Definitions of notably abnormal results will be included in the statistical plan. The following 
summaries will be generated by parameter and treatment arm:

Descriptive statistics for the change from Baseline to the worst post-baseline visit.

Listing of patients with clinically notable vital sign abnormalities. Notable values will be 
flagged
ECOG Performance Status

ECOG data will be listed for the safety set separately by treatment arm.
Mood Assessment
Mood assessment includes two self-rating mood questionnaires, the GAD-7 Anxiety scale and 
PHQ-9 Depression scales and is being administered to patients in the buparlisib/placebo arms 
only. The primary variable for the analyses of patient-reported outcomes will be the total 
scores of each of the two scales. Shift tables comparing the baseline severity score to worst 
post- baseline severity score will be provided by treatment arm (buparlisib plus letrozole vs 
buparlisib placebo + letrozole).
10.5.3.5 Tolerability
Tolerability will be studied in terms of dose reductions or drug interruption due to an AE. 
Reasons for dose reductions and interruptions will be summarized and listed by treatment arm.
10.5.4
Pharmacokinetics
Pharmacokinetic parameters will be determined for all PK-evaluable patients using 
non-compartmental method(s) using Phoenix WinNonlin (Version 6.4 - Pharsight, Mountain 
View, CA). PK parameters listed in Table 10-1 will be estimated and reported, when feasible. 
Exploratory PK analysis may be conducted using compartmental modeling if appropriate.
Pharmacokinetic parameters for BYL719, buparlisib (BKM120) and letrozole after single oral 
dose at Cycle 1 Day1 (single agent PK) will include Tmax, Cmax, AUCinf, AUClast, AUC0-


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24, CL/F, Vz/F and T1/2 (only BYL719 as T1/2 cannot be properly estimated for buparlisib 
due to its long half-life). Pharmacokinetic parameters for BYL719, buparlisib (BKM120) and 
letrozole after multiple oral doses at Cycle 4, Day 1 will include Tmax, Cmax, AUClast, 
AUC0-24, CLss/F, T1/2 (for BYL719), effective half-life (T1/2,eff for buparlisib only) and 
RAcc. For both compounds Clast and Tlast will be listed but not summarized. PK parameters 
will be used to determine the magnitude of the drug-drug interaction by determining Cmax 
and AUC ratios for letrozole.
PK parameters on Cycle 4 Day 1 will be compared between treatment arms using an ANOVA 
model in the letrozole FPAS. An ANOVA model will be fitted to the log-transformed PK 
parameters (AUC0-24 and Cmax) of letrozole including study treatment (letrozole alone, 
letrozole + BYL719, letrozole + buparlisib) as a fixed effect. The treatment difference 
between letrozole + BYL719 and letrozole alone and between letrozole + buparlisib and 
letrozole alone will be calculated and back transformed to produce point estimates and 90% 
CI for the ratios of the geometric means as described above.
Table 10-1
Non-compartmental PK parameters
Term
Definition
Cmax
Maximum observed plasma concentration after drug administration (ng/mL)
Tmax
Time to reach Cmax (hr)
Tlastt
Last measurable concentration sampling (hr)
Clast
Last measurable concentration (ng/mL)
AUClast
Area under the concentration-time curve from time zero to the last measurable concentration 
sampling time (Tlast) (h x ng/mL)
AUC0-24
Area under the concentration-time curve from time zero to 24 hours post dose (h x ng/mL)
AUCinf
The area under the plasma concentration-time curve from time zero to infinity (h x ng/mL)
AUCex1
Area under the plasma concentration-time curve extrapolated from the time t to infinity as a 
percentage of total AUC (%)
CL/F
Apparent oral total drug clearance calculated from AUCinf after a single oral dose (L/hr)
CLss/F
Apparent oral total drug total plasma clearance calculated from stead-state exposure data (L/hr)
Vz/F
The apparent volume of distribution during terminal phase (associated with lambda_z) (volume)
T1/2
Elimination half-life associated with the terminal slope (lambda_z) of a semi logarithmic 
concentration-time curve time
RAcc
Accumulation ratio calculated as AUCtau,ss/AUCtau,dose1 where tau is the dosing interval
Rsqadj1
Square of the correlation coefficient associated with lamda_z
1 AUCex and Rsqadj will be used in the interpretation of the primary PK parameters and therefore will be included 
in the listings only.
10.5.4.1 Data handling principles
10.5.4.1.1 Analysis sets
The plasma samples will be assayed for BYL719 or buparlisib (BKM120) and letrozole 
concentrations by Novartis or subcontractor using validated LC-MS/MS methods described in 
the [Laboratory Manual].


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BYL, BKM and LZ FPAS will be used in the non-compartmental analysis (NCA) of selected 
patient subpopulation and BYL, BKM and letrozole PAS will be used to assess trough levels
within all patients.
For plasma BYL719, buparlisib and letrozole, the LLOQ is 5.0 ng/mL, 1.0 ng/mL and 2.0 
ng/mL, respectively. All concentrations below the LLOQ or missing data will be labeled as 
such in the concentration data listings. Concentrations below the LLOQ will be treated as zero 
in summary statistics and omitted for data analysis. Exploratory PK analysis may also be 
conducted based on preliminary data prior to database lock, and nominal time instead of 
actual elapsed time may be used.
10.5.4.1.1
Basic Tables, Figures and Listings
Descriptive statistics (arithmetic mean, standard deviation, CV%, geometric mean, geometric 
CV% median, minimum and maximum) will be presented for all parameters by analyte, 
treatment arm and study day. When a geometric mean is presented, it will be stated as such. 
Only median, minimum and maximum will be given for Tmax. Similarly descriptive statistics 
will be presented for concentration by analyte, treatment arm, study day and scheduled 
sampling timepoint.
Descriptive graphical plots of individual plasma concentration by time will be generated, as 
will mean concentration time profiles for BYL719, buparlisib and letrozole. Further graphical 
exploratory analyses will be carried out if deemed appropriate and specified in the RAP. Any 
other exploratory analyses will be conducted if necessary.
10.5.5
Resource utilization
Not Applicable.
10.5.6
Patient-reported outcomes
None.
10.6
Exploratory objectives
10.6.1
Biomarkers
As a project standard, Novartis Oncology BDM will analyze only biomarkers collected in the 
clinical database. 
 
 
 
 
There may be circumstances when a decision is made to stop a sample collection, or not 
perform or discontinue the analysis of blood / archival tumor samples / fresh tumor biopsies / 
fine needle aspirates due to either practical or strategic reasons (e.g. issues related to the 
quality and/or quantity of samples or issues related to the assay that preclude the analysis of 


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samples). Under such circumstances, the number of samples may be inadequate to perform a 
rigorous data analysis and the available data will only be listed.
Further details regarding exploratory analyses of biomarker and efficacy data are presented in 
Section 10.6.
10.6.1.1 Outline of the data analysis
Additional analyses that may be performed after the completion of the end-of-study CSR will 
be documented in separate reports. These analyses may include but are not limited to the 
meta-analysis of data from this study combined with data from other studies or the analysis of 
biomarkers generated from samples collected during the study but analyzed after the database 
lock and completion of the CSR. The data analysis will be described in an addendum of the 
RAP or in a stand-alone analysis plan document, as appropriate.
10.6.1.2 Data handling principles
For IHC variables the H-score will be calculated using the following standard algorithm H-
score = Low level stain *1+ medium level stain *2+ high level stain*3. IHC is also used to 
assess Ki67, which is measured by percent positive cells, thus does not require an H-score 
computation.
Further details will be provided in the study RAP.
10.6.1.3 Data analysis principles
10.6.1.3.1
Analysis sets
The FAS set will be used for all biomarker analysis depending on the study phase to be 
analyzed. Unless otherwise specified, all statistical analyses of biomarker data will be 
performed on patients with biomarker data.
10.6.1.3.2
Basic tables, figures and listings
The biomarker data analysis will include the following:
Description of distribution of baseline level by using mean, standard deviation, median, 
minimum and maximum of raw data for quantitative biomarker data collected only at baseline. 
Categorical markers, such as mutation or amplification status, will be summarized using 
frequency and percentages for all baseline and post baseline time points.
Mean, standard deviation, median, minimum, and maximum of raw data, absolute change 
from baseline and percent change from baseline for IHC measured at baseline and at different 
time points.
The concordance/discordance of the PIK3CA mutation status between ctDNA and tumor 
tissue measured at study entry may be summarized.
All these analyses will be outlined in full in the RAP.
 
 
 


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10.6.1.3.3
Advanced analysis methods
None.
10.6.2
Efficacy
Exploratory analyses will be performed to assess the anti-tumor activity of buparlisib versus 
letrozole alone in increasing the pathologic complete response (pCR) rate and the ORR as 
assessed locally by the investigator during neo-adjuvant treatment among postmenopausal 
patients with HR+, HER2-negative breast cancer for each of the two cohorts: i) PIK3CA 
mutated and ii) PIK3CA wild tumor types based on tumor tissue and based on ctDNA. 
Additional exploratory analyses may be performed using the subpopulation of patients who 
receive the intermittent schedule if the PoC is established with buparlisib plus letrozole in at 
least one cohort
Exploratory analyses will also be performed to assess the anti-tumor activity of BYL719 plus 
letrozole and buparlisib plus letrozole versus letrozole alone regardless of PIK3CA mutational 
status, or between the combined group of patients treated with BYL719 or buparlisib plus 
letrozole versus those treated with letrozole alone. 
10.7
Interim analysis
No interim efficacy analysis will be performed.
10.8
Sample size calculation
A total of approximately 320 patients will be randomized. Patients will be assigned to one of
the two cohorts and within each cohort, patients will be randomized to one of the three arms 
(i.e. BYL719+letrozole, buparlisib+letrozole, or placebo+letrozole). Following the permanent 
stop of the enrollment in the buparlisib arm, the target number of 60 patients per arm in each 
cohort remains unchanged for the BYL719+letrozole and placebo+letrozole arms. However a 
lower number of patients will be randomized to buparlisib+letrozole.
Within the placebo+letrozole arm, patients will receive matching BYL719 (or buparlisib 
placebo, respectively only before amendment 5). The placebo groups within each cohort will 
be pooled together providing a total of 60 patients in placebo+letrozole within each cohort).
With 60 patients in the two arms BYL719+letrole and Placebo+letrozole within each cohort, 
the assessment of the PoC for BYL719 will have the following operating characteristics, using 
the PoC criteria described in Section 7.2.1 and assuming a pCR rate of 5% and an ORR of 45% 
in the letrozole arm:
True Treatment Effect on pCR 
(absolute increase in %)
True Treatment Effect on ORR 
(absolute increase in %)
Probability that PoC is 
declared on pCR or ORR
0
0
0.014
0.2
0.484
0.25
0.684


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True Treatment Effect on pCR 
(absolute increase in %)
True Treatment Effect on ORR 
(absolute increase in %)
Probability that PoC is 
declared on pCR or ORR
0.3
0.861
0.05
0
0.119
0.2
0.520
0.25
0.718
0.3
0.875
0.1
0
0.437
0.2
0.692
0.25
0.823
0.3
0.921
0.15
0
0.759
0.2
0.870
0.25
0.926
0.3
0.966
0.2
0
0.933
0.2
0.963
0.25
0.978
0.3
0.990
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 
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


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Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their CRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
Additional consent form
Sub-studies and studies with an optional Exploratory Biomarker component will have a 
separate consent form covering those studies. This form will be adapted for each Study based 
on a standard template used globally for all Studies. These informed consent forms will be 
submitted for ethical approval together with the Study Protocol and the main informed 
consent form of the Study. If a subject opts not to participate in the optional assessments, this 
in no way affects the subject’s ability to participate in the main research study.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in 
Section 4.3.
11.5
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.
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.


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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 (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported 
on the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF 
should be dated, initialed, and explained (if necessary) and should not obscure the original 
entry. For electronic CRFs an audit trail will be maintained by the system. The investigator 
should retain records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.
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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13
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Sanchez CG, Ma CX, Crowder RJ, et al (2011) Preclinical modeling of combined 
phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive 
breast cancer. Breast Cancer Research; 13(2):Article R21
Sansal I, Sellers WR (2004) The biology and clinical relevance of the PTEN tumor suppressor 
pathway. J Clin Oncol; 22:2954–2963.
Saura C, de Azambuja E, Dubsky P, et al. (2014) LORELEI: A Phase II randomized, double-
blind study of neoadjuvant letrozole plus taselisib (GDC-0032) versus letrozole plus placebo 
in postmenopausal women with ER-positive/HER2-negative, early stage breast cancer. San 
Antonio Breast Cancer Symposium, OT1-1-01.
Semiglazov VF, Semiglazov VV, Dashyan GA, et al. (2007) Phase 2 randomized trial of 
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Shah PD,  Moynahan ME, Modi S (2014). Phase I trial: PI3Ka inhibitor BYL719 plus 
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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 
buparlisib and/or 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
Cytochrome P450 Substrates
This list of CYP substrates was compiled from the Indiana University School of Medicine’s 
“Clinically Relevant” Table, from the FDA’s “Guidance for Industry, Drug Interaction 
Studies” and from the University of Washington’s Drug Interaction Database. 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
CYP2C8
Narrow Therapeutic 
index substrates of 
CYP2C8
Paclitaxel
Sensitive substrates of 
CYP2C8
Repaglinide
Other Substrates of 
CYP2C8
Amodiaquine, Benzphetamine, Carbamazepine, Cerivastatin, Docetaxel, Everolimus, 
Febuxostat, Fluvastatin, Isotretinoin, Phenytoin, Pioglitazone, Retinol, Repaglinide, 
Rosiglitazone, Tolbutamide, Torsemide, Verapamil, Zopiclone
CYP2C9
Narrow Therapeutic 
index substrates of 
CYP2C9
(S)-Warfarin, Phenytoin
Sensitive substrates of 
CYP2C9
(S)-Warfarin
Other Substrates of 
CYP2C9
Amitriptyline, Carvedilol, Celecoxib, Chlorpheniramine, Chloramphenicol, 
Clomipramine, Clopidogrel, Desogstrel, Diclofenac, Dronabinol, Febuxostat, 
Fluoxetine, Flurbiprofen, Fluvastatin, Formoterol, Glibenclamide, Glimepiride, 
Glipizide, Hexobarbital, Ibuprofen, Imipramine, Indomethacin, Irbesartan, Irinotecan, 
Ketamine, Lomoxicam, Losartan, Mefenamic acid, Meloxicam, Mephenytoin, 
Montelukast, Nateglinide, Omeprazole, Phenylbutazone, Piroxicam, Quetiapine, 
Rosiglitazone, Sertraline, Sildenafil, Sulfamethoxazole, Sulfinpyrazone, Suprofen, 
Tamoxifen, Tienilic acid, Tolbutamide, Torsemide, THC, Testosterone, Valdecoxib, 
Vardenafil, Valsartan, Voriconazole, Zafirlukast, Zileuton


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Category
Drug Names
CYP2C19
Narrow Therapeutic 
index substrates of 
CYP2C19
(S)-Mephenytoin (also sensitive)
Sensitive substrates of 
CYP2C19
Clobazam, Dexlansoprazole, Diazepam, Gliclazide, (R)-Mephobarbital, 
Lansoprazole, (R)-Lansoprazole, (S)-Lansoprazole, Omeprazole, (R)-Omeprazole, 
Pantoprazole, (+) Pantoprazole, Rabeprazole, Tilidine,
Other Substrates of 
CYP2C19
Antipyrine, Bosentan, Dapasone, Dexloxiglumide, Diclofenac, Esomeprazole, 
Flurbiprofen, Glyburide, Losartan, Moclobemide, Ospemifene, Phenytoin, 
Pitavastatin, Proguanil, Quinidine, Rabeprazole, Rosuvastatin, Sildenafil, 
Tolbutamide, Voriconazole 
CYP3A
Narrow Therapeutic 
index substrates of 
CYP3A
Alfentanil, Cyclosporine, Diergotamine, Ergotamine, Fentanyl, Pimozide, Quinidine, 
Sirolimus, Tacrolimus
Sensitive substrates of 
CYP3A
Alfentanil, Almorexant, Alpha-dihydroergocryptine, Aplaviroc, Aprepitant, Atazanavir, 
Atorvastatin, Avanafil, Bosutinib, Brecanavir, Brotizolam, Budesonide, Buspirone, 
Capravirine, Casopitant, Conivaptan, Danoprevir, Darifenacin, Darunavir, Dasatinib, 
Dronedarone, Ebastine, Eletriptan, Elvitegravir, Eplerenone, Everolimus, Felodipine, 
Fluticasone, Ibrutinib, Indinavir, Ivacaftor, Levomethadyl, Lomitapide, Lopinavir, 
Lovastatin, Lumefantrine, Lurasidone, Maraviroc, Midazolam, Midostaurin, Naloxegol, 
Neratinib, Nisoldipine, Perospirone, Quetiapine, Ridaforolimus, Saquinavir, Sildenafil, 
Simeprevir, Simvastatin, Sirolimus, Tacrolimus, Ticagrelor, Terfenadine, Ticagrelor, 
Tilidine, Tipranavir, Tolvaptan, Triazolam, Ulipristal, Vardenafil, Vicriviroc, 
Voclosporin
Other Substrates of 
CYP3A
Alprazolam, Ambrisentan, Amlodipine, Antipyrine, Aripiprazole, Artemether, 
Avosentan, Boceprevir, Bosentan, Buprenorphine, Carbamazepine, Dexloxiglumide, 
Dextromethorphan, Diazepam, Docetaxel, Enzalutamide, Gemigliptin, Halofantrine, 
Imipramine, Lansoprazole, Lidocaine, Linagliptin, Loperamide, Loratadine, Losartan, 
Lurasidone, Macitentan, Methadone, Mirodenafil, Montelukast, Morphine, Nelfinavir, 
Netupitant, Nevirapine, Nifedipine, Nilotinib, Nitrendipine, Omeprazole, Ospemifene, 
Oxycodone, Paclitaxel, Pazopanib, Pioglitazone, Quinine, Ranolazine, Repaglinide, 
Rifabutin, Ritonavir, Roflumilast, Saxagliptin, Selegiline, Sertraline, Sibutramine, 
Sotrastaurine, Telaprevir, theophylline, tirilazad, tolterodine, udenafil, Vincristine, 
Voriconazole
This list of CYP substrates was compiled from the Indiana University School of Medicine’s “Clinically Relevant” 
Table; from the FDA’s “Guidance for Industry, Drug Interaction Studies” and from the University of Washington’s 
Drug Interaction Database. Please note that this may not an exhaustive list. Dated July 2015.
1 Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-administered with a 
known potent inhibitor.
2 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).
3 Other substrates are these that have shown an in vivo ≥2-fold increase in AUC with co-administration of an 
inhibitor based on the UW database. 


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14.1.2
Cytochrome P450 Inhibitors and Inducers
This list of CYP inhibitors and inducers was compiled from the Indiana University School of 
Medicine’s “Clinically Relevant” Table, from the FDA’s “Guidance for Industry, Drug 
Interaction Studies” and from the University of Washington’s Drug Interaction Database. This 
list only meant to be used as a guide.
Table 14-2
List of moderate CYP3A4 inducers and inhibitors used with caution 
(buparlisib treatment arm)
Category
Drug Name
Moderate CYP3A Inhibitors
ACT-178882, Amprenavir, Aprepitant, Atazanavir, Casopitant, 
Cimetidine, Ciprofloxacin, Crizotinib, Cyclosporine, Darunavir, 
Diltiazem, Dronedarone, Erythromycin, FK1706, Fluconazole, 
Grapefruit juice (citrus paradisi fruit juice 240 mL QD), Imatinib, 
Ledipasivir, Netupitant, Schisandra sphenanthera1, Tofisopam, 
Verapamil
Moderate CYP3A Inducers
Bosentan, Efavirenz, Etravirine, Genistein, Lersivirine, Lopinavir, 
Modafinil, Nafcillin, Ritonavir and St. John’s wort, Semagacestat, 
Talviraline, Thioridazine, Tipranavir and Ritonavir
1Herbal product, 2P-gp inducer
Table 14-3
List of prohibited strong CYP3A4 inducers and inhibitors (buparlisib 
treatment arm)
Category
Drug Name
Strong CYP3A Inhibitors
Boceprevir, Clarithromycin, Cobicistat, Conivaptan, Danoprevir, 
Grapefruit juice (citrus paradisi fruit juice, 240 mL TID), Elvitegravir, 
Idealisib, Indinavir, Itraconazole, Ketoconazole, LCL161, Lopinavir, 
Mibefradil, Nefazodone, Nelfinavir, Posaconazole, Ritonavir, 
Saquinavir, Telaprevir, Telithromycin, Tipranavir, Troleandomycin, 
Voriconazole
Strong CYP3A Inducers
Avasimibe1,2, Carbamazepine, Enzalutamide, Mitotane, Phenobarbital, 
Phenytoin, Rifabutin, Rifampin (Rifampicin)2, St. John's wort (hypericum 
perforatum)2
1Herbal product; 2P-gp inducer
14.1.3
Drugs that prolong the QT interval and/or induce Torsades de Pointes
The Arizona Center for Education and Research on Therapeutics (CERT) keeps a 
comprehensive list of drugs that prolong the QT interval and/or induce Torsades de Pointes. 
Because the quality of the evidence for QT prolongation/TdP risk varies, drugs are further 
classified into three categories:

Known Risk of TdP: Substantial evidence supports the conclusion that these drugs 
prolong QT intervals and have a risk of TdP when used as directed in labeling.

Possible risk of TdP: Substantial evidence supports the conclusion that these drugs can 
cause QT prolongation but there is insufficient evidence that the drugs, when used as 
directed in labeling, have a risk of causing TdP.


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
Conditional risk of TdP: Substantial evidence supports the conclusion that these drugs 
prolong QT and have a risk of developing TdP but only under certain known conditions.
All QT-prolonging drugs with known risk (Table 14-4) are prohibited for all patients from
screening through permanent discontinuation of study treatment in this study. For a complete 
and most updated drug list, please check the website https://crediblemeds.org/healthcare-
providers/drug-list.
Please always refer to the QTDrug Lists database to double-check the QT risk classification of 
a drug before administration as drugs may be subject to reclassification!
Table 14-4
List of prohibited QT prolonging drugs
Drug
QT risk*
Comment
Anagrelide
known risk
Amiodarone
known risk
Females>Males, TdP risk regarded as low
Arsenic trioxide
known risk
Astemizole
known risk
No Longer available in U.S.; Substrate for 3A
Azithromycin
known risk
Bepridil
known risk
No Longer available in U.S.; Females>Males
Chloroquine
known risk
Chlorpromazine
known risk
Cilostazol
known risk
Ciprofloxacin
known risk
Drug metabolism inhibitor- Risk for drug interactions
Cisapride
known risk
No longer available in the U.S.; Substrate for 3A
Citalopram
known risk
Clarithromycin
known risk
Substrate for 3A4
Disopyramide
known risk
Females>Males
Dofetilide
known risk
Domperidone
known risk
Not available in the U.S.
Donepezil
known risk
Dronedarone
known risk
Substrate for 3A
Droperidol
known risk
Escitalopram
known risk
Erythromycin
known risk
Females>Males. Substrate for 3A
Flecainide
known risk
Fluconazole
known risk
Drug metabolism inhibitor- Risk for drug interactions
Halofantrine
known risk
Females>Males
Haloperidol
known risk
When given intravenously or at higher-than-
recommended doses, risk of sudden death, QT 
prolongation and torsades increases. Substrate for 3A4
Ibutilide
known risk
Females>Males
Levofloxacin
known risk
Levomethadyl
known risk
No longer available in U.S.
Mesoridazine
known risk
Methadone
known risk
Females>Males. Substrate for 3A4
Moxifloxacin
known risk
Ondansetron
known risk


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Drug
QT risk*
Comment
Pentamidine
known risk
Females>Males
Pimozide
known risk
Females>Males. Substrate for 3A4
Probucol
known risk
No longer available in U.S.
Procainamide
known risk
Not available in the U.S. (oral)
Propofol
known risk
Quinidine
known risk
Females>Males. Substrate for 3A4
Sevoflurane
known risk
Sotalol
known risk
Females>Males
Sparfloxacin
known risk
No longer available in U.S
Sulpiride
known risk
Not available in the U.S.
Terfenadine
known risk
No longer available in U.S.; Substrate for 3A4
Thioridazine
known risk
Vandetanib
known risk
Classification according to https://crediblemeds.org/ - Dated July 2015
Table 14-5
List of QT prolonging drugs to be used with caution
Drug
QT risk*
Comment
Alfuzosin
possible risk
Amantadine
conditional risk
Amisulpride
conditional risk
Amitriptyline
conditional risk
Risk of TdP with overdosage; Substrate of CYP2C19
Apomorphine
possible risk
Aripiprazole
possible risk
Atazanavir
possible risk
Atomoxetine
possible risk
Bedaquiline
possible risk
Bortezomib
possible risk
Bosutinib
possible risk
Chloral hydrate
conditional risk
Ceritinib
possible risk
Clomipramine
possible risk
Clozapine
possible risk
Crizotinib
possible risk
Dabrafenib
possible risk
Dasatinib
possible risk
Degarelix
possible risk
Desipramine
possible risk
Risk of TdP with overdosage
Dexmedetomidine
possible risk
Dihydroartemisinin + 
piperaquine
possible risk
Diphenhydramine
conditional risk
Risk of QT increase/TdP in overdosages
Dolasetron
possible risk
Doxepin
conditional risk
Eribulin
possible risk
Famotidine
possible risk


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Drug
QT risk*
Comment
Felbamate
possible risk
Fingolimod
possible risk
Fluoxetine
conditional risk
Foscarnet
possible risk
Furosemide
conditional risk
Galantamine
conditional risk
Gatifloxacin
possible risk
No longer available in U.S.
Gemifloxacin
possible risk
Granisetron
possible risk
Hydrochlorothiazide
conditional risk
Hydroxychloroquine
conditional risk
Hyroxyzine
conditional risk
Iloperidone
possible risk
Imipramine
possible risk
Risk of TdP in overdosage
Indapamide
conditional risk
Isradipine
possible risk
Itraconazole
conditional risk
Drug metabolism inhibitor- Risk for drug interactions
Ivabradine
conditional risk
not available in the United States
Ketoconazole
conditional risk
Drug metabolism inhibitor
Lapatinib
possible risk
Leuprolide
possible risk
Lithium
possible risk
Metoclopramide
conditional risk
Metronidazole
conditional risk
Mifepristone
possible risk
Mirabegron
possible risk
Mirtazapine
possible risk
Moexipril/HCTZ
possible risk
Nelfinavir
conditional risk
Nicardipine
possible risk
Nilotinib
possible risk
Norfloxacin
possible risk
Nortriptyline
possible risk
Ofloxacin
possible risk
Olanzapine
possible risk
Oxytocin
possible risk
Paliperidone
possible risk
Panobinostat
possible risk
Pantoprazole
conditional risk
Paroxetine
conditional risk
Pasireotide
possible risk
Pazopanib
possible risk
Perflutren lipid 
microspheres
possible risk
Pipamperone
possible risk
not available in the United States


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Drug
QT risk*
Comment
Posaconazole
conditional risk
Promethazine
possible risk
Quetiapine
possible risk
Substrate for 3A4
Quinine sulfate
conditional risk
Ranolazine
possible risk
Rilpivirine
possible risk
Risperidone
possible risk
Ritonavir
conditional risk
Substrate for 3A4
Roxithromycin
possible risk
not available in the United States
Saquinavir
possible risk
Sertindole
possible risk
not available in the United States
Sertraline
conditional risk
Solifenacin
conditional risk
Sorafenib
possible risk
Sunitinib
possible risk
Tacrolimus
possible risk
Substrate for 3A4
Tamoxifen
possible risk
Telaprevir
conditional risk
Telavancin
possible risk
Telithromycin
possible risk
Substrate for 3A4
Tetrabenazine
possible risk
Tizanidine
possible risk
Tolterodine
possible risk
Toremifene
possible risk
Toresemide
conditional risk
Trazodone
conditional risk
Substrate for 3A4
Trimethoprim-Sulfa
conditional risk
Trimipramine
conditional risk
Tropisetron
possible risk
Vardenafil
possible risk
Substrate for 3A4
Vemurafenib
possible risk
Venlafaxine
possible risk
Voriconazole
possible risk
Vorinostat
possible risk
Ziprasidone
possible risk
Classification according to https://crediblemeds.org/ - Dated July 2015
14.1.4
BCRP inhibitors
As clinical BCRP inhibition has been investigated and/or formally shown only in selected 
cases in the past the table encompasses also drugs and molecular entities for which inhibition 
of BCRP was only shown in vitro. Please note that this is not an exhaustive list. This list only 
meant to be used as a guide.


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Table 14-6
BCRP inhibitors to be used with caution
Category
Drug Name
BCRP inhibitors –
DDI potential shown in vivo
Atazanavir, Cyclosporine, Eltrombopag, Gefitinib
BCRP inhibitors –
Inhibition shown in vitro
A number of different compound and chemical classes such as steroid(-like) 
compounds, antivirals, immunosuppressant, estrogen agonists and antagonists, 
diketopiperazines, (dihydro)pyridines, azoles (e.g. PPIs and anti-infectives), 
statins and P-gp inhibitors have shown the potential to inhibit BCRP in vitro.
Examples include: Afatinib, Abacavir, Amprenavir, Aripiprazole, Atorvastatin, 
Axitinib, Cerivastatin, Curcumin, Daunomycin, Delavirdine, Efavirenz, Elacridar, 
Erlotinib, Fluvastatin, Fumitremorgin C, Ivermectin, Lapatinib, Lansoprazole, 
Lopinavir, Nelfinavir, Nilotinib, Omeprazole, Pantoprazole, Pitavastatin, 
Regorafinib, Rosuvastatin, Saquinavir, Simvastatin, Sulfasalazine, Sunitinib, 
SN-38 (irinotecan), Tacrolimus, Teriflunomide


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14.2
Appendix 2: 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 3.1: 29-Nov-2011
Version 3:0: 19-Oct-2009
Version 2:0: 18-Jan-2007
Version 1:0: 13-Dec-2002
Release date:
29-Nov-2011
List of Contributors
Authors (Version 3.1):
 
 
Authors (Version 3):
 
Authors (Version 2):
 
Authors (Version 1):


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Glossary
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
DFS
Disease-free survival
eCRF
Electronic Case Report Form
FPFV
First patient first visit
GBM
Glioblastoma multiforme
MRI
Magnetic resonance imaging
LPLV
Last patient last visit
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable disease
SOD
Sum of Diameter
TTF
Time to treatment failure
TTP
Time to progression
UNK
Unknown


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14.2.1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This 
document is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the 
revised RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 14.2.2 and the definition of best response in 
Section 14.2.16 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.2.17 is summarizing the “time to 
event” variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 14.2.27
of this guideline describes data handling and programming rules. This section is to be referred 
to in the RAP (Reporting and Analysis Plan) to provide further details needed for 
programming.
14.2.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) 
European Journal of Cancer; 45:228-247.
14.2.3
Definitions
14.2.3.1 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 14.2.25.
Measurable lesions (both nodal and non-nodal)

Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.


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
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.
14.2.4
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the 
study in some situations (e.g. in Phase III studies where PFS is the primary endpoint). 
However, it is recommended that patients be excluded from trials where the main focus is on 
the Overall Response Rate (ORR). Guidance on how patients with just non-measurable 
disease at baseline will be evaluated for response and also handled in the statistical analyses is 
given in Section 14.2.25.
14.2.5
Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v) contrast.
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.


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
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 change in technique (e.g. from CT to 
MRI, or vice-versa), or a change in any other imaging modality. A change in methodology 
will result by default in a UNK overall lesion response assessment. However, another 
response assessment than the Novartis calculated UNK response may be accepted from the 
investigator or the central blinded reviewer if a definitive response assessment can be 
justified, based on the available information.

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 the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD.

If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT are needed to determine if there is truly progression occurring at 
that Site (if so, the date of PD will be the date of the initial abnormal CT scan).

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.

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. 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 


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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.

Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed).

Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
14.2.6
Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF 
(even if it resides in the same organ).
Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 14.2.3.1.

Nodal target: See Section 14.2.3.1.
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.


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
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.
14.2.7
Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 14-7) and non-target lesions (Table 14-8) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target 
and non-target lesions together (Table 14-9) as well as the presence or absence of new lesions.
14.2.8
Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for 
the evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate 
lesion evaluation data are examined by the investigator in order to derive the overall visit 
response. Therefore all such data applicable to a particular visit should be associated with the 
same assessment number.
14.2.9
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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14.2.10
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.
14.2.11
Determination of target lesion response
Table 14-7
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. Methodology change See Section 14.2.5.
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 three possibilities:


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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 CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 14-7 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.


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
The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications.

Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all 
non-nodal target lesions have disappeared.

Once a CR target lesion response has been assigned a CR will continue to be 
appropriate (in the absence of missing data) until progression of target lesions.

Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 
mm and there is at least 20% increase in sum of the diameters of all nodal target 
lesions relative to nadir with at least 5 mm increase in the absolute sum of the 
diameters.
14.2.12
Determination of non-target lesion response
Table 14-8
Response criteria for non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions. In addition, all lymph nodes assigned a 
non-target lesions must be non-pathological in size (< 10 mm short axis)
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.1
Non-CR/Non-PD:
Neither CR nor PD
Unknown (UNK)
Progression has not been documented and one or more non-target lesions have 
not been assessed or have been assessed using a different method than baseline.
1. Although a clear progression of non-target lesions only is exceptional, in such circumstances, the opinion of the 
treating physician does prevail and the progression status should be confirmed later on by the review panel (or 
study chair).
Notes on non-target lesion response

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 any of the lesions was not assessed (in which case response is UNK) 
or there is unequivocal progression of the non-target lesions (in which case response is 
PD).

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 


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one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 14.2.11 for assigning PD following a CR for the 
non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.
14.2.13
New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page.

If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion.

If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 14.2.14).

A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to 10 mm for the first time in the study plus 5 
mm absolute increase.
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 14.2.5.
14.2.14
Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target 
lesion response, non-target lesion response and presence of new lesions as shown below in
Table 14-9.
Table 14-9
Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overall
lesion response
CR
CR
No
CR1
CR
Non-CR/Non-PD3
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR1
SD
Non-PD and not UNK
No
SD1, 2
UNK
Non-PD or UNK
No
UNK1
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1. This overall lesion response also applies when there are no non-target lesions identified at baseline.
2. Once confirmed PR was achieved, all these assessments are considered PR.
3. As defined in Section 14.2.7.
If there are no baseline scans available at all, then the overall lesion response at each 
assessment should be considered Unknown (UNK).


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If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen.
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
14.2.15
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.2.25 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
14.2.16
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.
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


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
PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required

SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).

PD = progression 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).

UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks)
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

Novartis calculated overall lesion response (based on measurements from either 
Investigator)


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The primary analysis of the best overall response will be based on the sequence of 
investigator/ /calculated (investigator)/calculated (central) overall lesion responses.
Based on the patients’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications.
Disease control rate (DCR) is the proportion of patients with a best overall response of CR 
or PR or SD.
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).
14.2.17
Time to event variables
14.2.18
Progression-free survival
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint.
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.
14.2.19
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”).


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Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be 
censored at the date of last known date patient alive.
14.2.20
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.
14.2.21
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.
14.2.22
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 


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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.
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.
14.2.23
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 14.2.22. 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 
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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.
14.2.24
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.
Start dates
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date.
For the calculation of duration of response the following start date should be used:

Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page).

Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease.

Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used.

Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.2.25).
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.

Date of discontinuation is the date of the end of treatment visit.


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
Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date.

Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
14.2.25
Handling of patients with non-measurable disease only at baseline
It is possible that patients with only non-measurable disease present at baseline are entered 
into the study, either because of a protocol violation or by design (e.g. in Phase III studies 
with PFS as the primary endpoint). In such cases the handling of the response data requires 
special consideration with respect to inclusion in any analysis of endpoints based on the 
overall response evaluations.
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints.
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with measurable 
disease is derived slightly differently according to Table 14-10.
Table 14-10
Overall lesion response at each assessment: patients with non-target 
disease only
Non-target lesions
New Lesions
Overall lesion response
CR
No
CR
Non-CR/Non-PD1
No
Non-CR/non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
1 As defined in Section 14.2.7.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.
For ORR it is recommended that the main (ITT) analysis includes data from patients with 
only non-measurable disease at baseline, handling patients with a best response of CR as 
“responders” with respect to ORR and all other patients as “non-responders”.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses 


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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.
14.2.26
Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well as 
addresses the issues of missing tumor assessments during the study. For instance, if one or 
more assessment visits are missed prior to the progression event, to what date should the 
progression event be assigned? And should progression event be ignored if it occurred after a 
long period of a patient being lost to follow-up? It is important that the protocol and RAP 
specify the primary analysis in detail with respect to the definition of event and censoring 
dates and also include a description of one or more sensitivity analyses to be performed.
Based on definitions outlined in Section 14.2.24, 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 14-11
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) N/A
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
Ignored
Progressed
F
New anticancer therapy given
(1) Date of last adequate assessment
(2) Date of secondary anti-cancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censored
Censored
Event
Ignored
G
Deaths due to reason other than 
deterioration of ‘Study indication’
(1) Date of last adequate assessment
Censored 
(only TTP and 
duration of 
response)
1.=Definitions can be found in Section 14.2.24
2.=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 14.2.24.
3.=The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.


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Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without 
documented progression: By default, option (1) is used for situation E as 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), i.e. censoring at last adequate assessment may be 
used as a default in this case.
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for 
potential bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for 
censoring and events only at scheduled visit dates. The latter could be handled by replacing in 
Table 14-11 the “Date of last adequate assessment” by the “Date of previous scheduled 
assessment (from baseline)”, with the following definition:

Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment.
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on 
the individual requirements for the specific study and disease area and have to be specified in 
the protocol or RAP documentation.
14.2.27
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).


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14.2.28
Study/project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation.
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock).
14.2.29
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

Protocol deviation

Technical problems

Subject/guardian decision

Death

Progressive disease

Study terminated by the sponsor

Non-compliant with study treatment

No longer requires treatment

Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given)
14.2.30
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

Protocol deviation


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
Technical problems

Subject/guardian decision

Death

New therapy for study indication

Progressive disease

Study terminated by the sponsor
14.2.31
Medical validation of programmed overall lesion response
As RECIST 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), these UNK 
assessments may be re-evaluated by clinicians at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on 
RECIST criteria. This may be queried for clarification. However, the investigator or central 
reader’s response assessment will never be overruled.
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion 
response at that specific assessment is to be kept in a dataset. This must be clearly 
documented in the RAP documentation and agreed before database lock. This dataset should 
be created and stored as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
14.2.32
Programming rules
The following should be used for programming of efficacy results:
14.2.33
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.
14.2.34
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 


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assessment date is calculated as outlined in Section 14.2.24). If all measurement dates have no 
day recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
14.2.35
Incomplete dates for last known date patient alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
14.2.36
Non-target lesion response
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’.
14.2.37
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
14.2.38
Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page.
For survival the following censoring reasons are possible:

Alive

Lost to follow-up
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:

Ongoing without event

Lost to follow-up

Withdrew consent

Adequate assessment no longer available*

Event documented after two or more missing tumor assessments (optional, see Table 14-
11)

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 14.2.24. 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 


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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.
14.2.39
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
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16


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14.3
Appendix 3: Guidelines on Calculating PEPI Score
The total PEPI score assigned to each patient is the sum of the risk points derived from the pT 
stage, pN stage, Ki67 level, and ER status of the surgical specimen. The total risk point score 
for each patient is the sum of all the risk points accumulated from the four factors in the 
model (please see Table 14-12).
Table 14-12
The preoperative endocrine prognostic index (PEPI) score
Pathology, biomarker
Status
RFS Points
Pathological tumor size
T1/2
0
T3/4
3
Node status
Negative
0
Positive
3
Ki67 level
0% – 2.7% (0 – 1† )
0
>2.7% – 7.3% (1 – 2 † )
1
>7.3% – 19.7% (2 – 3 † )
1
>19.7% – 53.1% (3 – 4 † )
2
>53.1% (>4 † )
3
ER status, Allred score
0 – 2
3
3 – 8
0
† The natural logarithm interval corresponding to the percent Ki67 
values on the original percentage scale.
(Ellis 2008)


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14.4
Appendix 4: Patient Self-Reported Mood Questionnaires
14.4.1
Scoring the PHQ-9 and GAD-7
14.4.1.1 Calculating the Total Score for the PHQ-9
Total scores from the PHQ-9 will be calculated to assess depression severity according to the 
developer’s guidelines [Instruction Manual: Instructions for PHQ and GAD-7 Measures. 
Accessed on 2010 Sept 9 from: //phqscreeners.com]. This is calculated by assigning scores of 
0, 1, 2, and 3, to the response categories of “not at all,” “several days,” “more than half the 
days,” and “nearly every day,” respectively. PHQ-9 total score for the nine items ranges from 
0 to 27.
PHQ-9 Scoring Example:
In the example below, the Total Score for the PHQ-9 depression severity is 8, where the score 
is the sum of four items scored “0” (questions: #3, 7, 8, 9), three items scored “1” (questions: 
#1, 4, 6), one item scored “2” (question: #2), and one item scored “3” (question: #5).


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14.4.1.2 Calculating the Total Score for the GAD-7
Similar to the PHQ-9, scores for the GAD-7 will calculated to assess anxiety severity 
according to the developer’s guidelines [1]. This is calculated by assigning scores of 0, 1, 2, 
and 3, to the response categories of “not at all,” “several days,” “more than half the days,” and 
“nearly every day,” respectively. A total score for the GAD-7 can range from 0 to 21.
GAD-7 Scoring Example:
In the example below, the Total Score for the GAD-7 anxiety severity is 9, where the score is 
the sum of two items scored “0” (questions: #6, 7), two items scored “1” (questions: #2, 3), 
two items scored “2” (questions: #1, 5), and one item scored “3” (question: #4).


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14.5
Appendix 5: Guidelines for the treatment of study drug 
combination induced diarrhea
Mild to moderate diarrhea has been reported within the ongoing studies of single-agent 
BYL719 and buparlisib. In order to effectively manage diarrhea and mitigate the escalation in 
severity or duration of diarrhea, patient education as well as proper management of diarrhea is 
mandatory. The following section outlines the recommended algorithm for management and 
treatment of BYL719 and buparlisib-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 14-13).
Table 14-13
NCI CTCAE version 4.03 grading of diarrhea for patients without 
colostomy
Toxicity
0
1
2
3
4
Diarrhea
None
Increase of < 4 
stools per day 
over baseline
Increase of 4-6 
stools per day 
over baseline
Increase of 7 stools per 
day over baseline; 
incontinence; 
hospitalization indicated; 
limiting self-care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Diarrhea is defined as: A disorder characterized by frequent and watery bowel movements.
First report of diarrhea

Obtain history of onset and duration of diarrhea

Description of number of stools and stool composition (e.g. watery, blood, mucus in stool)

Assess patient for fever, abdominal pain, cramps, distension, bloating, nausea, vomiting, 
dizziness, weakness (i.e., rule out risk for sepsis, bowel obstruction, dehydration)


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Protocol No. CBYL719A2201

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 eCRF.
Loperamide is the first-line treatment of diarrhea (any Grade) in this recommended algorithm. 
Persistent symptoms may require the administration of high dose loperamide followed by 
treatment with second-line agents such as opium tincture and octreotide acetate, based on 
severity and duration of diarrhea and related signs/symptoms. Another first-line treatment for 
diarrhea is diphenoxylate hydrochloride/atropine sulfate. This medication may be used in 
place of loperamide however it is important to note that loperamide and diphenoxylate 
hydrochloride/atropine sulfate must not be used in conjunction with one another due to the 
risk of developing paralytic ileus. Upon treatment with any antidiarrheal agents, the patient’s 
response to treatment should be observed and appropriately documented in the source 
document and eCRF.


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Protocol No. CBYL719A2201
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). 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

SAP_000.pdf: 
Clinical Development
BYL719/alpelisib
BYL719A2201 / NCT01923168
A phase II randomized, double-blind placebo controlled, 
study of letrozole with or without BYL719 or buparlisib, for 
the neoadjuvant treatment of postmenopausal women with 
hormone receptor-positive HER2-negative breast cancer
Statistical Analysis Plan (SAP) Amendment 1
Author:
Document type:
SAP Documentation
Document status:
Final
Release date:
7-Feb-2017
Number of pages:
72
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
Version
Date
Changes
Initial 
version 
- Final
10-
Jun-
2014
N/A – Initial approved version
Amend
ment 1 -
Final
7-Feb-
2017
Summary of changes: alignment with protocol amendments #2 to #7, new
Novartis SAP template language, new Novartis guidelines for safety 
analyses, new Oncology Standard Outputs v3.0 for safety, new Novartis 
guideline for biomarkers analysis.
Major changes were the following ones:
Section 1 Introduction: mentioned that content of the SAP was based on 
protocol CBYL719A2201 Amendment 7 and that all decisions regarding 
final analysis, as defined in the SAP document, were made prior to 
database lock and unblinding of the study data, as per the new SAP 
template.
Section 2 Study objectives and study design: updated to align with 
protocol amendments #2 and #5, especially: 
-
Updated details on study design, randomization and number of 
patients enrolled due to the permanent stop of the accrual in the 
buparlisib/buparlisib-placebo treatment arms;
-
Mentioned new dosing schedule of buparlisib;
-
Changed ORR from secondary to primary endpoint; changed the 
assessment of the anti-tumor activity of buparlisib into an 
exploratory objective;
-
Removed central review for pathological response.
-
Mentioned the safety review done by an internal DMC
Section 3.1 Definitions: deleted the possibility to analyze one cohort 
earlier as per protocol amendment #5; added definitions of windows for 
multiple assessments and last contact date.
Section 3.2 Analysis sets: 
-
Removed pre-screened patients set and clarified screened patients 
set (correction based on information collected in the CRF); 
-
Updated definitions of Safety set and actual treatment received as 
per protocol amendment #5 and new safety guidance; 
-
Revised per-protocol set based on updated Protocol deviations 
defined for the study; 
-
Corrected definition of alpelisib and buparlisib PAS; 
-
Updated buparlisib FPAS as per protocol amendment #2 and all 
the FPASs as per protocol amendment #5; 


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Version
Date
Changes
-
Mentioned that all listings were to be produced by cohort and 
treatment groups; 
-
Added management of data collected after withdrawal of
informed consent.
Section 3.3 Implementation of RECIST criteria: mentioned that BOR was 
to be determined without restriction to on-treatment assessments; 
clarified that applicable new antineoplastic therapies were medications 
and radiotherapies.
Section 3.4 Patient disposition: corrected information summarized as per 
the data collected in the eCRF page.
Section 3.5 Analysis sets: added display by stratum as per new OSO.
Section 3.7 Background and demographic characteristics: added
summaries of age groups by sex, and race in the safety set as per new 
OSO; added information for description of stratification factors; added
relevant variables for diagnosis and extent of cancer; deleted summary 
tables for antineoplastic therapies since discontinuation of study 
treatment
Section 3.8 Study treatment: added definitions of last date of exposure, 
planned cumulative dose and average daily dose; revised categories for 
exposure and cumulative dose for buparlisib intermittent regimen; 
clarified definition of dose reductions for some specific situations; 
deleted cumulative exposure.
Section 3.9 Prior and concomitant medications: clarified the period 
considered for summaries; added listing of concomitant medications.
Section 3.10 Primary objective: 
-
As per protocol amendment #5, updated primary objectives and 
endpoints details for ORR, added details for PoC on ORR and
updated statistical analysis details to remove buparlisib from the 
PoC assessment.
-
Mentioned that 80% and 95% credible intervals and a plot were 
to be provided for bayesian posterior difference between 
treatment groups.
-
Added 80% and 95% confidence intervals on observed difference 
between treatment groups using Chan and Zhang (1999) exact 
method, and 95% confidence intervals by treatment arm based on 
Clopper-Pearson (1934).
-
Defined handling of missing values/censoring/discontinuations
for ORR as per protocol amendment #5.
-
Removed sensitivity analysis based on central assessment of pCR 
as per protocol amendment #5.


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Version
Date
Changes
Section 3.11 Secondary objectives: updated the objectives and removed
ORR which was now a primary endpoint as per protocol amendment #5;
added 95% confidence intervals for breast conserving surgery, and a 
summary on the overall population for PEPI results; added summary 
tables and a plot for KI67; removed analysis in the overall population for 
the breast conserving surgery.
Section 3.12 Exploratory efficacy objectives: added similar exploratory 
analysis on ORR as done on pCR; added 80% and 95% confidence 
intervals on the observed difference versus placebo and 95% confidence 
intervals by treatment arm; added exploratory analysis on the efficacy of 
buparlisib based on the description of pCR and ORR; removed
exploratory analysis using a different definition of pCR assessed centrally 
as per protocol amendment #5.
Sections 3.13 to 3.16 on safety assessment: 
-
Changes throughout those sections to align with new guidance for 
safety evaluations and new OSO recommendations, including
addition of summary tables for overview of AEs, disclosure to 
CT.gov/EudraCT, all deaths, on-treatment deaths and SAEs with 
fatal outcome; reviewed the strategy to display AEs tables by 
SOC and/or PT, by All Grades and Grades ≥ 3 or with full detail 
by maximum grade as per new OSO; updated notable criteria for
ECG and vital signs; 
-
Added details on AESI definition, CRS analysis as per new safety 
guidance.
-
Added some summary tables for AEs by cohort.
-
Added the possibility to analyze time to first occurrence of any 
CTC grade ≥ 2 AESI for alpelisib.
-
Added display of trends over time for HbA1c, fasting glucose and 
fasting C-peptide, and a plot of hepatic function tests and listings 
for new liver event CRF pages.
-
Deleted shift table of overall interpretation for cardiac imaging 
and replaced by summary of LVEF based on CTC grade as per 
new OSO.
Section 3.17 Mood assessments: mentioned analysis of compliance to 
questionnaire completion.
Section 3.20 Subgroup analysis: added relevant subgroups for efficacy
Section 3.21: Pharmacokinetic analysis: added T1/2, eff for buparlisib as 
per protocol amendment #2; added trough concentration analysis; defined
primary PK parameters
Section 3.22 Biomarkers: added relevant details and definitions as per the 
new guidance on biomarker analysis; clarified objectives applicable to 


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Version
Date
Changes
this SAP as biomarkers available before the database lock; mentioned
possible analysis of pCR and ORR by categorical biomarkers; added TILs 
biomarker analysis; updated details for IHC as per the database.
Section 4 Sample size calculation: new section as per new SAP template 
and update sample size details as per protocol amendment #5.
Section 5 Change to protocol specified analyses: new section as per new 
SAP template
Section 6 Appendix: new section as per new SAP template in order to 
provide details on imputations rules, AE coding/grading, laboratory 
parameters derivations and statistical models
Section 7 References: added Chan and Zhang (1999) to the reference list.
Minor clarifications and corrections, illustration with key examples, were 
also made throughout the document.


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Table of contents
Table of contents .................................................................................................................6
List of tables ........................................................................................................................8
List of figures ......................................................................................................................9
1
Introduction .......................................................................................................................12
2
Study objectives and study design.....................................................................................12
2.1
Primary objective...................................................................................................12
2.1.1
Endpoints for primary objective............................................................12
2.2
Secondary objectives .............................................................................................13
2.2.1
Endpoints for secondary objectives ......................................................13
2.3
Exploratory objectives...........................................................................................14
2.3.1
Endpoints for exploratory objectives ....................................................14
2.4
Study design...........................................................................................................15
3
Statistical methods.............................................................................................................21
3.1
Definitions .............................................................................................................21
3.1.1
Study drug and study treatment.............................................................21
3.1.2
Date of first administration of study drug.............................................21
3.1.3
Date of last administration of study drug..............................................21
3.1.4
Date of first administration of study treatment .....................................21
3.1.5
Date of last administration of study treatment ......................................21
3.1.6
Study day...............................................................................................22
3.1.7
Baseline.................................................................................................22
3.1.8
On-treatment assessment/event.............................................................23
3.1.9
Screening failure ...................................................................................24
3.1.10
Time unit...............................................................................................24
3.1.11
Data included in analyses......................................................................24
3.2
Analysis sets ..........................................................................................................26
3.2.1
Screened patients...................................................................................26
3.2.2
Full analysis set.....................................................................................26
3.2.3
Safety set ...............................................................................................26
3.2.4
Per-protocol set .....................................................................................26
3.2.5
Pharmacokinetic analysis set.................................................................27
3.2.6
Patient classification..............................................................................29
3.3
Implementation of RECIST criteria.......................................................................30
3.3.1
Tumor assessment .................................................................................30
3.3.2
Response and progression evaluation ...................................................31


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3.4
Patient disposition..................................................................................................33
3.5
Protocol deviations ................................................................................................33
3.6
Analysis sets ..........................................................................................................34
3.7
Background and demographic characteristics .......................................................34
3.7.1
Basic demographic and background data..............................................34
3.7.2
Baseline stratification factors................................................................34
3.7.3
Diagnosis and extent of cancer .............................................................34
3.7.4
Medical history......................................................................................35
3.7.5
Antineoplastic therapy ..........................................................................35
3.8
Study treatment......................................................................................................35
3.8.1
Duration of exposure to study drug.......................................................36
3.8.2
Duration of exposure to study treatment...............................................36
3.8.3
Cumulative and average daily dose.......................................................37
3.8.4
Dose intensity and relative dose intensity.............................................38
3.8.5
Dose reduction, interruption and permanent discontinuation ...............39
3.9
Prior and concomitant medication.........................................................................43
3.10
Primary objective...................................................................................................44
3.10.1
Statistical hypothesis, model, and method of analysis..........................44
3.10.2
Sensitivity and other supportive analyses of the primary endpoints.....46
3.10.3
Handling of missing values/censoring/discontinuations.......................47
3.11
Secondary efficacy objectives ...............................................................................47
3.11.1
Breast conserving surgery (BCS) rate...................................................48
3.11.2
Preoperative endocrine prognostic index (PEPI) score.........................48
3.11.3
Ki67.......................................................................................................49
3.12
Exploratory efficacy objectives .............................................................................49
3.13
Safety evaluation ...................................................................................................49
3.13.1
Adverse events ......................................................................................50
3.13.2
Dictionary coding of adverse events.....................................................50
3.13.3
Grading of adverse events.....................................................................50
3.13.4
General rules for AE reporting..............................................................50
3.13.5
Adverse events summaries....................................................................51
3.13.6
Adverse events of special interest.........................................................52
3.14
Laboratory data......................................................................................................55
3.14.1
Grading of laboratory data ....................................................................55
3.14.2
Laboratory data summary .....................................................................55
3.15
Vital signs ..............................................................................................................56


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3.16
Cardiac assessments...............................................................................................57
3.16.1
Electrocardiogram (ECG) parameters...................................................57
3.16.2
Cardiac imaging (MUGA / ECHO) ......................................................58
3.17
Mood assessments .................................................................................................58
3.18
ECOG performance status .....................................................................................59
3.19
Other safety data....................................................................................................59
3.20
Subgroup analyses .................................................................................................59
3.20.1
Efficacy .................................................................................................59
3.21
Pharmacokinetic analysis.......................................................................................60
3.21.1
Pharmacokinetic analysis......................................................................60
3.21.2
Data handling principles .......................................................................62
3.22
Biomarkers.............................................................................................................62
3.22.1
Outline of data analysis.........................................................................62
3.22.2
Exploratory biomarker objectives.........................................................63
3.22.3
Biomarker analysis set ..........................................................................63
3.22.4
General data handling and preprocessing .............................................64
3.22.5
Immunohistochemistry (IHC) biomarker data......................................64
3.22.6
Somatic or Germline biomarker data ....................................................65
3.22.7
Other biomarker assays.........................................................................66
4
Sample size calculation .....................................................................................................66
5
Change to protocol specified analyses ..............................................................................67
6
Appendix ...........................................................................................................................67
6.1
Imputation rules.....................................................................................................67
6.1.1
Study drug .............................................................................................67
6.1.2
AE, ConMeds and safety assessment date imputation..........................68
6.2
AEs coding/grading ...............................................................................................70
6.3
Laboratory parameters derivations ........................................................................70
6.4
Statistical models...................................................................................................71
7
References .........................................................................................................................71
List of tables
Table 3-1
Patient classification based on protocol deviations...............................29
Table 3-2
Definition of last date of exposure of study drug..................................36
Table 3-3
Examples of dose reductions for alpelisib/placebo...............................40


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Table 3-4
Examples of dose reductions for buparlisib/Placebo ............................41
Table 3-5
The preoperative endocrine prognostic index (PEPI) score..................48
Table 3-6
AESI for alpelisib..................................................................................53
Table 3-7
AESI for buparlisib ...............................................................................53
Table 3-8
Notable criteria for vital signs...............................................................57
Table 3-9
Notable criteria for ECG values............................................................57
Table 3-10
Classification of severity based on depression and/or anxiety 
questionnaire scores ..............................................................................59
Table 3-11
ECOG Performance status ....................................................................59
Table 3-12
PK parameters .......................................................................................61
Table 3-13
Biomarker summary table.....................................................................63
Table 6-1
Imputation of start dates (AE, CM) and assessments (LB, EG, VS) ....68
Table 6-2
Imputation of end dates (AE, CM)........................................................69
List of figures
Figure 2-1
Assumptions for end of recruitment after protocol amendment 5 ........16
Figure 2-2
Study design until clinical study protocol amendment 4 ......................18
Figure 2-3
Study design from clinical study protocol amendment 5......................19


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List of abbreviations
AE
Adverse event
AESI
Adverse event of specific interest
ATC
Anatomical Therapeutic Chemical
BCS
Breast Conserving Surgery
BOR
Best overall response
bpm
beats per minute
C.I.
Confidence Interval
CR
Complete response
CRF
Case Report Form
CSP
Clinical study protocol
CSR
Clinical study report
CT
Computed tomography
CTC 
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
DAR
Dosage administration record
DCR
Disease control rate
DI
Dose Intensity
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case report/record form
EOT
End of treatment
FAS
Full analysis set
GPS
Global Programming & Statistical environment
IHC
Immunohistochemistry
ITT
Intent To Treat
IVR/IRT
Interactive Voice Response/ Interactive Response Technology
LSH
Life Sciences Hub
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MRI 
Magnetic resonance imaging
NSCLC
Non-small cell lung cancer
NMQ
Novartis MedDRA queries
ORR 
Overall response rate 
PAS
Pharmacokinetic analysis set
pCR
Pathological Complete Response
PD
Progressive disease
PDs
Protocol Deviations
PDI
Planned dose intensity
PIK3CA
PIK3CA Gene which encodes the p110alpha catalytic subunit
PK
Pharmacokinetic
PoC
Proof of Concept
PPS
Per Protocol Set
PR
Partial response
PS
Performance status
PT
Preferred term


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QD/od
once a day
RAP
Report and Analysis Process
RDI
Relative dose intensity
RECIST
Response Evaluation Criteria In Solid Tumors
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
Stable disease
sd
Standard deviation
SDTM
Study Data Tabulation Model
SEC
Safety Event Categories
SLD
Sum of the longest diameter
SMQ
Standardized MedDRA queries
SOC
System organ class
TA
Tumor assessment
TEAE
Treatment-emergent adverse event
TFLs
Tables, Figures, Listings
ULN
Upper limit of normal
UNK
Unknown
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary


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1
Introduction
This Statistical Analysis Plan (SAP) describes all planned analysis for the Clinical Study Report 
(CSR) of study CBYL719A2201 study using Novartis Clinical Data Standards in Oncology 
Clinical Development.
The content of this SAP is based on protocol CBYL719A2201 Amendment 7 version dated 18 
October 2016. All decisions regarding final analysis, as defined in the SAP document, have 
been made prior to database lock for the primary analysis and unblinding of the study data.
CBYL719A2201 is a multicenter phase II randomized, double-blind placebo controlled study
of letrozole with or without alpelisib or buparlisib, for the neoadjuvant treatment of 
postmenopausal women with hormone receptor (HR)-positive HER2-negative breast cancer.
Standards for assessment of response based on RECIST 1.1 are not described in this document. 
They are provided in the Novartis guidance document guidelines for response assessment, 
which is included as an appendix of the Clinical Study Protocol (CSP).
The shells for the tables, figures and listings used for the Clinical Study Report will be inthe 
TFLs document. Programming specifications will be given in the Programming Dataset 
Specifications.
All data will be analyzed by Novartis. It is planned that the data from all the centers that 
participate in this protocol will be pooled. Analysis data sets and statistical outputs will be 
produced using the SAS system Version 9.2 or higher (UNIX environment), or in R v2.13.2 (or 
higher) in the global programming & statistical environment (GPS). Outputs will be stored in 
GPS under CBYL719A/CBYL719A2201 folder.  
2
Study objectives and study design
2.1
Primary objective
The primary objective is:
To assess the anti-tumor activity of alpelisib QD plus letrozole versus letrozole alone in 
increasing the pathologic complete response (pCR) rate during neo-adjuvant treatment among 
postmenopausal patients with HR-positive, HER2-negative breast cancer for each of the two 
cohorts: i) PIK3CA mutated and ii) PIK3CA wild-type tumors based on tumor tissue.
and
To assess the anti-tumor activity of alpelisib QD plus letrozole versus letrozole alone in 
increasing the objective Response Rate (ORR) during neo-adjuvant treatment among 
postmenopausal patients with HR+, HER2-negative breast cancer for each of the two cohorts: 
i) PIK3CA mutated and ii) PIK3CA wild tumor types based on tumor tissue.
The primary objective of the study will be considered met if either one or both of these two 
objectives are met in any cohort.
2.1.1
Endpoints for primary objective
The primary efficacy endpoints are:


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pCR rate per investigator assessment is defined as percentage of patients with an absence of 
any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast 
specimen and all sampled ipsilateral lymph nodes (ypT0/Tis ypN0) following 24 weeks of 
treatment.
and 
ORR is defined as the percentage of patients with a Best Overall Response (BOR) of Complete 
Response (CR) or Partial Response (PR) based on local investigator’s assessment according to 
RECIST 1.1.
2.2
Secondary objectives

To assess the anti-tumor activity of alpelisib QD plus letrozole versus letrozole alone in 
increasing the pCR rate and ORR for each of the two cohorts: i) PIK3CA mutated and ii) 
PIK3CA wild tumor types, based on ctDNA. (1)To evaluate the safety and tolerability of 
the combinations.

To estimate the rate of breast conserving surgery for each of the two cohorts, namely i) 
PIK3CA mutated and ii) PIK3CA wild-type based on tumor tissue.

To evaluate the association between changes in Ki67 from baseline to day 15, and from 
baseline to surgery, with pCR for each of the two cohorts, namely i) PIK3CA mutated and 
ii) PIK3CA wild-type based on tumor tissue.

To assess centrally the Preoperative Endocrine Prognostic Index (PEPI) score for each of 
the two cohorts, namely, i) PIK3CA mutated and ii) PIK3CA wild-type based on tumor 
tissue.

To characterize the pharmacokinetics (PK) of alpelisib/buparlisib and letrozole when given 
in combination
(1) Not covered in this CSR SAP as it is foreseen that ctDNA will not be available before the 
database lock.
2.2.1
Endpoints for secondary objectives

pCR rate per investigator assessment and ORR per investigator assessment and according 
to RECIST v1.1 in PIK3CA mutated and PIK3CA wild tumor types, based on ctDNA.

Frequency and severity of AEs, laboratory abnormalities

Rate of breast conserving surgery defined by the percentage of patients with no mastectomy 
following completion of 24 weeks of treatment

Correlation between pCR and change in Ki67 from baseline to day 15 and from baseline to 
surgery

PEPI response is defined as percentage of patients with central PEPI score of 0 at the surgery

Plasma concentration-time profiles of alpelisib and buparlisib as well as appropriate 
individual PK parameters (e.g. AUCtau, Cmax, Tmax and other PK parameters if deemed 
appropriate)

Plasma concentration-time profiles of letrozole and appropriate individual PK parameters
(e.g. AUCtau, Cmax, Tmax and other PK parameters if deemed appropriate)


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2.3
Exploratory objectives

To assess the anti-tumor activity of buparlisib (QD continuous or QD 5 days on/2 days off) 
plus letrozole versus letrozole alone in increasing the pCR rate during neo-adjuvant 
treatment among postmenopausal patients with HR+, HER2-negative breast cancer for each 
of the two cohorts: i) PIK3CA mutated and ii) PIK3CA wild tumor types based on tumor 
tissue and ctDNA.
and
To assess the anti-tumor activity of buparlisib (QD continuous or QD 5 days on/2 days off) 
plus letrozole versus letrozole alone in increasing the objective response rate during neo-
adjuvant treatment among postmenopausal patients with HR+, HER2-negative breast 
cancer for each of the two cohorts: i) PIK3CA mutated and ii) PIK3CA wild tumor types 
based on tumor tissue and ctDNA.

To assess the anti-tumor activity of alpelisib QD plus letrozole and buparlisib (QD or QD 5 
days on/2 days off) plus letrozole versus letrozole alone in increasing pCR rate during neo-
adjuvant treatment among postmenopausal patients with HR-positive, HER2-negative 
breast cancer regardless of PIK3CA mutational status (overall patient population)

To assess the anti-tumor activity of a PI3K inhibitor when added to letrozole (alpelisib QD 
plus letrozole and buparlisib QD or QD 5 days on/2 days off) plus letrozole - both arms 
pooled together) versus letrozole alone in increasing the pCR rate during neo-adjuvant 
treatment among postmenopausal patients with HR-positive, HER2-negative breast cancer 
for the overall patient population (regardless of PIK3CA mutational status)

To explore the change in cell proliferation and cell death in the context of letrozole treatment 
alone versus letrozole treatment in combination with alpelisib or buparlisib
2.3.1
Endpoints for exploratory objectives

pCR per investigator assessment following 24 weeks of treatment and ORR per investigator 
assessment according to RECIST v1.1.

 

Ki67 and other markers of cell death 
 

 


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2.4
Study design
This is a multicenter phase II randomized, double-blind placebo controlled, study comparing 
safety and efficacy of letrozole to letrozole with alpelisib or with buparlisib, for the 
neoadjuvant treatment of postmenopausal women with HR-positive HER2-negative breast 
cancer.
Patients will be assigned to one of the two cohorts (i.e. PIK3CA mutated and PIK3CA wild-
type).
Until protocol amendment 5, patients were randomized to one of the following treatment arms
in a 1:1:1 ratio within each cohort of PIK3CA mutated and PIK3CA wild-type patients:

Alpelisib + letrozole

Buparlisib + letrozole

Placebo + letrozole: within the placebo+letrozole arm, half the patients received
matching alpelisib or buparlisib placebo.
From protocol amendment 5 following the termination of enrollment in buparlisib/buparlisib 
placebo arms, newly randomized patients were randomized to one of the following treatment 
arms in a 1:1 ratio within each cohort of PIK3CA mutated and PIK3CA wild-type patients:

Alpelisib + letrozole

Placebo + letrozole: where all patients received matching alpelisib placebo.
Overall approximately 320 patients will be randomized in the study so that 60 patients would 
be randomized to alpelisib and placebo within each cohort. This is based on status at the time 
of the stop of the enrollment to buparlisib/buparlisib placebo, and assuming a 2:1 ratio for 
number of patients randomized to alpelisib : alpelisib placebo and to buparlisib : buparlisib 
placebo: see Figure 2-1.


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Figure 2-1
Assumptions for end of recruitment after protocol amendment 5
Note: Number of patients randomized by cohort and by blinded treatment group 
alpelisib/alpelisib placebo or buparlisib/buparlisib placebo are known, whereas numbers of 
patients randomized to alpelisib / buparlisib / alpelisib placebo or buparlisib placebo are 
assumptions.
Within each cohort, randomization will be stratified according to Ki67% (<14% vs. ≥14%, as 
measured by Novartis designated central lab) and lymph node status (positive or negative).
Note: It was discovered in the course of the study that the stratification was not performed 
within each cohort as planned, but on the overall population. This issue has been corrected when 
the randomization scheme was modified to remove buparlisib/buparlisib placebo arms 
following protocol amendment 5. 
pCR and ORR per RECIST1.1, as assessed by local investigator’s review are the primary 
endpoints in this study.
The primary analysis will be performed after all patients in each cohort (i.e. PIK3CA mutated 
and PIK3CA wild-type) have completed 24 weeks of treatment and have pCR evaluation 
available or have discontinued study treatment due to any reason. 
No formal interim efficacy analysis is planned in this study. An internal DMC will monitor 
safety data by blinded treatment group, or semi-blinded upon their request, every 6 months 
during the conduct of the trial since protocol amendment 5.


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A sample from the diagnostic biopsy (slides or core) will be required for all patients for 
assessment of the PIK3CA status prior to randomization in order to evaluate the effect of the 
letrozole+alpelisib and letrozole+buparlisib vs. letrozole+placebo according to PIK3CA 
mutation status.
Study treatment should be started as soon as possible and no later than 3 days after the 
randomization of the patient.


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Figure 2-2
Study design until clinical study protocol amendment 4


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Figure 2-3
Study design from clinical study protocol amendment 5
Patients received buparlisib 100 mg QD dose or matching placebo, given once daily 
continuously starting from Cycle 1 Day 1 until protocol amendment 2 which introduced 100 
mg 5 days on / 2 days off as a starting dose; or alpelisib 300 mg QD or matching placebo given 
once daily continuously starting from Cycle 1 Day 1. In addition, letrozole 2.5 mg QD was
administered continuously starting at Cycle 1 Day 1.
A core biopsy (14 to 16 gauge recommended) will be performed in all patients at the end of 
second week of treatment to assess Ki67 status and additional biomarkers as described in 
Section 7.2.4 of the study protocol.


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Patients will be treated for a maximum of 24 weeks or until surgery, or progression, or 
unacceptable toxicity or discontinuation from the study treatment for any other reason.
Tumor evaluations will be performed at baseline, at cycle 4 day 1 (with a window of +/ - 7 days) 
and at maximum of 7 days before surgery. Disease progression should always be documented 
radiologically, if needed adding earlier than planned time point for tumor evaluation.
Patients who discontinue letrozole without progression (e.g. because of toxicity attributed to 
letrozole or at the discretion of the investigator) will be allowed to continue alpelisib/alpelisib 
placebo or buparlisib/buparlisib placebo until treatment is completed or until surgery or
discontinued due to progression or unacceptable toxicity and vice versa. Patients will be 
followed up for safety to 30 days post treatment. End of study is defined when the treatment 
phase and safety follow up is completed for all patients. No follow up other than safety follow 
up for 30 days after treatment discontinuation will be done.
After patients have completed 24 weeks of therapy, surgery will be performed as early as 
possible but not more than 14 days after the last dose of study treatment. In the case that surgery 
is not immediately performed after the last dose of alpelisib/placebo or buparlisib/buparlisib 
placebo, letrozole will be continued until the day of surgery. Surgery is not considered as a 
study assessment.
Adjuvant treatment after surgery (endocrine therapy, chemotherapy or radiotherapy) is left to 
the judgment of the investigator and is outside the scope of this study.
Surgical specimen will be assessed for Ki67 and molecular alterations as described in Section 
7.2.4 of the study protocol.
.


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3
Statistical methods
3.1
Definitions
3.1.1
Study drug and study treatment
Study treatment refers to alpelisib + letrozole, alpelisib matching placebo + letrozole,
buparlisib + letrozole and buparlisib matching placebo + letrozole
Study drug can refer to alpelisib/alpelisib matching placebo and buparlisib/buparlisib matching 
placebo or letrozole. Study drug may also be referred to as components of study treatment.
Alpelisib matching placebo or buparlisib matching placebo will be referred to as “placebo” in 
the remainder of this document.
3.1.2
Date of first administration of study drug
The date of first administration of study drug is derived as the first date when a non-zero dose
of study drug (alpelisib/buparlisib/placebo or letrozole) is administered as per the Dosage 
Administration Case Report Form (CRF). For the sake of simplicity, the date of first 
administration of study drug is referred to as start date of study drug. Start date of study drug 
is defined for each drug which is part of study treatment.
The date of first administration for alpelisib/buparlisib/placebo and letrozole is recorded on the 
corresponding “Dosage Administration Record” (DAR) eCRF page.
3.1.3
Date of last administration of study drug
The date of last administration of study drug is defined as the last date when a non-zero dose of 
study drug is administered. This date will also be referred to as last date of study drug. Last 
date of study drug is defined for each drug which is part of study treatment.
The date of last administration for alpelisib/buparlisib/placebo and letrozole is recorded on the 
corresponding “DAR” eCRF page.
3.1.4
Date of first administration of study treatment
The date of first administration of study treatment is derived as the first date when a non-zero 
dose of any component of the study treatment (alpelisib /buparlisib/placebo or letrozole) is 
administered as per the Dosage Administration (e)CRF. For the sake of simplicity, the date of 
first administration of study treatment will also be referred to as start date of study treatment.
For example: if the 1st dose of alpelisib/placebo is taken on the 15MAR2014, and the 1st dose 
of letrozole is taken on the 14MAR2014, then the date of first administration of study treatment 
is 14MAR2014.
3.1.5
Date of last administration of study treatment
The date of last administration of study treatment is derived as the last date when a non -zero 
dose of any component of study treatment (alpelisib/buparlisib/placebo or letrozole) is 
administered as per Dose Administration (e)CRF. For the sake of simplicity, the date of last 
administration of study treatment will also be referred as the last date of study treatment.


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For example: if the last dose of alpelisib/placebo is taken on the 30NOV2014, and the last dose 
of letrozole is taken on the 05DEC2014, then the date of last administration of study treatment 
is on 05DEC2014.
3.1.6
Study day
The study day describes the day of the event or assessment date, relative to the reference start 
date (randomization date or start date of study treatment). 
The reference start date is designated as Study Day 1. Study Day –1 is the day that precedes 
Day 1. Study Day 0 is not defined.  
The reference start date for all safety assessments (e.g. adverse event onset, laboratory 
abnormality occurrence, vital sign measurement, dose interruption, PK etc.) will be start date 
of study treatment. 
The reference start date for all efficacy assessments (e.g. pCR surgery date, tumor assessment,
disease progression, and tumor response) will be the randomization date. For any non-safety 
screening assessments or events such as baseline disease characteristics or medical history (e.g., 
time since diagnosis of disease), or for any safety assessment which would be also described as 
part of demographics (e.g. ECOG), that occurred prior to randomization the reference start date 
will be also the randomization date.
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative.
Study day is not to be used in numerical computations, for example in calculating exposure.
The study day will be calculated as:

The date of the event (visit date, onset date of an event, assessment date etc.) minus
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.) minus
reference start date if event precedes the reference start date.
Example for safety assessments: if start of study treatment is on 05-Jan-2014 and start date of 
an adverse event is on 09-Jan-2014 then the study day of the adverse event onset is 5. For safety 
assessments before start of study treatment, the study day is negative and derived by date of 
event – start date of study treatment. For example: if start of study treatment is on 05-Jan-2014 
and date of lab measurement is on 02-Jan-2014 then the study day of the laboratory abnormality 
is -3. Note, the day of start of study treatment is day 1, and the day before the date of first study 
treatment is day – 1, not day 0
3.1.7
Baseline
Baseline is the result of an investigation describing the “true” uninfluenced state of the patient. 
For efficacy evaluations, the last non-missing assessment, including unscheduled assessments 
on or before the date of randomization is taken as “baseline” value or “baseline” assessment. In 
the context of baseline definition, the efficacy evaluations also include performance status.  


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For safety evaluations, the last non-missing assessment, including unscheduled assessments on 
or before the day of start of study treatment, is defined as “baseline” value or “baseline” 
assessment.
In rare cases where multiple measurements meet the baseline definition, with no further flag or 
label that can identify the chronological order, then the following rule should be applied: if 
values are from central and local laboratories, the value from central assessment should be 
considered as baseline. If multiple values are from the same laboratory (local or central) or 
collected for ECGs or vital signs, then the last value should be considered as baseline.
If patients have no value as defined above, the baseline value will be missing.
Note: Deviations from the above rules for particular assessments, e.g. biomarkers are detailed 
in the relevant sections.
3.1.8
On-treatment assessment/event
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of subject’s first informed consent to the day before first 
administration of study treatment 
2. 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 for on-
treatment adverse events, excluding start date for other safety parameters) 
3. 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 pre and post-treatment period) will be listed and 
those collected during the post-treatment period will be flagged.
An on-treatment adverse event is defined as any adverse event reported in the following time 
interval (including the lower and upper limits):

date of first administration of study treatment; to date of last administration to study 
treatment + 30 days;
This rule is consistent with the definition of treatment emergent AEs (TEAE) given in the 
protocol, i.e. AEs that started or worsened during the on-treatment period (see protocol Section 
10.5.3.2).
An on-treatment assessment is defined as any assessment performed after the date of first 
administration of study treatment i.e. assessments performed in the following time interval 
(including the lower and upper limits):

date of first administration of study treatment + 1; date of last administration to study 
treatment + 30 days;


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Furthermore, assessments collected post-dose on the date of first administration of study 
treatment are on-treatment assessments.
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period cannot 
be made, then the respective data will be assigned to the on-treatment period.
3.1.9
Screening failure
Screening failures are patients who have signed main informed consent and/or pre-screening 
informed consent and failed screening criteria in the study, based on the “Screening phase 
disposition” eCRF page with a subject status other than “completed”. These patients are not 
randomized. 
Patients who are randomized, but never received any study drug, are not screening failures. 
The following information is collected for screening failures:

Reason for not completing screening phase

Data on serious Adverse Events/Death
3.1.10
Time unit
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25 / 12). If 
duration is to be reported in months, duration in days is divided by 30.4375. If duration is to be 
reported in years, duration in days will be divided by 365.25.
3.1.11
Data included in analyses
Periodic 
review 
of 
safety 
data 
aggregated 
by 
blinded 
treatment 
group 
(alpelisib/buparlisib/placebo) will be performed and results will be shared with study steering 
committee (until protocol amendment 5) or with an internal Data Monitoring Committee.
The analysis cut-off date for the primary and final analysis will be established after all patients 
randomized have completed 24 weeks of treatment or have discontinued study treatment and 
have completed the safety follow-up and the pCR response is reported (if relevant). The study 
will end when the treatment phase and follow-up for safety period have ended for all patients.
All statistical analysis will be performed using all data collected in the clinical database up to 
the data cut-off date. A cut-off date will be defined and will be specified in the outputs. Only 
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 such an analysis. For example, 
if the cut-off date is 15 June 2014 then an AE starting on 13 June 2014 will be reported, whereas 
an AE with start date on 17 June 2014 will not be reported. Any data collected beyond the cut-
off date will not be included in the analysis and will not be used for any derivations.
All events with a start date either before or on the cut-off date and an end date after the cut-off 
date will be reported as ‘ongoing’ (the end date will be missing in the listings). The same rule 
will be applied to events starting either 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 
listings.


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If it is required to impute an end date to be able to perform a specific analysis, the missing end 
date is imputed with the cut-off date and is displayed and flagged in the listings
3.1.11.1 Windows for multiple assessments 
In order to summarize labs parameters as applicable, collected over time (including unscheduled 
visits), the assessments will be time slotted.
Table 3-1 Time windows for labs
Assessment (1)
Target day of assessment
Time Interval
Baseline
        
≤ Day 1 
Cycle 1 Day 8
8
Day 2 to day 11
Cycle 1 Day 15
15
Day 12 to day 18
Cycle 1 Day 22
22
Day 19 to day 25
Cycle 2 Day 1
29
Day 26 to day 35
Cycle 2 Day 15
43
Day 36 to day 49
Cycle 3 Day 1
57
Day 50 to day 70
Cycle 4 Day 1
85
Day 71 to day 98
Cycle k Day 1 (k≥5)
d=(k-1)*28+1
Day d-14 to day d+13
End of Treatment
Assessment taken at the 
end of treatment visit
(1) HbA1c is measured on-treatment at Cycle 3 Day 1 and EOT and same rule applies.
For laboratory parameters, all scheduled/unscheduled assessments should be assigned to time 
windows. In case of multiple values per window, the one closest to the planned visit date should 
be used. If 2 values are equidistant to the planned visit date, the selection should be made by
selecting the one assessed by central (if any) and otherwise - for multiple central assessments 
equidistant to the planned visit - the last value.
3.1.11.2 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:

Assessment dates (e.g. laboratory, vital signs, ECOG performance status, PHQ-9, GAD-
7, ECG, cardiac imaging, tumor imaging, PK assessment, EOT completion, surgery date
etc.).

Medication and procedures dates including study medication, concomitant medications, 
surgical and medical procedures, antineoplastic therapies administered after study drug 
discontinuation (with non-missing medication/procedure term).

Adverse event start and end dates (with non-missing verbatim AE term present)

Study treatment start/end date (Non-missing dose. Doses of 0 are allowed).

Randomization date
The last contact date is defined as the latest complete date from the above list or the cut -off date, 
whichever comes first. The cut-off date will not be used for last contact date, unless the patient 


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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. 
3.2
Analysis sets
The following analysis sets will be used in this study. 
3.2.1
Screened patients
Screened patients are all patients who completed the “Screening phase disposition” eCRF page
and have signed the pre-screening informed consent or main informed consent.
3.2.2
Full analysis set
The Full Analysis Set (FAS) comprises of all randomized patients in the study. Following the 
intent to treat (ITT) principle, patients will be analyzed according to the treatment , cohort 
(PIK3CA mutant or PIK3CA wild-type) and strata they have been assigned to during the 
randomization procedure. 
The FAS will be the main population for analyses of patient disposition, demographics and 
other baseline characteristics. The FAS will be the primary population for the efficacy analyses.
3.2.3
Safety set
The Safety Set will comprise all patients who received at least one dose of study treatment. 
Subjects will be analyzed according to the treatment actually received. 
The actual treatment received corresponds to: 
-
the randomized treatment if patients took at least one dose of that treatment. 
-
the first treatment received if the randomized treatment was never received 
3.2.4
Per-protocol set
The per-protocol set (PPS) comprises all patients in the FAS who are compliant with 
requirements of the CSP (i.e. do not have any protocol deviations that could confound the 
interpretation of the primary analyses conducted on the FAS). 
The following list of protocol deviations will lead to exclusion of the patient from the Per -
Protocol Set:
Inclusion / exclusion criteria not met

Patient was not an adult (INCL01)

Patient does not have histologically and/or cytologically confirmed diagnosis of breast 
cancer (INCL02)

Patient was not postmenopausal as defined in the protocol (INCL03)

Patient does not have [T1c-T3, any N, M0] operable breast cancer (INCL04)

Patient does not have measurable tumor (INCL05)


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
Patient does not have diagnostic biopsy available (INCL06)

Patient does not have [estrogen-receptor and/or progesterone positive] breast cancer
(INCL07)

Patient does not have HER2 negative breast cancer (INCL08)

Patient does not have PIK3CA mutation status known (PIK3CA mutated or wild-type), 
as defined by a Novartis designated laboratory (INCL09)

Patient does not have ECOG performance status < or = to 1 which the investigator 
believes is stable at the time of screening (INCL11)

Patient is not able to swallow and retain oral medication (INCL12)

Patient was not a female (INCL19)

Patient has locally recurrent or metastatic disease (EXCL01)

Patient has inflammatory breast cancer (EXCL02)

Patient has a concurrent malignancy or malignancy within 3 years (EXCL04)

Patient has received any systemic therapy or radiotherapy for current breast cancer 
disease before study entry (EXCL05)

Patient is concurrently using other approved or investigational antineoplastic agent 
(EXCL27)
Treatment not taken as per protocol

Patient was given different treatment than originally randomized to (TRT02)

Patient randomized but did not take study treatment (TRT36)

Patient randomized in the wrong cohort (TRT40)
Use of prohibited concomitant medications

Concurrent other anti-cancer therapy, or investigational therapy while on study
(COMD03)
Additional criteria (not PDs) leading to exclusion from pCR PPS

Patients treated with study treatment for less than 16 weeks

Surgery not performed within 28 days after discontinuation of study treatment
3.2.5
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) consists of all patients who received at least one dose 
of alpelisib, buparlisib or letrozole and have at least one evaluable post-treatment concentration 
PK data.


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3.2.5.1
Alpelisib Pharmacokinetic Analysis Set (BYL PAS)
The BYL PAS will include all patients who received at least one dose of alpelisib and had at 
least one evaluable post-treatment alpelisib concentration measurement.
3.2.5.2
Alpelisib Full Sampling Pharmacokinetic Analysis Set (BYL FPAS)
The BYL FPAS will include the subset of the patients in the BYL PAS who:

received all planned doses of alpelisib for the last consecutive 3 days preceding full PK 
profile assessment on Cycle 4 Day 1

did not vomit within 4 hours of alpelisib and/or letrozole dosing on the day of full PK 
profile assessment (Cycle 1 Day 1 and Cycle 4, Day 1)

received all planned doses of letrozole for the last consecutive 7 days and received ≥ 70% 
of all planned doses preceding full PK profile assessment Cycle 4, Day 1

had an evaluable full PK profile on the day of full PK assessment (C1D1 and C4D1)
3.2.5.3
Buparlisib Pharmacokinetic Analysis Set (BKM PAS)
The BKM PAS will include all patients who received at least one dose of buparlisib and had at 
least one evaluable post-treatment buparlisib concentration measurement.
3.2.5.4
Buparlisib Full Sampling Pharmacokinetic Analysis Set (BKM FPAS)
The BKM FPAS will include the subset of the patients in the BKM PAS who:

received all planned doses of buparlisib on 10 days out of 14 days (including cycle 4 day 
1) preceding full PK profile assessment on Cycle 4, Day 1

did not vomit within 4 hours of buparlisib and/or letrozole dosing on the day of full PK 
profile assessment (Cycle 1 Day 1 and Cycle 4, Day 1)

received all planned doses of letrozole for the last consecutive 7 days and received ≥ 70% 
of all planned doses preceding full PK profile assessment Cycle 4, Day 1.

had an evaluable full PK profile on the day of full PK assessment (C1D1 and C4D1).
3.2.5.5
Letrozole Pharmacokinetic Analysis Set (LZ PAS)
The LZ PAS will include all patients who received at least one dose of letrozole and had at least 
one evaluable post-treatment letrozole concentration measurement.
3.2.5.6
Letrozole Full Sampling Pharmacokinetic Analysis Set (LZ FPAS)
The LZ FPAS will include the subset of the patients in the LZ PAS who:

received all planned doses of letrozole for the last consecutive 7 days and received ≥ 90% 
of all planned doses preceding full PK profile assessment Cycle 4, Day 1.

did not vomit within 4 hours of letrozole dosing on the day of full PK profile assessment 
(Cycle 1 Day 1 and Cycle 4, Day 1)

had an evaluable full PK profile on the day of full PK assessment


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3.2.6
Patient classification
All protocol deviations will be reviewed and entered into the database before database lock. 
Patients may be excluded from the analysis sets defined above based on the protocol deviations 
entered in the database and/or on specific patient classification rules.
Table 3-1
Patient classification based on protocol deviations
Efficacy analyses will be performed on the FAS. Safety analyses and exposure to study 
treatment will be performed on the Safety set.
Analysis set
Protocol 
deviations 
leading to exclusion
Non protocol deviation leading 
to exclusion
FAS 
No written inform consent
Not applicable
Safety set
No written inform consent
No 
dose 
of 
study 
treatment
Not applicable
Per-protocol set
See definition of PP set
Patient not in the FAS
pCR Per-protocol set
Not applicable
Patient not in the Per-protocol 
set
Patients treated with
study 
treatment for less than 16 weeks
Surgery not performed within 
28 days after discontinuation of 
study treatment
BYL PK Analysis set
No written inform consent
No dose of alpelisib 
No evaluable post-treatment 
alpelisib concentration 
measurement
BKM PK Analysis set
No written inform consent
No dose of buparlisib
No
evaluable post-treatment 
buparlisib
concentration 
measurement
LZ PK Analysis set
No written inform consent
No dose of letrozole
No
evaluable post-treatment 
letrozole
concentration 
measurement
Full PK Analysis Set
No written inform consent
See definition of alpelisib, 
buparlisib and letrozole FPAS


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The listings will be provided for the FAS unless otherwise specified. They will be produced by 
cohort and treatment group.
Withdrawal of Informed Consent
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis. The date on which a patient 
withdraws full consent is recorded in the eCRF. 
Additional data for which there is a separate informed consent, e.g. PK, biomarker etc., 
collected in the clinical database without having obtained that consent will not be included in 
the analysis. These data will be excluded by the presence of the appropriate protocol deviation 
criterion.
3.3
Implementation of RECIST criteria
Response and progression evaluation in solid tumors are determined according to the Response 
Evaluation Criteria In Solid Tumor (RECIST) Novartis guidelines version 3.0 (based on 
RECIST v1.1), provided as Appendix 2 (Section 14.2) of the CSP.
In general, the definitions and the details regarding the derivations are provided in the guideline 
and are not detailed here again.
The Sections below give instructions and study level conventions to be implemented.
3.3.1
Tumor assessment
3.3.1.1
Data and determination of adequate tumor assessment
Lesion measurements and overall lesion response based on local radiological assessment are
collected on the RECIST eCRF pages.
Details on adequate tumor assessments (TAs) are given in protocol Section 14.2.24 of RECIST 
Novartis guidelines which are based on RECIST version 1.1 (Eisenhauer et al 2009).
3.3.1.2
Determination of missing adequate tumor assessments
The term ‘missing adequate tumor assessment’ is defined as a tumor assessment not done or 
tumor assessment with overall lesion response ‘Unknown’. For the sake of simplicity, a 
‘missing adequate tumor assessment’ will also be referred to as a ‘missing assessment’
An exact rule to determine whether there is no, one or two missing TAs is therefore needed. 
This rule is based on the interval between the last adequate tumor assessment date and the event 
date. Two thresholds are defined: D1 and D2
In this study, the first tumor assessment is planned 12 weeks after randomization (+/- 7 days) 
and the subsequent assessment is planned maximum 7 days before the surgery (planned no more 
than 2 weeks after the treatment period of 24 weeks). 
If the first post-baseline tumor assessment (12 weeks ± 7 days post randomization) is missing:


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
If the interval is greater than D1=91 days (12 weeks*7+7) and is less than or equal to 
D2=182 days (24 weeks* 7+14) then the number of missing assessments is 1.

If the interval is greater than D2=182 days (24 weeks* 7+14) then the number of 
missing assessments is ≥ 2.
If the first post-baseline tumor assessment (12 weeks ± 7 days post randomization) is not 
missing:

If the interval is greater than D1=98 days (12 weeks*7+7*2) and is less than or equal 
to D2=182 days (24 weeks* 7+14) then the number of missing assessments is 1.
If the interval is greater than D2=182 days (2*12 weeks* 7+7*2) then the number of missing 
assessments is ≥ 2.
3.3.1.3
Change of imaging modality
Details are given in protocol Section 14.2.5.
In particular it is described that “A change in methodology will result by default in a UNK 
overall lesion response assessment. However, another response assessment than the Novartis-
calculated unknown response may be accepted from the investigator if a definitive response 
assessment can be justified based on the available information.”
3.3.1.4
Other screening methods
Not applicable
3.3.2
Response and progression evaluation
3.3.2.1
Overall lesion response
Details are given in the protocol Section 14.2.14.
The overall lesion response at a given assessment will be provided from different sources:

Reported overall lesion response by the investigator, which is used for efficacy analyses.

Calculated overall lesion response based on individual lesion measurements from the 
investigator, which is used only for validation purposes (queries and data cleaning process).
3.3.2.2
Best overall response (BOR)
Details are given in protocol Section 14.2.16.
The best overall response will be determined from all response assessments without any 
restriction to on treatment assessments. TAs performed before the start of any further 
antineoplastic therapy (i.e. any additional secondary antineoplastic medications or radiotherapy) 
will be considered in the BOR determination.
The start dates of further antineoplastic therapies are identified; from the date collected on all 
antineoplastic therapy eCRF pages i.e.; antineoplastic therapy since discontinuation of study 
treatment – medication or radiotherapy
Continuation of letrozole monotherapy as 1st new anti-neoplastic therapy after end of treatment 
without prior PD and collected in the ‘antineoplastic therapy since discontinuation of study 


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treatment- Medication’ eCRF, will not be considered as an anti-neoplastic therapy for the
assessment of BOR.
The best overall response date will be derived based on the protocol Section 14.6.25 from the 
‘RECIST target lesion response’, ‘RECIST non-target lesion assessment’ and ‘RECIST new 
lesion’ eCRF pages.
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules:
-
CR = one determination of CR prior to progression 
-
PR = one determination of PR prior to progression (and not qualifying for a CR)
-
SD = at least one SD assessment (or better) > 5 weeks after randomization (and not 
qualifying for CR or PR).
-
PD = progression ≤ 26 weeks after randomization (and not qualifying for CR, PR or SD).
-
UNK = all other cases (i.e. not qualifying for CR or PR and without SD after more than 5
weeks or early progression within the first 26 weeks)
3.3.2.2.1 Complete or partial response
No confirmation of complete and partial response (CR or PR) is required; please refer to the 
protocol Section 10.4.1.
3.3.2.2.2 Progressive disease
Details are given in the protocol Section 14.2.16.
Only objective progression per RECIST 1.1 i.e. PD identified using objective tumor assessment 
method (e.g. CT scan/MRI, etc.) is considered.
In particular, discontinuation due to PD or death due to study indication without supporting 
radiological evidence will not be considered as PD in the BOR determination.
3.3.2.2.3 Unknown response
Patients with ‘unknown’ BOR will be summarized by reason for having unknown status. The 
following reasons will be used:

No valid post-baseline assessment

All post-baseline assessments have overall lesion response UNK

New anti-neoplastic therapy started before first post-baseline assessment

Stable disease (SD) too early

PD too late
Note 1: A SD is considered as ‘a SD too early’ if the SD is documented within the first 6 weeks 
(i.e. 6*7 – 7=35), i.e. up until Study Day 36.
Note 2: A PD is considered as ‘a PD too late’ if the first documentation of PD is recorded more 
than D2 days after the reference start date with no valid post-baseline assessment in between.


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Note 3: Special (and rare) cases where BOR is ‘unknown’ due to both too early SD and too late 
PD will be classified as ‘SD too early’.
3.4
Patient disposition
The number and percentage of patients included in the FAS will be presented overall and by 
treatment group. The number and percentage of patients who are still on treatment, who 
discontinued the study treatment phase and the reason for discontinuation will also be presented.
The following summaries will be provided (% based on the total number of FAS patients):

Number (%) of patients who were randomized (based on data from IRT system)

Number (%) of patients who were randomized but not treated (based on ‘DAR’ eCRF page 
not completed for any study treatment component)

Primary reason for not being treated (based on “End of Treatment Phase Completion” eCRF 
page)

Number (%) of patients who were treated (based on ‘DAR’ eCRF pages of each study 
treatment component completed with non-zero dose administered)

Number (%) of patients who are still on-treatment (based on the ‘End of Treatment Phase 
Completion’ eCRF page not completed)

Number (%) of patients who discontinued the study treatment (based on the ‘End of 
Treatment Phase Completion’ eCRF page completed)

Primary reason for study treatment phase discontinuation (based on the ‘End of Treatment 
Phase Completion’ eCRF page completed)
All the above summaries will be repeated for the PIK3CA mutated subpopulation and PIK3CA
wild type subpopulation by treatment group in the FAS.
The number (%) of screened and not-randomized patients, the number and percentage of 
patients completing or not screening phase, and the primary reason for not completing screening 
phase will be presented on a separate output.
3.5
Protocol deviations
The number and percentage of patients in the FAS with any protocol deviation will be tabulated 
by deviation category (as specified in the Study Specification Document) overall and by 
treatment group. 
Reasons for exclusion from analysis sets (including protocol deviations) will be tabulated 
separately overall and by treatment group. All protocol deviations will be listed.
All the above summaries will be repeated for each cohort (PIK3CA mutated subpopulation, 
PIK3CA wild-type subpopulation) by treatment group in the FAS.


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3.6
Analysis sets
The number and percentage of patients in each analysis set will be summarized overall by 
treatment group. Summaries will be also displayed by cohort, treatment group and stratum.
3.7
Background and demographic characteristics 
The FAS will be used for all baseline and demographic summaries and listings. Summaries will 
be reported by treatment arm and for all patients, overall and by PIK3CA cohort, and listings 
will be reported by cohort and treatment arm to assess baseline comparability. No inferential 
statistics will be provided.
3.7.1
Basic demographic and background data
Descriptive statistics (e.g. mean, median, standard deviation, minimum and maximum) will be 
presented for continuous variables (e.g. age). The number and percentage of patients in each 
category will be presented for categorical variables e.g. age groups, race, ethnicity, ECOG 
performance status). The number and percentage of patients with missing data will also be 
provided. 
All summaries will be presented for the full population, PIK3CA mutant subpopulation and 
PIK3CA wild type subpopulation by treatment group in the FAS.
In addition, summaries of age groups by sex, and race will be presented in the Safety set.
Biomarker assessment characteristics (archival tumor and its source) will also be presented.
Other data collected at baseline will be summarized or listed as appropriate.
Inclusion/exclusion criteria not met for screened patients will be summarized and listed.
3.7.2
Baseline stratification factors
The number (%) of patients in each stratum (Lymph Node status (Positive, Negative) & KI67 
(≤ 14%, > 14%)) based on data obtained from the IRT system will be summarized overall and 
by treatment group, for the FAS overall and by PIK3CA cohort. Discordances between the 
stratum recorded in IRT at the time of randomization and the actual stratum recorded in the 
clinical database through the data collected on eCRF or biomarkers will be summarized overall 
and by PI3KCA cohort and listed.
3.7.3
Diagnosis and extent of cancer
Summary statistics will be tabulated for the full population, PIK3CA mutated subpopulation 
and PIK3CA wild type subpopulation by treatment group in the FAS for diagnosis and extent 
of cancer.
Categorical data will include primary site of cancer, details of predominant histology/cytology,
histological
grade,
stage (primary tumor, lymph node, metastases) at study entry, 
presence/absence of target and non-target lesions, HER2 receptor status, estrogen receptor (ER) 
status, progesterone receptor (PgR) status and hormone receptor (ER and/or PgR) status, and 
multicentric disease.


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Time since initial diagnosis of primary site will be summarized in months.
ER status and Ki67 assessed centrally will also be summarizedThis event time (in months) is
defined as:
[(reference start date) – (date of initial diagnosis of primary site) + 1]/30.4375
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 (if any) will be based 
on diagnosis page.
3.7.4
Medical history
Medical history and ongoing conditions including cancer-related conditions and symptoms will 
be summarized overall and by treatment group and listed in the FAS. Separate summaries will 
be presented for ongoing and historical medical conditions. The summaries will be presented 
by primary system organ class (SOC) and preferred term (PT).
Medical history/current medical conditions will be coded using Medical Dictionary for
Regulatory Activities (MedDRA) terminology. The MedDRA version used for reporting the 
study will be specified in the CSR and as a footnote in the related tables and listings (if possible). 
The latest version available at that time of the analyses will be used.
Medical history will be summarized for the full population, PIK3CA mutated subpopulation 
and PIK3CA wild type subpopulation by treatment group.
3.7.5
Antineoplastic therapy
Prior anti-neoplastic surgery will be listed. 
Anti-neoplastic therapies (medication, radiotherapy, surgery other than the surgery to assess 
pCR) since study treatment discontinuation will be listed by treatment group in FAS.
Anti-neoplastic medications will be coded using the WHO Drug Dictionary (WHO-DD); anti-
neoplastic surgery will be coded using MedDRA. The MedDRA and WHO-DD version used 
for reporting the study will be specified in the CSR and as a footnote in the related outputs (if 
possible). The latest version available at that time of the analyses will be used.
3.8
Study treatment
The following parameters will be listed and summarized in the full population, PIK3CA 
mutated subpopulation and PIK3CA wild type subpopulation by treatment group for the Safety 
set.
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity 
(RDI) will be summarized by treatment arm, separately for each component of study treatment. 
The duration of exposure will also be presented for the study treatment. Duration of exposure 
will be categorized into time intervals; frequency counts and percentages will be presented for 
the number (%) of subjects in each interval. The number (%) of subjects who have dose 
reductions, interruptions and discontinuations, with the corresponding reasons, will be 
summarized by treatment group. 


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Subject level listings of all doses administered on treatment along with dose change reasons 
will be produced.  
3.8.1
Duration of exposure to study drug
Duration of exposure to study drug (for alpelisib/buparlisib/placebo and letrozole) is defined as 
outlined below:
Duration of exposure (days) = (last date of exposure to study drug) – (date of first administration 
of study drug) + 1.
The duration includes the periods of temporary interruption.
Note 1: If the last record in DAR CRF page is a zero dose, this record will not be used in the 
analysis of duration of exposure.
Note 2: For patients who have ongoing treatment and had one (or more than one) last dosing 
record(s) of interruption for study drug at the time of the cut-off date, duration of exposure of 
study drug will be calculated using the end date of last non-zero dose prior to dose interruption, 
and this interruption will not be counted.
The definition of last date of study drug exposure for alpelisib/buparlisib/placebo or letrozole 
is defined in Table 3-2.
Table 3-2
Definition of last date of exposure of study drug
Scenario
Definition of last date of exposure 
of study drug 
Example
Daily/intermittent
schedule
Date of last administration of a non-zero 
dose of the study drug.
A 
patient 
had 
a 
permanent 
discontinuation of the study drug on 
06Jan2013 after being put on a 
temporary 
interruption 
since 
01Jan2013. In this case the last date of 
exposure is 31Dec2012. 
The categorical summaries of exposure will use weeks and the continuous summaries (i.e. mean, 
standard deviation etc.) will use days.
The categories of exposure to study drug will be ≤8 weeks, > 8 - ≤16 weeks, > 16 - ≤24 
weeks, > 24 weeks.
3.8.2
Duration of exposure to study treatment
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to its each drug component:
Duration of exposure (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 
alpelisib/buparlisib/placebo and letrozole (see Table 3-2).


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The categories of exposure to study treatment will be ≤8 weeks, > 8 - ≤16 weeks, > 16 - ≤24 
weeks, > 24 weeks. Summaries (i.e. mean, standard deviation etc.) based on continuous variable 
will be displayed in days.
3.8.3
Cumulative and average daily dose
Cumulative dose is defined as the total dose given during the study drug exposure and is
summarized for each study drug separately.
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. 
Note: For buparlisib/buparlisib placebo, the planned starting dose will be either “100 mg daily” 
or “100 mg 5 days out of 7”. This will be determined from the first entry in the DAR page with 
dose 100 mg and no dosing error ticked. 
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the subject is on the study treatment as documented in the Dose Administration eCRF.
For patients who do not receive any study drug, the cumulative dose is equal to zero. Cumulative 
dose should be reported in the same units as the prescribed dose.
For continuous dosing, for alpelisib/alpelisib placebo, letrozole and buparlisib/buparlisib 
placebo when applicable, 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, for buparlisib/buparlisib placebo when applicable, the actual 
cumulative dose is defined based on the days when the subject is assumed to have taken a non-
zero dose during dosing periods.
For instance for buparlib or buparlisib placebo administered at X mg /day and dosing schedule 
of 5 days on 2 days off: the Actual cumulative dose (mg) is calculated as: X(mg)*5*W + 
X(mg)*min(D,5),
where W = integer part of (intermittent dosing period on X(mg)) which represents the number 
of full weeks the subject is on this dosing period prior to the last week o f this dosing period, 
and D = (duration of the intermittent dosing period on X(mg) – 7*W), which is the number of 
remaining days the subject is on this X(mg) intermittent dosing in the last week.
The planned cumulative dose in this setting would be defined in similar manner except that it 
would be based on the planned starting dose instead of the actual dose over the non -zero dosing 
days as shown above. The examples below illustrate the derivation of the actual and planned 
cumulative dose under different scenarios of dosing.
Subject 1: A subject’s assigned dose is 100mg/d daily and duration of exposure is 15 days at 
the assigned dose. In this case the planned and the actual cumulative dose is 100*15=1500 mg.
Subject 2: A subject’s assigned dose is 100mg/d, intermittent schedule 5 days on 2 days off and 
duration of exposure is 15 days at the assigned dose. For this scenario, W=2 and D=1 and 


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therefore the actual cumulative dose = 2*5*100 + 100*min(1,5) = 1100 mg. The planned 
cumulative dose is the same as the actual cumulative dose.
Subject 3: A subject’s assigned dose is 100mg/d daily and duration of exposure is 15 days. 
During this dosing period the subject has been treated with 100 mg/day on days 1–7, zero dose 
on days 8-9 and 100 mg/day (intermittent dosing 5 days on 2 days off) on days 10-15. For the 
daily dosing period the actual cumulative dose = 100*7 = 700 mg. For the intermittent dosing 
period (6 days), W=0 and D=6 and therefore the actual cumulative dose = [(100*5*0) + 
(100*min(6,5)]= 500 mg. Therefore the total actual cumulative dose = 1200 mg. The planned 
cumulative dose is 100*15=1500 mg.
Subject 4: A subject’s assigned dose is 100mg/d intermittent schedule 5 days on 2 days off and 
duration of exposure is 15 days. During this dosing period the subject has been treated with 100 
mg/day (5 days on 2 days off) on days 1–8, and 80 mg/day (5 days on 2 days off) on days 9-15. 
For the 100 mg intermittent dosing period (8 days), W=1 and D=1 and therefore the actual 
cumulative dose = 1*5*100 + 100*min(1,5) = 600 mg. For the 80 mg intermittent dosing period 
(7 days), W=1 and D=0 and therefore the actual cumulative dose = 1*5*80 = 400 mg .Therefore 
the total actual cumulative dose = 1000 mg. For the total planned cumulative dose over the 
entire dosing period W=2, D=1 and is therefore calculated as: 2*5*100 + 100*min(1,5) = 1100 
mg.
The cumulative dose is calculated from the DAR eCRF pages and is expressed in mg for 
alpelisib/buparlisib and letrozole:

The sum of ‘dose administered’ (mg/d) during the exposure to buparlisib

The sum of ‘dose administered’ (mg/d) during the exposure to alpelisib

The sum of ‘dose administered’ (mg/d) during the exposure to letrozole
Average daily dose = [Cumulative dose (mg) / Number of dosing days], drug free day(s) are 
not counted.
Note: the number of dosing days is the duration of exposure to study drug minus the periods of 
temporary interruption.
Note: There might be subjects in the Safety Set who did not take one component of study 
treatment and the cumulative dose for that component would be zero.
3.8.4
Dose intensity and relative dose intensity
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows: 
DI (mg/day) = Actual cumulative dose (mg) / Duration of exposure (day).
Considering the example of subject 3 in the previous section:
DI (mg/day) = Actual Cumulative dose (mg) / Duration of exposure (day)
= 1200 (mg) / 15 (Day) = 80 (mg/day)
For patients who did not take any drug the DI is equal to zero. 
Planned dose intensity (PDI) is the assigned dose by unit of time planned to be given to patients 
as per protocol in the same dose unit and unit of time as that of the Dose Intensity.


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PDI (mg/day) = Planned Cumulative dose (mg) / Duration of exposure (day).
Relative dose intensity (RDI) is defined as follows:
RDI = DI (mg/day) / PDI (mg/day).
DI and RDI will be summarized separately for each study drug, using the individual exposure 
duration for each study drug.
3.8.5
Dose reduction, interruption and permanent discontinuation
The number (%) of patients with dose reductions or interruptions
and permanent 
discontinuations and associated reasons, will be summarized separately for each study drug.
‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the Dosage 
Administration CRF pages (DAR) will be used to determine the dose interruptions and 
permanent discontinuations, respectively. Dose reductions will be derived programmatically 
using the dosing information as described below.
The corresponding fields ‘Reason for dose change/dose interrupted’ and ‘Reason for permanent 
discontinuation’ will be used to summarize the reasons.
Dose administered (mg) and dosing frequency from the DAR eCRF pages will be used to 
determine the dose reductions. Fields with zero dose administered will be used to determine 
interruptions.
3.8.5.1
Dose interruption
An interruption is defined as a zero dose administered on one or more days, followed by 
resumption of dosing. 
The number (%) of dose interruptions along with the reasons will be summarized.
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.
Note 1: The last zero dose of alpelisib/buparlisib or letrozole (followed by permanent 
discontinuation) is not considered as a dose interruption. 
Note2: Two consecutive zero doses of alpelisib (e.g. in the sequence 300 mg daily, 0 mg, 0 mg, 
300 mg daily) or buparlisib/letrozole will be counted as one interruption if the reasons for these 
two consecutive dose interruption are the same.
Note 3: For buparlisib dose administered at 100 mg 5 days out of 7 days, an interruption is 
defined as a zero dose on the scheduled 5 days. 
3.8.5.2
Dose reduction
A reduction is defined as a decrease in dose from the protocol planned starting dose or a 
decrease from the previous non-zero dose, even if this decrease has been directly preceded by 
an interruption. Any dose change to correct a dosing error will not be considered a dose 


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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. For example:

A decrease in dose from the protocol planned starting dose or a decrease from the 
previous non-zero dose will be counted as a dose reduction even if this decrease has 
been directly preceded by an interruption: see example 3 in Table 3-3.

For buparlisib, a dose reduction is defined as a decrease in dose from the protocol 
planned starting dose (e.g. 100 mg daily to 80 mg daily or “100 mg 5 days out of 7” to 
“80 mg 5 days out of 7”) or a change in dosing frequency (i.e. from 80 mg daily to 100 
mg 5 days out of 7), even if the dose decrease or change in dosing frequency has been 
directly preceded by an interruption: see examples 3, 4 and 7 in Table 3-4. 

If the dose decrease is followed by an interruption, with the dose resuming at the same 
level prior to the interruption, the second dose decrease or change in dosing frequency 
will not be counted as dose reduction: see example 1 in Table 3-3 and example 1 in 
Table 3-4.

If, due to a dosing error, a patient receives higher than protocol planned starting dose 
and moves down to the planned starting dose then this is not a dose reduction: see 
example 14 in Table 3-3 and example 21 in Table 3-4. However if the change is directly 
from a higher than planned starting dose down to a lower than protocol planned starting 
dose, then this is a dose reduction: see example 15 in Table 3-3 and example 22 in Table 
3-4.

If, due to a dosing error, a patient receives lower than previous non-zero dose and 
resumes later at the protocol specified dose reduction, then lower dose received due to 
dosing error and protocol specified dose reduction are dose reductions: see example 7 
in Table 3-3 and example 14 in Table 3-4.

If, due to a dosing error, a patient receives lower than previous non-zero dose and 
resumes later at lower than previous non-zero dose, then 2 dose reductions will be 
counted: see example 10 in Table 3-3 and example 12 in Table 3-4.

For buparlisib/buparlisib placebo, the protocol planned starting dose was “100 mg daily” 
until protocol amendment 1 and then “100 mg 5 days out of 7” for patients enrolled after 
protocol amendment 2 (or later amendments). Since the information of the amendment 
on which the patient was enrolled is not collected, for patients enrolled under protocol 
amendment 1 and starting at “100 mg 5 days out of 7” by error, it is assumed that this 
will be ticked as a dose change with dose change reason ‘Dosing error” and this will be 
counted as a dose reduction: see example 23 in Table 3-4. Otherwise, it will be assumed 
that the starting dose is correct and this will not be counted as a dose reduction: see 
example 4 in Table 3-4. 
Table 3-3
Examples of dose reductions for alpelisib/placebo
Example
Sequence
Reduction
With dose change


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Example
Sequence
Reduction
1
300 mg daily - 250 mg daily – 0 mg -
250 mg daily 
1 reduction (the 1st 250 mg)
2
300 mg daily – 300 mg daily – 0 mg -
250 mg daily
1 reduction (250 mg)
3
300 mg daily – 0 mg – 250 mg daily
1 reduction (250 mg)
With interruption 
4
300 mg daily – 0 mg - 300 mg daily 
0 reduction 
With dosing error
5
300 mg daily – 250 mg daily – 200 mg 
daily* 
2 reductions (250 mg, 200 mg)
6
300 mg daily – 200 mg daily* - 300 
mg daily
1 reduction (200 mg)
7
300 mg daily – 200 mg daily* - 250 
mg daily
2 reductions (200 mg, 250 mg)
8
300 mg daily – 400 mg daily* - 350 
mg daily*
0 reduction since 400 mg and 350 mg 
are higher doses than planned
9
300 mg daily – 150 mg daily* - 300 
mg daily
1 reduction (150 mg)
10
300 mg daily – 150 mg daily* - 100 
mg daily*
2 reductions (150 mg and 100 mg)
With dosing error at the 1st administration
11
150 mg daily* - 300 mg daily
1 reduction (150 mg)
12
150 mg daily* - 0 mg – 150 mg*- 300 
mg daily
1 reduction (150 mg)
13
150 mg daily* - 300 mg daily – 0 mg -
250 mg daily
2 reductions (150 mg and 250 mg)
14
350 mg daily* – 300 mg daily – 0 –
250 mg daily
1 reduction (250 mg)
15
350 mg daily* – 250 mg daily – 0 –
200 mg daily
2 reduction (250 mg and 200 mg)
*dosing error
Table 3-4
Examples of dose reductions for buparlisib/Placebo
Example
Sequence
Reduction
With dose change
1
100 mg od – 80 mg od- 0 mg- 80 mg od 
1 reduction (the 1st 80 mg od)


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Example
Sequence
Reduction
2
100 mg od – 100 mg od – 0 mg – 80 mg od
1 reduction (80 mg od)
3
100 mg od – 0 mg – 80 mg od
1 reduction (80 mg od)
4
100 mg 5 days out of 7 – 0 mg – 80 mg 5 
days out of 7
1 reduction (80 mg 5 days out of 7)
5
100 mg 5 days out of 7 – 0 mg – 80 mg 5 
days out of 7 – 0 - 60 mg 5 days out of 7
2 reductions (80 mg 5 days out of 7 and 
60 mg 5 days out of 7)
With dose frequency change
6
100 mg od – 80 mg od – 80 mg 5 days out of 
7 – 80 mg od
2 reductions (80 mg od, 80 mg 5 days 
out of 7)
7
100 mg od – 100 mg 5 days out of 7 – 0 mg
-100 mg 5 days out of 7
1 reduction (the 1st 100 mg 5 days out 
of 7)
With dose change & dose frequency change
8
100 mg od – 0 mg – 80 mg od – 0 mg -100 
mg 5 days out of 7
2 reduction (80 mg od, 100 mg 5 days 
out of 7 )
9
100 mg od – 0 mg – 80 mg od – 0 mg -100 
mg 5 days out of 7 – 0 mg- 80 mg 5 days out 
of 7
3 reductions (80 mg od, 100 mg 5 days 
out of 7, 80 mg 5 days out of 7 )
10
100 mg od – 0 mg – 80 mg od – 0 mg – 100 
mg 5 days out of 7 – 0 mg - 80 mg 5 days out 
of 7 – 70 mg* 5 days out of 7 – 0 mg – 80 
mg 5 days out of 7
4 reductions (80 mg od, 100 mg 5 days 
out of 7, the 1st 80 mg 5 days out of 7, 
70 mg 5 days out of 7)
With interruption 
11
100 mg od- 0 mg -100 mg od 
0 reduction 
12
100 mg 5 days out of 7 – 0 mg -100 mg 5 
days out of 7
0 reduction
With dosing error
13
100 mg od – 80 mg od – 70 mg od* – 60 mg 
od*
3 reductions (80 mg od, 70 mg od and 
60 mg od)
14
100 mg od – 70 mg od* – 100 mg od
1 reduction (70 mg od)
15
100 mg od – 70 mg od* – 80 mg od
2 reductions (70 mg od, 80 mg od)
16
100 mg od – 300 mg od* – 250 mg od*
0 reduction since 300 mg od and 250 
mg are dosing errors (i.e higher dose 
than planned)
17
100 mg od – 200 mg od* – 100 mg od
0 reduction since 200 mg od is a dose 
escalation not reduction
18
100 mg od – 50 mg od* – 100 mg od
1 reduction (50 mg od)
With dosing error at the 1st administration


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Example
Sequence
Reduction
19
50 mg od* – 100 mg od
1 reduction (50 mg od)
20
50 mg od* – 0 mg – 50 mg* – 100 mg od
1 reduction (50 mg od)
21
50 mg od* – 100 mg od – 0 mg – 80 mg od
2 reductions (50 mg od and 80 mg od)
22
150 mg od* – 100 mg od - 0 mg – 80 mg od
1 reduction (80 mg od)
23
150 mg od* – 80 mg od - 0 mg – 100 mg 5 
days out of 7
2 reduction (80 mg od and 100 mg 5 
days out of 7)
24
100 mg 5 days out of 7* - 0 mg - 80 mg 5 
days out of 7 
2 reduction (100 mg 5 days out of 7 and 
80 mg 5 days out of 7)
* dosing error
Since there is no planned dose reduction for letrozole – so no reason for letrozole dose reduction 
is planned to be collected in the eCRF.
The number (%) of dose reductions along with reasons will be summarized.
3.8.5.3
Permanent discontinuations
“Dose permanently discontinued” ticked box from the DAR eCRF page will be used to 
determine the permanent discontinuations. Reasons for permanent discontinuation from the 
study drug will be summarized for the study drug.
3.9
Prior and concomitant medication
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 WHO-DD; Surgical and medical procedures 
will be coded using MedDRA. The MedDRA and WHO-DD version used for reporting the 
study will be specified in the CSR and as a footnote in the related tables (if possible). The latest 
version available at that time of the analyses will be used.
Concomitant medications, procedures and significant non-drug therapies taken concurrently 
with study treatment will be listed and will be summarized by lowest Anatomical Therapeutic 
Chemical (ATC) class and preferred term/SOC and preferred term using frequency counts and 
percentages. 
These summaries will include:
1. 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
2. Medications starting prior to start of study treatment and continuing after the start of 
study treatment.


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All concomitant therapies will be listed. Any prior medications, procedures and significant 
non-drug therapies starting and ending prior to the start date 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 tables and listings. Summary tables will only include on 
treatment assessments. All data collected later than last treatment +30 days will only be listed.
Summaries will be tabulated for the full population, PIK3CA mutated subpopulation and 
PIK3CA wild-type subpopulation by treatment group in the safety set.
3.10
Primary objective
The primary objective is:
To assess the anti-tumor activity of alpelisib QD plus letrozole versus letrozole alone in 
increasing the pCR rate as assessed locally by the investigator during neo-adjuvant treatment 
among postmenopausal patients with HR-positive, HER2-negative breast cancer for each of the 
two cohorts: i) PIK3CA mutated and ii) PIK3CA wild tumor types based on tumor tissue.
and
To assess the anti-tumor activity of alpelisib QD plus letrozole versus letrozole alone in 
increasing the Objective Response Rate during neo-adjuvant treatment among postmenopausal 
patients with HR+, HER2-negative breast cancer for each of the two cohorts: i) PIK3CA 
mutated and ii) PIK3CA wild tumor types based on tumor tissue.
The primary objective of the study will be considered met if either one or both of these two 
objectives are met in any cohort.
The primary efficacy endpoints are:
pCR defined as percentage of patients with an absence of any residual invasive cancer on 
hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral 
lymph nodes following completion of 24 weeks of treatment by local assessment (ypT0/Tis
ypN0). Patients who experience progression of disease while undergoing neoadjuvant therapy, 
or who do not receive surgery for any reason, or receive antineoplastic treatment other than 
study drug(s) before surgery will be considered as non-responders for the calculation of pCR 
rate. 
and 
ORR defined as the percentage of patients with a BOR of Complete Response or Partial 
Response based on local investigator’s assessment according to RECIST 1.1. It is defined in 
greater details in section 3.3.2.2
3.10.1
Statistical hypothesis, model, and method of analysis
The primary objective of this study is to assess the treatment effect of alpelisib plus letrozole 
vs. letrozole alone on pCR rate and ORR in each of the following two cohorts of HR-positive, 
HER2-negative breast cancer patients: (i) PIK3CA mutated and (ii) PIK3CA wild type based 
on tumor tissue.


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These comparisons will be performed separately for PIK3CA mutated and PIK3CA wild type 
tumors. There is no formal plan to compare the alpelisib and buparlisib combination arms. 
Since this study is double-blinded with respect to placebo but not whether a patient is on 
alpelisib or buparlisib, some patients in the control arm of letrozole will receive letrozole plus 
alpelisib-matching placebo and some patients will receive letrozole plus buparlisib-matching
placebo. Letrozole plus alpelisib placebo and letrozole plus buparlisib placebo will be combined 
together within a cohort for all analyses.
Pathologic Complete Response
Based on published results, the pCR rate with letrozole is expected to be 5% or less. A 10% 
absolute improvement in the pCR rate to 15% is considered clinically meaningful among HR-
positive patients. Therefore a Proof of Concept (PoC) about efficacy of treatment based on pCR
will be declared if both of the following conditions are met for any cohort:

Posterior probability that the difference in the pCR rate is more than 0 is > 90% and

Estimated mean difference of the pCR rate between combination arm and letrozole is at 
least 10%
Overall Response Rate
Based on published results, the ORR with letrozole is expected to be around 45%. A 20% 
absolute improvement in the ORR is considered clinically meaningful among hormone 
receptor-positive patients. Therefore a PoC about efficacy of treatment based on ORR will be 
declared if both of the following conditions are met for any cohort:

Posterior probability that the difference in the ORR is more than 0 is > 90% and

Estimated mean difference in the ORR between combination arm and letrozole is at least
20%
Proof of concept will be declared in a given cohort if the PoC criteria are met for pCR or ORR.
Each comparison will be performed separately using Beta-binomial model as follows:
Let us assume that yis out of nispatients have a response in treatment for arm i and strata s. 
Where i= 1 (alpelisib plus letrozole), 2 (letrozole alone) and s= 1 (PIK3CA mutated), 2 
(PIK3CA wild tumor). The likelihood function is
                                             yis ~  Bin(nis, pis)
where pis denote response rate for arm i and strata s . Assume pis follows a beta prior 
distribution:
                                            [pis] ~ Beta(ais, bis), where ais > 0 , bis > 0
The posterior distribution of pis is therefore (Spiegelhalter et al 2004)
                                         [pis | yis] ~ Beta(ais + yis, bis + nis - yis)


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The posterior distribution of treatment Difference is                                         
         alpelisib plus letrozole vs letrozole alone:    [δ1s] =   [p1s | y1s] -  [p2s | y2s]
         
As a prior a minimally informative unimodal Beta(0.05/0.95,1) distribution (Neuenschwander 
2008) will be used for pCR and Beta(0.45/0.55,1) distribution will be used for ORR. The prior 
parameters are chosen so that the prior mean for pCR rates is equal to 5% and the prior mean 
for ORR is 45%. To determine the PoC, the posterior distribution of the [δ1s] will be used.
The posterior distribution of the treatment difference [δ1s] is not tractable analytically. Therefore 
a simulation approach will be considered by drawing 100,000 random samples from each of t he 
posterior distribution [pis | yis] on treatment and control arms to calculate the difference δ1s for 
each simulation. Both PoC criteria will be determined using this empirical distribution of δ1s.
The 80% credible interval (based on 10th and 90th percentiles) and 95% credible interval (based 
on 2.5th and 97.5th percentiles) will also be provided.
The primary analysis will be performed based on full analysis set (FAS).The FAS comprises 
all patients who are randomized to study treatment. According to the intent to treat principle, 
patient will be analyzed according to the treatment and strata they have been assigned to during 
the randomization procedure.
A plot for the posterior distribution of difference in PCR rates and ORR between alpelisib and 
placebo will also be provided by cohort.
There is no formal plan to compare the alpelisib and buparlisib combination arms. The pCR 
rates and ORR will be summarized by cohort with descriptive measures including 80% and 95% 
confidence intervals by treatment arm using Clopper and Pearson (1934) exact method , along 
with the observed difference in response rates versus placebo and its 80% and 95% CI 
confidence intervals using Chan and Zhang (1999) exact method. The Disease Control Rate 
(DCR: CR+PR+SD) will also be reported.
The following information will be also summarized with number of patients (%) in each 
category: surgery performed (Yes / No / Unknown if the surgery page has not been filled out 
for any reason), residual tumor classification, post-treatment pathologic tumor stage, lymph 
nodes stage and tumor grade.
Reasons for “Unknown” BOR
Patients with ‘unknown’ BOR will be summarized by reason for having unknown status for 
each of the cohort. 
3.10.2
Sensitivity and other supportive analyses of the primary endpoints
As a sensitivity measure, primary efficacy analysis for pCR and ORR will be repeated using 
the PPS in a given cohort if the PoC is established, and if the PPS and FAS are considered 
different in this cohort. Other supportive analyses may be conducted if necessary.


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3.10.3
Handling of missing values/censoring/discontinuations
Patients with no pCR evaluation will be considered non-responders.
Patients who experience progression of disease while undergoing neoadjuvant therapy, or who 
do not receive surgery for any reason, or receive antineoplastic treatment other than study drug(s) 
before surgery will be considered as non-responders for the calculation of pCR rate. If a surgery
was performed after the start of a new antineoplastic therapy, then the corresponding results 
will not be summarized in the pCR/surgery summary table (e.g. surgery performed will be 
considered as unknown and surgery results as not applicable).
Only tumor assessments performed on or before the start of antineoplastic treatment other than 
study drug(s) will be considered in the assessment of BOR. Patients with unknown best overall 
response will be considered as non-responders for the calculation of ORR.
Patients with no baseline tumor assessment
If there is no baseline tumor assessment, all post-baseline overall lesion responses are expected 
to be ‘Unknown’.
For the computation of ORR, these patients will be included in the FAS analysis and will be 
counted as ‘failures’. Similar approaches are followed for any response rate.
Patients with no post-baseline tumor assessment
If no valid post-baseline tumor assessments are available, the best overall response must be 
“Unknown”, unless progression was reported.
For the computation of ORR, these patients will be included in the FAS analysis and will be 
counted as ‘failures’. 
Patients with PR or CR
Partial or Complete Responses reported prior to any additional antineoplastic therapy will be 
considered for ORR computation irrespective of the number of missed assessments before 
response.
Missing Dates
All dates must be complete. For any incomplete dates, the imputation rules described in protocol 
Section 14.2.34 are followed.
3.11
Secondary efficacy objectives
All secondary efficacy analyses will be reported for PIK3CA mutated subpopulation and 
PIK3CA wild type subpopulation by treatment groups. Analysis will be based on the FAS 
unless otherwise specified.
As described in Section 2.2, the secondary efficacy objectives are

To assess the anti-tumor activity of alpelisib QD plus letrozole versus letrozole alone in 
increasing the pCR rate and ORR for each of the two cohorts: i) PIK3CA mutated and ii) 
PIK3CA wild tumor types, based on ctDNA (1).


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
To estimate the rate of breast conserving surgery for each of the two cohorts, namely i) 
PIK3CA mutated and ii) PIK3CA wild types based on tumor tissue.

To evaluate the association between changes in Ki67 from baseline to day 15, and 
baseline to surgery, with pCR for each of the two cohorts, namely i) PIK3CA mutated and 
ii) PIK3CA wild types based on tumor tissue.

To assess centrally the Preoperative endocrine prognostic index (PEPI) score for each of 
the two cohorts, namely, i) PIK3CA mutated and ii) PIK3CA wild types based on tumor 
tissue.
(1) Not covered in this CSR SAP as it is foreseen that ctDNA will not be available before 
the database lock.
3.11.1
Breast conserving surgery (BCS) rate
Rate of breast conserving surgery (BCS) is defined as the percentage of patients with no 
mastectomy following completion of 24 weeks of treatment. Descriptive statistics (N, 
percentage, two-sided 80% and two-sided 95% confidence intervals using Clopper & Pearson 
(1934) method) will be used to summarize the BCS rate by treatment group and cohorts based 
on tumor tissue. The number and proportion of patients who undergo breast conserving surgery, 
mastectomy, and no surgery will be reported.
3.11.2
Preoperative endocrine prognostic index (PEPI) score
PEPI score is related to risk of relapse and is a prognostic model that incorporates standard 
pathological staging variables and “on-treatment” biomarker values.
The total PEPI score assigned to each patient is the sum of the risk points derived from the pT 
stage, pN stage, Ki67 level, and ER status of the surgical specimen. The total risk point score 
for each patient is the sum of all the risk points accumulated from the four factors in the model 
(please see Table 14-10 in protocol section 14.3).
Table 3-5
The preoperative endocrine prognostic index (PEPI) score
Pathology, biomarker
Status
RFS Points
BCSS Points
Pathological tumor size
T1/2
0
0
T3/4
3
3
Node status
Negative
0
0
Positive
3
3
Ki67 level
0% – 2.7% (0 – 1† )
0
0
>2.7% – 7.3% (1 – 2 † )
1
1
>7.3% – 19.7% (2 – 3 † )
1
2
>19.7% – 53.1% (3 – 4 † )
2
3
>53.1% (>4 † )
3
3
ER status, Allred score
0 – 2
3
3


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Pathology, biomarker
Status
RFS Points
BCSS Points
3 – 8
0
0
† The natural logarithm interval corresponding to the percent Ki67 values on the original percentage scale.
(Ellis 2008)
Summary statistics as well as the number of patients (%) with a score of 0 will be presented for 
PEPI score by treatment group separately for PIK3CA mutated cohort and PIK3CA wild type 
cohort based on tumor tissue, and by treatment group regardless of PIK3CA mutational status.
3.11.3
Ki67
The association between changes in Ki67 with pCR will be evaluated by summarizing (e.g. with 
arithmetic mean, geometric mean, median, SD, coefficient of variation CV (%), geometric mean 
CV (%), minimum and maximum) the changes from baseline to day 15 and changes from 
baseline to surgery in Ki67, as well as by summarizing the number of patients (%) in each of 
the KI67 categories used for the PEPI score, by responders / non-responders. This will be done 
by treatment group and by cohort based on tumor tissue, and by treatment group regardless of 
PIK3CA mutational status. The response will be based on ORR from RECIST 1.1 and pCR if 
a sufficient number of responders are observed.
Some plots of KI67 percent change from baseline at C1D15 by cohort based on tumor tissue, 
and by treatment group will also be provided.
3.12
Exploratory efficacy objectives
Analysis will be based on the FAS unless otherwise specified.
Exploratory objectives are described in Section 2.3.
The pCR rates and ORR will be summarized regardless of the PIK3CA mutational status
(overall patient population) for the three treatment arms, as well as for the pool of alpelisib and 
buparlisib (Pi3K inhibitors) vs placebo. Descriptive measures including 80% and 95% 
confidence intervals by treatment arm using Clopper and Pearson (1934) exact method will be 
provided, along with the observed difference in response rates versus placebo and its 80% and 
95% CI confidence intervals using Chan and Zhang (1999) exact method. 
Exploratory analyses will be performed to assess the anti-tumor activity of buparlisib versus 
letrozole alone in increasing the pCR rate and the ORR as assessed locally by the investigator 
during neo-adjuvant treatment among postmenopausal patients with HR+, HER2-negative 
breast cancer for each of the two cohorts: i) PIK3CA mutated and ii) PIK3CA wild tumor types 
based on tumor tissue. Descriptive measures including 80% and 95% confidence intervals by 
treatment arm using Clopper Pearson (1934) exact method will be provided, along with the 
observed difference in response rates versus placebo and its 80% and 95% CI confidence 
intervals using Chan and Zhang (1999) exact method.
3.13
Safety evaluation
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. 
electrocardiogram, vital signs) will be considered as appropriate. Risks identified in the Safety 


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Profiling Plan will mainly be analyzed by frequency of events; further exploratory analyses may 
be performed as appropriate. The latest version of the SPP and Case retrieval Strategy (CRS) 
available at the time of an analysis will be used.
All safety outputs will use the Safety set and be presented by treatment group on pooled cohorts’ 
data. Some key safety outputs will be also provided by treatment group and cohort in the safety 
set.
On treatment period
The safety summary tables include only on-treatment assessments/events (refer to Section 3.1.8
for definition). All safety assessments are listed and those collected outside of the on-treatment 
period are flagged.
3.13.1
Adverse events
3.13.2
Dictionary coding of adverse events
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology and will be reported by primary system organ class (SOC) and 
preferred term (PT), by Standard MedDRA Queries (SMQs) and Novartis MedDRA Queries 
(NMQs) (for safety topics of interest).The MedDRA version used for reporting the study will 
be specified in the CSR and as a footnote in the related tables (if possible). The latest version 
available at that time of the analyses will be used.
3.13.3
Grading of adverse events
Adverse events will be graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version v4.03. In case of an update of the CTC criteria and for legacy studies 
using an older version of CTC some mapping may be necessary when data need to be pooled.
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 twice as bad as a grade 1).
If CTCAE grading does not exist for an adverse event, grades 1 – 4 corresponding to the severity 
of mild, moderate, severe, and life-threatening will be used. CTCAE grade 5 (death) is not used; 
If an AE results in death it is documented in the outcome (“fatal”).
3.13.4
General rules for AE reporting
The number and percentage of patients reporting any on-treatment AEs will be summarized by 
system organ class (SOC) and/or preferred term (PT). Additional summaries will be provided 
by severity and relationship to study treatment.
If the patients reported more than one AE with the same preferred term, the AE with the greatest 
severity will be presented. If the patients reported more than one AE within the same primary 
system organ class, the patient will be counted only once with the greatest severity at the system 
organ class level, where applicable.


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Summary will be provided for study treatment related adverse events, death, serious adverse 
events, grades 3 and 4 adverse events, other significant adverse events leading to 
discontinuation, adverse events requiring additional therapy and adverse events leading to dose 
adjustment and/or study treatment interruption.
3.13.5
Adverse events summaries
AE summaries will include all AEs occurring during on treatment period. 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 subjects 
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 subject with multiple occurrences of an 
AE will be counted only once in the respective AE category. A subject 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 arm alpelisib + 
letrozole.
The following adverse event summaries will be produced by treatment group: overview of 
adverse events and deaths (number and % of subjects who died, with any AE, any SAE, any dose 
reductions/interruptions), AEs by SOC and PT, summarized by relationship (all AEs and AEs 
related to study treatment), seriousness (SAEs and non-SAEs), leading to treatment 
discontinuation, leading to dose interruption/adjustment, requiring additional therapy and 
leading to fatal outcome. In addition, a summary of serious and non-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) as per EudraCT requirements. 
Separate summaries for on-treatment and all deaths (including post-treatment death) will be 
produced by treatment group, system organ class and preferred term. 
All deaths will be listed for the safety set; post treatment deaths will be flagged. A separate 
listing of deaths prior to starting treatment will be provided for all screened subjects.
The following summaries will be provided by treatment group

Overview of AEs (All grades and Grades ≥ 3)

AEs, regardless of study treatment relationship by  PT (All grades and Grades ≥ 3)

AEs, regardless of study treatment relationship, by SOC (All grades and Grades ≥ 3)

AEs, regardless of study treatment relationship by primary SOC, PT, maximum CTCAE 
grade

AEs suspected to be related to the study treatment by primary SOC and PT (All grades 
and Grades ≥ 3)

AEs suspected to be related to the study treatment by PT (All grades and Grades ≥ 3)


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
On-treatment deaths, by primary SOC, PT

On-treatment deaths and serious adverse events with fatal outcome, by PT

All deaths, by primary SOC and PT

Serious adverse events (SAEs), regardless of study treatment relationship, by PT (All 
grades and Grades ≥ 3)

Serious adverse events (SAEs), regardless of study treatment relationship, by primary
SOC and PT (All grades and Grades ≥ 3)

SAEs suspected to be related to the study treatment, by primary SOC and PT(All grades 
and Grades ≥ 3)

AEs leading to discontinuation, regardless of study treatment relationship, by primary 
SOC and PT (All grades and Grades ≥ 3)

AEs leading to discontinuation, regardless of study treatment relationship, by PT (All 
grades and Grades ≥ 3)

AEs suspected to be related to the study treatment and leading to discontinuation, by 
primary SOC and PT (All grades and Grades ≥ 3)

AEs requiring dose adjustment or study treatment interruption, regardless of study 
treatment relationship, by primary SOC and PT (All grades and Grades ≥ 3)AEs requiring 
additional therapy, regardless of study treatment relationship, by primary SOC and PT
(All grades and Grades ≥ 3)

Non-serious AEs with occurrences

SAEs and deaths with occurrences.
The following summaries will be provided by treatment group and by PIK3CA cohort:

AEs, regardless of study treatment relationship by primary SOC and PT (All grades and 
Grades ≥ 3)

AEs suspected to be related to the study treatment by primary SOC and PT (All grades 
and Grades ≥ 3)

AEs leading to discontinuation, regardless of study treatment relationship, by primary 
SOC and PT (All grades and Grades ≥ 3)

On-treatment deaths and serious adverse events with fatal outcome, by PT

Serious adverse events (SAEs), regardless of study treatment relationship, by SOC and PT 
(All grades and Grades ≥ 3)
Deaths and SAEs will also be listed for screening failures.
3.13.6
Adverse events of special interest 
Specific groupings of Adverse Events of Special Interest (AESI) will be considered and the 
number of patients with at least one event in each grouping will be reported. Such groups consist 
of AEs for which there is a specific clinical interest in connection with alpelisib or buparlisib 
treatment (i.e. where alpelisib / buparlisib may influence a common mechanism of action 


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responsible for triggering them) or AEs which are similar in nature (although not identical). The 
groups are defined according to the MedDRA terms defined in the program Case Retrieval 
Strategy (CRS) documents for alpelisib and buparlisib and will be summarized. The latest 
versions of the CRS documents available at the time of the analyses will be used. 
All AESI groupings are defined through the use of Preferred Terms (PT), High Level Terms 
(HLT) or System Organ Classes (SOC) or through a combination of these three components. 
An Excel file with the exact composition of the AEs groupings is to be used to map reported 
AEs to the AESI groupings. This file may be updated (i.e. it is a living document) based on 
review of accumulating trial data. Note that certain AEs may be reported within multiple 
groupings. Final deliverables will be aligned with the final excel file. A listing of all grouping 
levels down to the MedDRA preferred terms used to define each AESI will be generated.
Table 3-6
AESI for alpelisib
AESI grouping
Definition*
Hyperglycemia
SMQ Hyperglycaemia /new onset diabetes mellitus (narrow)
Rash
Rash [BYL719] NMQ
Pneumonitis
SMQ Interstitial lung disease (narrow)
Nausea, Vomiting, Diarrhea
HLT Diarrhoea (excl infective)
HLT Nausea and Vomiting symptoms
* At the time of the analyses, MedDRA-defined (SMQ) or Novartis-defined (NMQ) groupings 
described in the latest version of the CRS document available for alpelisib will be used
Table 3-7
AESI for buparlisib
AESI grouping
Definition*
Hyperglycemia
Hyperglycaemia /new onset diabetes mellitus (SMQ, narrow)
Mood disorders
Mood disorders and disturbances NEC (HLGT),
Personality disorders and disturbances in behaviour (HLGT),
Suicidal and self-injurious behaviours NEC (HLGT),
Psychiatric and behavior symptoms NEC (HLGTs)
Hypersensitivity, Rash (including 
DRESS, photosensitivity) 
Hypersensitivity/Allergy (SMQ, narrow)
HLT Photosensitivity conditions and photodermatosis 
conditions
HLT Eosinophilic disorders
PTs Eosinophilic count increased, Eosinophil count abnormal, 
Eosinophil percentage increased,
Eosinophil percentage abnormal
Liver toxicity
SMQs (narrow):
Cholestasis and jaundice of hepatic origin; Hepatic failure, 
fibrosis and cirrhosis and other liver
damage-related conditions; Hepatitis, non-infectious; Liver 
related investigations, signs and symptoms
Posterior Reversible 
Encephalopathy Syndrome (PRES)
HLT Encephalopathies NEC


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AESI grouping
Definition*
Asthenia, Fatigue 
HLT Asthenic conditions
Nausea, Vomiting, Diarrhea
HLT Diarrhoea (excl infective)
HLT Nausea and Vomiting symptoms
Pneumonitis 
SMQ Interstitial lung disease (narrow).
* At the time of the analyses, MedDRA-defined (SMQ) or Novartis-defined (NMQ) groupings 
described in the latest version of the CRS document available for buparlisib will be used
For each specified AESI, number and percentage of subjects with at least one event of the AESI 
occurring during on-treatment period will be summarized. This will be done also by PIK3CA 
cohort.
Summaries of all AESIs for alpelisib and some of the AESIs for buparlisib (i.e. Hypersensitivity, 
Rash (including DRESS, photosensitivity) , Liver toxicity, Mood disorders and hyperglycemia)
will be provided by treatment group (specifying grade, SAE, relationship, leading to treatment 
discontinuation, leading to dose adjustment/interruption, fatal outcome, etc.). If sufficient 
number of events occurred, analysis of time to first occurrence of any CTC grade ≥ 2 AESI for 
alpelisib will be applied. 
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated.
All AEs in a given AESI will be listed.
Time to first occurrence of any CTC grade ≥2 AESI for alpelisib
Time to onset of CTC grade ≥2 events will be summarized using the Kaplan-Meier method. 
Median time to onset and 95% CI will be provided. In addition, ascending Kaplan-Meier plots 
will be generated.
Time to onset of CTC grade ≥2 event is defined as the time from the start of treatment to the
start date of the first incidence of an event of CTC grade ≥2 i.e. time in days is calculated as 
(start date of first occurrence of the event) – (date of first dose of study treatment) +1.
A patient will be censored if:
The patient discontinues from the study treatment without experiencing any CTC grade ≥1 
event during the on-treatment period.
The patient dies without experiencing any CTC grade ≥2 event.
The patient receives a new antineoplastic therapy (with the exception of letrozole monotherapy) 
before experiencing any CTC grade ≥2 event.
The censoring date will be the earliest of the following dates: death date, new anticancer 
antineoplastic therapy start date, end date of on-treatment period (end of study treatment + 30 
days) or withdrawal of informed consent date.


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3.14
Laboratory data
3.14.1
Grading of laboratory data
Laboratory data grades will be converted into Standard International (SI) units and will be 
derived programmatically according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version v4.03. The calculation of CTC grades will be based on the observed 
laboratory values only, clinical assessments will not be taken into account. The criteria to assign 
CTC grades are given in “Novartis internal criteria for CTC grading of laboratory parameters”. 
The latest available version of the document based on the underlying CTCAE version 4.03 at 
the time of analysis will be used.
A severity grade of 0 will be assigned for all non-missing values not graded as 1 or higher. 
Grade 5 will not be applicable. For laboratory tests where grades are not defined by CTCAE
v4.03, results will be categorized as low/normal/high based on laboratory normal ranges.
Laboratory values with missing units or normal range may not be able to be graded or included 
in laboratory tables.
3.14.2
Laboratory data summary
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 
than 30 days after the last study treatment administration date.
The summary of laboratory evaluations will be presented by treatment group for two groups of 
laboratory tests: hematology (including coagulation) and biochemistry.
The following summaries will be produced for the laboratory data (by laboratory parameter and 
treatment):
For laboratory tests where grades are defined by CTCAE v4.03

Worst post-baseline CTC grade (regardless of the baseline status). Each subject will be 
counted only for the worst grade observed post-baseline.

Shift tables using CTC grades to compare baseline to the worst 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) may
be displayed via boxplots based on time windows and corresponding tables displaying the 
statistics used for the box plots by the selected time points: HbA1c, fasting glucose and fasting 
C-peptide.
The following listings will be produced for the laboratory data:

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 reference ranges

Listing of patients with CTC grade 3 or 4 laboratory toxicities.


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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 in the 
following categories will be summarized:
• ALT or AST > 3xULN
• ALT or AST > 5xULN
• ALT or AST > 10xULN
• ALT or AST > 20xULN
• ALP > 1.5xULN• TBIL > 1.5xULN• ALT or AST > 3xULN & TBIL > 2xULN (without 
time window)
• ALT or AST > 3xULN & TBIL > 2xULN & ALP < 2xULN (without time window)
Potential Hy’s Law events (candidates) are defined as those subjects with AST or ALT > 
3xULN and TBIL > 2xULN and ALP < 2xULN at any visit during the on-treatment period.
Further medical review has to be conducted to assess potential confounding factor such as liver 
metastases, liver function at baseline etc.
Additional categories may be added to the above list based on any updates to the internal 
guidelines on collection, analysis, and presentation of liver safety data.
A figure displaying time course of hepatic function tests (ALT, AST, TBIL, ALP) in patients 
with potential Hy’s law cases will be displayed.
3.15
Vital signs
Vital sign assessments are performed in order to characterize basic body functions. The 
following parameters were collected: height (cm), weight (kg), pulse rate (beats per minute), 
systolic and diastolic blood pressure (mmHg).
Vital signs collected during on-treatment will be summarized. Values measured during the post-
treatment period will be flagged in the listings.
The following summary table will be produced by parameter:

The number and percentage of patients with notable vital signs values (High / Low) will 
be presented by treatment group. Notable criteria are provided in Table 3-8 below.
The following listing will be produced by treatment group:

A listing of all vital sign assessments will be produced by treatment group and notable 
values will be flagged. 

Separate listing of only the subjects with notable vital sign values
In the listings, the assessments collected during the post-treatment period will be flagged.


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Table 3-8
Notable criteria for vital signs
Vital Sign (unit)
Notable high value
Notable low value
Weight (kg)
increase >= 10% from baseline
decrease  >= 10% from baseline
Systolic blood 
pressure (mmHg)
≥ 180 and increase from Baseline of ≥ 20
≤ 90 and decrease from Baseline 
of ≥ 20
Diastolic blood 
pressure (mmHg)
≥ 105 and increase from Baseline of ≥ 15
≤ 50 and decrease from Baseline 
of ≥ 15
Pulse Rate (bpm)
≥ 100 and increase from Baseline of 
>25%
≤ 50 and decrease from Baseline 
of >25%
3.16
Cardiac assessments
The summary tables will include only on-treatment assessments in the Safety set. All 
assessments will be listed and those collected outside of the treatment period will be flagged.
3.16.1
Electrocardiogram (ECG) parameters
As recommended in the FDA guidance on Clinical Evaluation of QT/QTc interval prolongation 
and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, the number and percentage of 
patients having notable ECG interval values will be summarized by treatment group.
The following summary table will be produced by parameter:

Number and percentage of patients with notable ECG values will be presented by 
treatment group.
Notable ECG criteria are provided in Table 3-9.
Table 3-9
Notable criteria for ECG values
ECG parameter (unit)
Clinically notable criteria
QTcF (ms) and QT (ms)
New value of > 450 ms and ≤ 480 ms
New value of > 480 ms and ≤ 500 ms
New value of > 500 ms
Increase from Baseline > 30 ms to ≤  60 ms
Increase from Baseline > 60 ms
PR duration (ms)                                
Increase > 25% from Baseline and to a value>200 ms
New value of > 200 ms
QRS duration (ms)
Increase > 25% from Baseline and to QRS duration >120 ms
New values of QRS > 120 ms
Heart Rate (bpm)
decrease from Baseline of >25% and to a value < 50 bpm
increase from Baseline of >25% and to a value > 100 bpm
Baseline is defined as the average of available sequential ECG measurements taken at pre-dose 
on Cycle 1 Day 1. The percentage of patients having notable ECG interval values is based on 
the total number of patients in the Safety set.
The following listing will be produced by treatment group:


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
A listing of all ECG assessments will be produced by treatment group and notable values 
will be flagged.

Patients with at least one notable ECG value
In the listings, the assessments collected during the post-treatment period will be flagged. 
3.16.2
Cardiac imaging (MUGA / ECHO)
Note: If there is any change in the methodology used throughout the study compared to Baseline, 
the post-baseline values will be discarded in the tables presenting comparisons to Baseline.
For left ventricular ejection fraction (LVEF) a shift table using CTC grades for ’Ejection 
fraction - decrease’ as defined per CTCAE version v4.03 to compare baseline to the worst on-
treatment value will be provided.
All data will be listed and those occurring more than 30 days after last study treatment will be 
flagged.
3.17
Mood assessments
This section is applicable to buparlisib/buparlisib placebo part only. Mood assessment includes 
two self-rating patient questionnaires, the GAD-7 and PHQ-9 scales.
The primary variable for the analyses of the mood questionnaires will be the study-derived total 
scores from the PHQ-9 and GAD-7. Analysis will be performed based on the Safety set. For 
each scale, a total score will be derived by adding column scores. Categorization will be 
performed as described in the protocol Section 14.4 to assess severity.
In case of a missing answer to at least one item, the total score value will be missing except if 
available answers translate into a severe score (for example: a patients fills in PHQ-9 
questionnaire as followed: for questions from 1 to 7, the answer is “nearly every day” (3) and 
the questions 8 and 9 are not answered. The total score is unknown but equal to 21 or more. The 
toxicity is severe.)
Number and percentage of patients will be described at each time point according to PHQ-9 
total score categories (0-4, 5-9, 10-19, 20-27). Shift tables (from Baseline to worst post-baseline 
total score) based on the classification above will be produced. Similar analysis will be 
performed to report answer to question 9 of PHQ-9 questionnaire.
Number and percentage of patients will be described at each time point according to GAD-7 
total score categories (0-4, 5-9, 10-14, ≥15). Shift tables (from baseline to worst post-baseline 
total score) based on the classification above will be produced.
Compliance will be analyzed using a ratio of the number of completely responded assessments 
(i.e., no missing answer or no missing evaluation) and the number of planned assessments. 
Compliance will be described by time point. 
If a patient has more than one assessment at the same visit, the worst total score will be used.


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Table 3-10
Classification of severity based on depression and/or anxiety 
questionnaire scores
3.18
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).
Table 3-11
ECOG Performance status
Score
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
ECOG PS will be listed. The analysis will be performed on the safety set.
3.19
Other safety data
Other safety data (e.g. pulmonary function test, slit lamp exam, Liver event – imaging, Liver 
Event - History of Alcohol Use 6 Weeks prior to Liver Event, Liver Event - Drugs of Abuse 
History, Liver Event – Pathology) will be listed in the safety set.
3.20
Subgroup analyses
3.20.1
Efficacy
Summaries of primary endpoints will be performed based on below subgroups in an exploratory 
manner in a given cohort if the PoC is established in that cohort:

Age (<65 years vs ≥65 years)

Race (Caucasian, Asian vs others)

ER status (positive or negative)

PR status (positive or negative)

Estrogen receptor and Progesterone receptor status (++/+-/-+)
PHQ-9 (depression)
GAD-7 (anxiety)
Score
Severity
Score
Severity
0-4
None
0-4
None
5-9
Mild
5-9
Mild
10-19
Moderate
10-14
Moderate
20-27
Severe
≥ 15
Severe


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Subgroup analysis based on stratification factors will be performed in the FAS by cohort and 
on the overall population:

Ki67 status (<14% vs ≥14%)

Lymph node status (positive or negative)
In each of the subgroup, the pCR rates and ORR in each of the treatment groups will be 
summarized by cohort using descriptive measures including 80% and 95% confidence intervals 
by treatment arm using Clopper and Pearson (1934) exact method, along with the observed 
difference in response rates versus placebo and its 80% and 95% CI confidence intervals using 
Chan and Zhang (1999) exact method. Efficacy analyses in subgroups will be purely 
exploratory and are intended to explore the consistency of overall treatment effect.
3.21
Pharmacokinetic analysis
In general, the pharmacokinetic analysis set (PAS) will be used for all tables and figures while 
the full analysis set will be used for all listings in all pharmacokinetic data analyses unless 
otherwise is specified.
3.21.1
Pharmacokinetic analysis
The plasma concentration of the patients included in the FPAS (BKM FPAS, BYL FPAS and 
LZ FPAS) will be used to generate derived PK parameters using a non-compartmental approach. 
The aim of this PK analysis is to have a preliminary PK assessment of any potential impact of 
letrozole on the pharmacokinetics of alpelisib/buparlisib.
The concentration-time profiles (treatment arms) will be presented by tabulating descriptive 
statistics : n (number of values to be reported), m (number of non-zero values to be reported), 
arithmetic mean, geometric mean, median, SD, coefficient of variation CV (%), geometric mean 
CV (%), minimum and maximum by time point and by plotting geometric and arithmetic mean 
(SD) concentration-time profiles, for alpelisib, buparlisib and letrozole for both the linear and 
semi-log view at each occasion (Cycle 1 Day 1 and Cycle 4 Day 1). Trough concentration will 
be reported for the PAS, and PK profile concentrations will be reported separately and by visit 
for the FPAS. Descriptive graphical plots of individual plasma concentration by-time profiles 
will also be generated for alpelisib, buparlisib and letrozole for the semi-log view for the full 
analysis set.
Descriptive statistics: n (number of values to be reported), arithmetic mean, geometric mean, 
median, SD, coefficient of variation CV (%), geometric mean CV (%), minimum and maximum 
will be presented for subjects in the FPAS for the PK parameters for buparlisib, alpelisib and 
letrozole at cycle 1 day 1: Tmax, Cmax, AUCinf, AUClast, AUC0-24, CL/F, Vz/F and T1/2
(only for alpelisib as T1/2 cannot be properly estimated for buparlisib due to its long half-life).
Descriptive statistics: n (number of values to be reported), arithmetic mean, geometric mean, 
median, SD, coefficient of variation CV (%), geometric mean CV (%), minimum and maximum 
will be presented for subjects in the FPAS for the PK parameters for buparlisib, alpelisib and 
letrozole at cycle 4 day 1: Tmax, Cmax, AUClast, AUC0-24, CLss/F, T1/2 (for alpelisib), 
effective half-life T1/2,eff (for buparlisib only) and Racc.


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Primary PK parameters will be Tmax, Cmax, AUClast and AUC0-24. For all compounds Clast 
and Tlast will be listed but not summarized. Trough concentrations will be listed.
Pharmacokinetic parameters listed in Table 3-12 will be determined using non-compartmental 
method(s) by the pharmacokineticist and transferred to the database.
Listing will be provided for all concentrations and PK parameters mentioned below for the full 
analysis set. 
PK parameters on Cycle 4 Day 1 will be compared between letrozole treatment arms using an 
ANOVA model in the letrozole FPAS. An ANOVA model will be fitted to the log-transformed 
PK parameters (AUC0-24 and Cmax) of letrozole including study treatment (letrozole alone, 
letrozole + alpelisib, letrozole + buparlisib) as a fixed effect. The treatment difference between 
letrozole + alpelisib and letrozole alone and between letrozole + buparlisib and letrozole alone 
will be calculated. A point estimate and corresponding 90% confidence interval for the 
treatment difference (letrozole + alpelisib and letrozole alone and between letrozole + buparlisib
and letrozole alone) will be calculated. This will be back transformed to obtain the point 
estimate and the 90% CI for the ratio of the geometric means on the original scale. 
Table 3-12
PK parameters
Term
Definition
Cmax
The maximum (peak) observed plasma drug concentration after single dose
administration [ng ml-1]
Tmax
The time to reach Cmax [hr]
Tlast
The time to last measurable concentration sampling [hr]
Clast
The last measurable concentration [ng x ml-1]
AUClast
The area under the concentration-time curve from time zero to the last measurable 
concentration sampling time (Tlast) [ng hr ml-1]
AUC0-24
The area under the concentration-time curve from time zero to 24 hours post dose [ng
x hr x ml-1]
AUCinf 
The area under the plasma concentration-time curve from time zero to infinity [ng x hr
x ml-1]
AUCex1
The area under the plasma concentration-time curve extrapolated from the time t to 
infinity as a percentage of total AUC (%)
CL/F
Apparent oral total drug clearance calculated from AUCinf after a single oral dose [L x 
hr-1]
CLss/F
Apparent oral total drug total plasma clearance calculated from stead-state exposure 
data [L x hr-1]
Vz/F
The apparent volume of distribution during terminal phase (associated with lambda_z) 
[L]
T1/2
Elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve time
RAcc
Accumulation ratio calculated as AUCtau,SS/AUCtau,dose1 where tau is the dosing 
interval
Rsqadj1
Square of the correlation coefficient associated with lambda_z
1 AUCex and Rsqadj will be used in the interpretation of the primary PK parameters and therefore will 
be included in the listings only.


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3.21.2
Data handling principles
3.21.2.1 Analysis sets
The plasma samples will be assayed for alpelisib or buparlisib and letrozole concentrations by 
Novartis or subcontractor using validated LC-MS/MS methods described in the [Laboratory 
Manual].
BYL, BKM and LZ FPAS will be used in the non-compartmental analysis (NCA) of selected 
patient subpopulation and BYL, BKM and letrozole PAS will be used to assess trough levels
within all patients.
For plasma alpelisib, buparlisib and letrozole, the LLOQ is 5.0 ng/mL, 1.0 ng/mL and 2.0 
ng/mL, respectively. All concentrations below the LLOQ will be labeled as such in the 
concentration data listings. Concentrations below the LLOQ will be treated as zero in summary 
statistics and omitted for data analysis. 
3.21.2.2 Basic Tables, Figures and Listings
Descriptive statistics (arithmetic mean, standard deviation, CV%, geometric mean, geometric 
CV% median, minimum and maximum) will be presented for all parameters by analyte, 
treatment arm and study day. When a geometric mean is presented, it will be stated as such. 
Only median, minimum and maximum will be given for Tmax. Similarly descriptive statistics 
will be presented for concentration by analyte, treatment arm, study day and scheduled sampling 
time-point.
Descriptive graphical plots of individual plasma concentration by time will be generated, as 
will mean concentration time profiles for alpelisib, buparlisib and letrozole. 
3.22
Biomarkers
As a project standard, Novartis Oncology BDM will analyze only biomarkers collected in the 
clinical database.
 
 
 
 
There may be circumstances when a decision is made to stop a sample collection, or not perform 
or discontinue the analysis of blood / archival tumor samples / fresh tumor biopsies / fine needle 
aspirates due to either practical or strategic reasons (e.g. issues related to the quality and/or 
quantity of samples or issues related to the assay). Under such circumstances, the number of 
samples may be inadequate to perform a rigorous data analysis and the available data will only
be listed and potentially summarized.
3.22.1
Outline of data analysis
Additional analyses that may be performed after the completion of the end -of-study CSR will 
be documented in separate reports. These analyses may include but are not limited to the meta-


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analysis of data from this study combined with data from other studies or the analysis of 
biomarkers generated from samples collected during the study but analyzed after the database 
lock and completion of the CSR. The data analysis will be described in an adden dum of the 
RAP or in a stand-alone analysis plan document, as appropriate.
The analyses of biomarkers will be reported in the CSR if data are available at the time of 
clinical database lock and CSR preparation. Otherwise, the results may be reported in a separate 
report document.
3.22.2
Exploratory biomarker objectives
The exploratory biomarker objectives covered in this CSR SAP are the following ones:
-
 
-
To explore the change in cell proliferation and cell death in the context of letrozole 
treatment alone versus letrozole treatment in combination with alpelisib or buparlisib
-
 
-
 
 
-
 
3.22.3
Biomarker analysis set
The FAS will be used for all biomarker analysis. Unless otherwise specified, all statistical 
analyses of biomarker data will be performed on patients with biomarker data.  
3.22.3.1 List of biomarkers evaluated and the collection time points
Table 3-13
Biomarker summary table
Biomarker
Time point
Sample
Method
Dataset
PI3K Activation Status
PIK3CA 
mutation
Baseline
Archival tumor sample
Fresh tumor biopsy (if 
archival not available)
PCR
B1(Y7 
for 
stratificatio
n data)


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ER
Baseline, EOT
Fresh tumor biopsy
Archival sample can be used 
in place of  baseline tumor 
biopsy if fresh tumor biopsy 
tissue 
is 
limited 
or 
unavailable
Immunohisto-
chemistry
B1
3.22.4
General data handling and preprocessing
Data preprocessing and transformations are described in detail in the Programming Dataset
Specifications document.
3.22.4.1 Definition of baseline and summarizing replicate data values
The screening assessment will be used as the baseline assessment. In case several results would 
be available, the last non-missing assessment on or before the date of randomization will be
taken as “baseline”
For PIK3CA mutational status at baseline, archival tumor biopsy will be used or else fresh 
tumor biopsy if archival is not available. For other assessments performed in tumor biopsies, 
fresh biopsy results will be used for baseline when both archived and fresh tumor samples are 
available.
When more than one biomarker data value are available for a subject at any time point, the 
mean of the replicate values will be used for all statistical analyses.
3.22.5
Immunohistochemistry (IHC) biomarker data
3.22.5.1 Handling of IHC data: Computation of H scores
Immunohistochemistry (IHC) data reported from the lab will include quantitative data such as 
percent tumor and percent positive cells and H-scores (ranging between 0 and 300 and 
calculated by the lab based on percent cells showing slight (1+), moderate (2+), or strong (3+) 
staining in a specific compartment). 
 
 


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Ki67 is reported using the % of positive cells and for practicality, only the field (1+) 
(CELLOC1C=1, 4 or 7) is reported. When only the field (1+) is populated (CELLOC1C=1, 4 
or 7) the lab will be consulted to confirm that the % of positive cells, and not the H-Score, is 
reported.
Derivation of Change and Percent Change Variables
Absolute and relative change (percent change) and fold change from baseline will be calculated 
for each subject and or treatment group.
Percent change is computed as ((visit i – baseline) / baseline) * 100. To compute the average 
percent change from baseline is to compute the average expression level at each time point and 
then compute the percent change using the average values. Please note the number of subjects 
for the average of percent change from baseline might vary due to potential missing values at 
respective timepoints.
3.22.5.2 IHC summary statistics
When an expression status is being reported by the lab 
, expression status will
be summarized using counts and percentages. 
For each IHC assay (e.g. % positive cells, H-scores), the mean, standard deviation, %CV, 
median, minimum, maximum, inter-quartile range, number and percent of the H-score values 
for each treatment group at each time point, for change from baseline and percent change from 
baseline at each timepoint, will be reported. Interquartile range is the number of data points 
between the 25th and 75th percentile. The expression status and/or the H-scores will be listed for 
each subject for all time points and ordered by cohort and the treatment group.
3.22.6
Somatic or Germline biomarker data
3.22.6.1 Handling of Somatic or Germline biomarker data
Overall, somatic mutation status (wild type or mutant) will be derived from the mutational status 
of the interrogated exons for any of the genes. These may be non-exclusive and the presence of 
mutation across more than one exon will be reported in separate categories.
The mutation status of PIK3CA will be assessed in all patients in the study. 
3.22.6.2 Mutation summary statistics
3.22.6.2.1
Somatic mutations
All somatic mutation data will be reported using counts and percentages by the mutation type 
in the form of contingency tables with the rows containing the different mutations assayed, 
(grouped by the gene) and the treatment groups in the columns.
All the mutation categories for a gene will also be aggregated into mutant, wild type or 
missing/unknown groups and counts/percentages will be reported by these three categories as 
well.
If somatic mutations are analyzed in multiple samples from a subject (e.g. biopsy) fresh and/or 
frozen sample, the patient may be considered having a mutation if a mutation is observed in at 
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pCR and ORR may be summarized by treatment group and categorical biomarker at baseline
(e.g. 
, if a sufficient number of patients is available per category).
All the mutation data will be listed for each subject ordered by cohort and treatment group.
3.22.7
Other biomarker assays
Summary statistics will be provided for TILs by responders / non-responders. The response will 
be based on ORR from RECIST 1.1 and pCR if a sufficient number of responders is observed.
Further description may be considered by tumor area (resected vs core needle biopsies)
depending on the number of patients per categories.
TILs data will be listed by cohort and treatment group. 
4
Sample size calculation
A total of approximately 320 patients will be randomized. Patients will be assigned to one of
the two cohorts, and within each cohort patients will be randomized to one of the three arms 
(i.e. alpelisib+letrozole, buparlisib+letrozole, or placebo+letrozole). Following the permanent 
stop of the enrollment in the buparlisib arm, the target number of 60 patients per arm in each 
cohort remains unchanged for the alpelisib+letrozole and placebo+letrozole arms. However a 
lower number of patients will be randomized to buparlisib+letrozole.
Within the placebo+letrozole arm, patients will receive matching alpelisib (or buparlisib 
placebo, respectively only before amendment 5). The placebo groups within each cohort will 
be pooled together providing a total of 60 patients in placebo+letrozole within each cohort.
With 60 patients in the two arms alpelisib+letrole and placebo+letrozole within each cohort, the 
assessment of the PoC for alpelisb will have the following operating characteristics, using the 
PoC criteria described in Section 4.7.1 and assuming a pCR rate of 5% and an ORR of 45% in 
the letrozole arm:
True Treatment 
Effect
on pCR (absolute 
increase in %)
True Treatment Effect
on ORR (absolute increase in %)
Probability that PoC is declared
on pCR or ORR
0
0
0.014
0.2
0.484
0.25
0.684
0.3
0.861
0.05
0
0.119
0.2
0.520
0.25
0.718
0.3
0.875
0.1
0
0.437
0.2
0.692
0.25
0.823
0.3
0.921
0.15
0
0.759


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True Treatment 
Effect
on pCR (absolute 
increase in %)
True Treatment Effect
on ORR (absolute increase in %)
Probability that PoC is declared
on pCR or ORR
0.2
0.870
0.25
0.926
0.3
0.966
0.2
0
0.933
0.2
0.963
0.25
0.978
0.3
0.990
5
Change to protocol specified analyses
The following main changes have been made as compared to the protocol specified analyses:
-
Definition of the Per Protocol Set will not be restricted to patients who have completed 
24 weeks of therapy as it would lead to exclusion of all patients who have progressed 
prior to 24 weeks, which is too restrictive. Also, it will not exclude patients with no 
post-baseline RECIST assessment, and those patients will be considered as non-
responders in the per-protocol set analysis.
-
For biomarkers, analysis of ORR and pCR by PIK3CA cohort based on ctDNA 
(secondary objective of the protocol) or analysis of NGS data (exploratory objective) is 
not covered in this SAP for the CSR, since it is foreseen that those data will not be 
available before the database lock. Depending on the feasibility of the assay, they will 
be described in a separate report.
-
All exploratory analyses planned only on pCR (such as analysis regardless of PIK3CA 
mutational status, or assessment of the anti-tumor activity of a PI3K inhibitor) will be 
repeated on ORR as well.
6
Appendix
6.1
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.
6.1.1
Study drug
The following rule should be used for the imputation of the dose end date for a given study 
treatment component:
If the date of last administration is completely or partially missing and the EOT eCRF page is 
available (prior to any death date or withdrawal of consent date, if available): 


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Case 1: The date of last administration is completely missing, and the EOT date is complete, 
then this latter date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date: 
Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for the date of last administration, and 
yyyy  = the year of EOT date and mm < the month of EOT date:  
Use last day of the Month (mm).
After imputation, compare the imputed date with the start date of that specific record, if the 
imputed date is < start date of that record
Use the start date of that record.
Subjects with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If the date of first administration is missing, 
then the date of last administration should not be imputed.
6.1.2
AE, ConMeds and safety assessment date imputation
Table 6-1
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


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Missing 
Element
Rule
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 6-2
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. 
6.1.2.1
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 


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a previous and following assessment is not available, this assessment will not be used for any 
calculation.
6.2
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). 
6.3
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. 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 analysis will be used. For laboratory 
tests where grades are not defined by CTCAE 4.03, results will be graded by the 
low/normal/high 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]


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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.
6.4
Statistical models
Proof of concept 
The methodology is described in section 3.10.1.
Confidence interval for binary endpoint rate (e.g. Breast Conserving Surgery) 
Responses will be summarized in terms of percentage rates with two-sided 80% and 95% 
confidence interval using exact binomial confidence interval (implemented using SAS
procedure FREQ with EXACT statement for one-way table [Clopper and Pearson 1934].
Confidence interval for response rate difference (e.g. ORR or pCR)
The difference in proportions response will be computed as alpelisib – placebo or buparlisib –
placebo.
The two-sided 80% and 95% confidence intervals of the difference of proportions between two 
groups will be estimated by the exact unconditional confidence limits using the score statistic
[Chan and Zhang 1999]. It will be implemented via SAS procedure FREQ with the TABLES 
statement and RISKDIFF option in the EXACT statement.
The SAS syntax is specified as follows:
PROC FREQ DATA = <input_dataset>;
  TABLES <treat_var> * <response> / riskdiff(cl=(exact));
  EXACT RISKDIFF(method=FMSCORE);
RUN;
7
References
Allison PD (2000). Survival analysis using the SAS system. Cary, NC, SAS Institute Inc.
Chan, I. S. F. and Zhang, Z. (1999). Test-based exact confidence intervals for the difference of 
two binomial proportions. Biometrics 55, 1202-1209
Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika 26, 404-413.


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Ellis MJ, Tao Y, Luo J, et al. (2008). Outcome prediction for estrogen receptor – positive breast 
cancer based on postneoadjuvant endocrine therapy tumor characteristics. J Natl Cancer Inst 
100, 1380-1388.
FDA (2007). Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs 
and Biologics, US Department of Health and Human Services.
International Conference on Harmonization. E9: Statistical Principles for Clinical Trials.
Neuenschwander B, Branson M, Gsponer T (2008). Critical aspects of the Bayesian approach 
to phase I cancer trials. Statistics in Medicine 27, 2420-2439.
Spiegelhalter DJ, Abrams KR, Myles JP (2004). Bayesian approaches to clinical trials and 
health-care evaluation. Chichester: Wiley.